CN113355332B - HEG1 gene mutant and application thereof - Google Patents

Abstract

The invention belongs to the technical field of genetic engineering, and relates to a HEG1 gene mutant and application thereof. In particular to an isolated HEG1 mutant nucleic acid, an isolated polypeptide, a method for screening a biological sample susceptible to dilated cardiomyopathy and a kit for screening the biological sample susceptible to dilated cardiomyopathy. Wherein the isolated nucleic acid encoding HEG1 mutant hybridizes with SEQ ID NO: 1, the nucleic acid has at least one mutation selected from c.78_80delGCC and c.2286_2303 dupcttcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctc. By detecting whether the mutant exists in the biological sample at the same time, whether the biological sample is susceptible to dilated cardiomyopathy can be effectively detected.

Description

HEG1 gene mutant and application thereof

The technical field is as follows:

the invention belongs to the technical field of genetic engineering, and relates to a HEG1 gene mutant and application thereof. In particular to an isolated nucleic acid for encoding HEG1 mutant, an isolated polypeptide, a method for screening a biological sample susceptible to dilated cardiomyopathy and a kit for screening the biological sample susceptible to dilated cardiomyopathy.

Background art:

dilated Cardiomyopathy (DCM) is a cardiac disease with unknown causes characterized by dilatation of the cardiac chambers (left and/or right ventricles) and impaired myocardial contractile function. DCM has now become one of the most common causes of heart failure and is the most common indication for heart transplantation worldwide. The incidence of cardiomyopathy is reported to be approximately 1.1/100,000 to 1.5/100,000 in people under 18 years of age. The children's DCM incidence rate is about 0.58/100,000, about 66% of all types of cardiomyopathy are diagnosed with heart failure, about 70% -90% of children have heart failure as a main manifestation, and the 5-year survival rate of DCM children is only 40%, which is one of the main causes of death of teenagers and children. Therefore, it is imperative to enhance the clinical awareness and management of early DCM. The cardiomyopathy has no specific etiology and treatment mainly aims at relieving the symptoms of a patient and preventing and treating complications.

At present, the mechanism of DCM induction by gene mutation is not completely clear, the precise pathogenic mechanism from molecules and cells to clinical phenotype is still lacked, and the exploration of a treatment means aiming at the gene level is expected to become the key for solving the DCM in the future. Association analysis and genome-wide association studies (GWAS) in large cohorts have successfully screened for disease-associated genes and genetic variations. To date, over 400 pathogenic variants have been identified in nearly 60 genes, most of which encode proteins that play a role in the myocardial cytoskeleton and function, and their connection to sarcomere and nucleus. There have been reports showing that there are thousands of patients with DCM who receive gene screening, and there are genotype-phenotype related studies, and many genes are focused on TTN, LMNA, PLN, RBM20, MYBPC3, MYH7, TNNT2 or TNNI3, etc. Among them, TTN truncation mutations are a common cause of DCM, occurring in approximately 25% of familial cases and 18% of sporadic cases of idiopathic dilated cardiomyopathy, with clinical manifestations and symptoms, and morbidity and mortality rates similar to non-carriers. LMNA mutations account for approximately 5-10% of the different DCM cases and are associated with a high risk of sudden cardiac death, with ventricular arrhythmias occurring in about half of the mutation carriers. However, genetic etiology is currently only found in less than one-third of cases, and only a few mutations can be detected repeatedly in additional familial or unrelated patients. More and more studies confirm the core pathogenic gene of DCM, but the whole genetic map is still not complete enough.

Therefore, the method has the advantages of pertinently developing genetic research on DCM, determining pathogenic genes and pathogenic mechanisms thereof, having potential clinical significance on genetic consultation and individualized prevention and treatment of DCM patients, providing research directions and new theoretical bases for early diagnosis and effective treatment of DCM, and providing new molecular targets for researching and developing special-effect medicines for treating DCM in practice.

The invention content is as follows:

the invention aims to overcome the defects in the prior art and provide a mutant of a pathogenic gene of dilated cardiomyopathy.

To achieve the above object, the present invention provides an isolated nucleic acid encoding a mutant HEG1, which is substantially identical to SEQ ID NO: 1, the nucleic acid has at least one mutation selected from c.78_80delGCC and c.2286_2303 dupcttcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcctcct. The invention determines that the HEG1 mutant is closely related to the development of the dilated cardiomyopathy, so that whether the biological sample is susceptible to the dilated cardiomyopathy can be effectively detected by detecting whether the new mutation exists in the biological sample.

The invention also provides an isolated HEG1 mutant polypeptide that is homologous to the polypeptide of SEQ ID NO: 2 compared to 2, with at least one mutation selected from p.ala27del and p.ser763_ Ser768 dup. By detecting whether the polypeptide is expressed in the biological sample, whether the biological sample is susceptible to dilated cardiomyopathy can be effectively detected.

The invention also provides a method for screening biological samples susceptible to dilated cardiomyopathy. The method comprises the following steps: extracting a nucleic acid sample from the biological sample; determining the nucleic acid sequence of the nucleic acid sample; the nucleic acid sequence of the nucleic acid sample is identical to the sequence shown in SEQ ID NO: 1, a compound heterozygous mutation having c.78_80delGCC and c.2286_2303dupCTCTTCCTCCTCCTCC is indicative of susceptibility of the biological sample to dilated cardiomyopathy. By the method for screening the biological sample susceptible to the dilated cardiomyopathy, disclosed by the invention, the biological sample susceptible to the dilated cardiomyopathy can be effectively screened.

The present invention also provides a kit for screening a biological sample for dilated cardiomyopathy, the kit comprising: reagent suitable for detecting HEG1 gene mutant, wherein the HEG1 gene mutant is similar to the HEG1 gene mutant shown in SEQ ID NO: 1 compared with c.78_80delGCC and c.2286_2303 dupCTCTTCCTCCTCCTCCTCC composite heterozygous mutation. By using the kit provided by the invention, biological samples susceptible to dilated cardiomyopathy can be effectively screened.

Compared with the prior art, the invention firstly determines the HEG1 gene as the pathogenic related gene of the dilated cardiomyopathy, and determines two mutation sites of the pathogenic gene by a whole genome sequencing and candidate gene mutation verification method, thereby providing a new direction for the detection of the dilated cardiomyopathy.

Description of the drawings:

fig. 1 is a family atlas of a dilated cardiomyopathy patient according to example 1 of the present invention.

FIG. 2 is a graph of Sanger sequencing verification peaks at c.78_80delGCC mutation sites of the expanded cardiomyopathy proband its parent HEG1 gene of example 1 to which the present invention relates, wherein A is proband; b is the father of the first person; c is the mother of the proband.

FIG. 3 is a Sanger sequencing verification peak diagram of the expanded cardiomyopathy probands and parents HEG1 base c.2286_2303dupCTCTTCCTCCTCCTC mutation sites thereof related to example 1, wherein A is proband; b is the mother of the first person; c is the father of the first-child.

FIG. 4 shows the lentivirus of example 1 knocking down the expression of HEG1 in mouse cardiomyocytes, the expression of HEG1 and its dilated cardiomyopathy marker molecules Anp, Bnp at mRNA level.

The specific implementation mode is as follows:

the invention is further illustrated by the following specific examples in combination with the accompanying drawings.

Example 1:

this example relates to an isolated nucleic acid encoding a mutant of the HEG1 gene having at least one mutation selected from c.78_80delGCC and c.2286_2303 dupcttcctcctcctcctcctcctcctcctcctcctcctcctc compared to SEQ ID No. 1. The nucleic acid encoding the HEG1 gene mutant refers to the nucleic acid substance corresponding to the gene encoding the HEG1 gene mutant, i.e., the type of the nucleic acid is not limited, and can be any polymer containing deoxyribonucleotides and/or ribonucleotides corresponding to the gene encoding the HEG1 gene mutant, including but not limited to DNA, RNA or cDNA.

The nucleic acid may actually comprise either or both of the complementary strands. For convenience, in this embodiment, although only one strand is shown, the other strand complementary thereto is actually disclosed. For example, reference is made to SEQ ID NO: 1, actually including its complement. One skilled in the art will also appreciate that one strand may be used to detect the other strand and vice versa.

The nucleic acid encoding the HEG1 mutant is a mutation on a pathogenic gene of the dilated cardiomyopathy determined by the inventor through a whole genome sequencing combined mutation verification method. Although there are reports on the gene of dilated cardiomyopathy, the inventors of the present invention have confirmed for the first time that the mutation site of the HEG1 gene related to dilated cardiomyopathy is not mentioned in the prior art. The cDNA sequence of the wild-type HEG1 gene is shown as SEQ ID NO: 1, comprises 4146 bases in total. The protein encoded by the wild-type HEG1 gene contains 1381 amino acids, and the amino acid sequence of the protein is shown as SEQ ID NO: 2, respectively.

The HEG1 gene mutant is similar to the mutant shown in SEQ ID NO: 1, has at least one mutation selected from c.78_80delGCC and c.2286_2303 dupCTCTTCCTCCTCCTCTC, namely, compared with the wild-type HEG1 gene, the HEG1 gene mutant of the invention has GCC base deletion at position 78-80 and/or CTCTTCCTCCTCCTCCTC repeated sequence inserted at position 2286 in cDNA, thereby the encoded product has at least one mutation selected from p.Ala27del and p.Ser763_ Ser768dup compared with protein (SEQ ID NO: 2).

The cDNA nucleotide sequence (4146nt) of the wild-type HEG1 is shown in SEQ ID NO: 1, and the coded amino acid sequence (1381aa) is shown as SEQ ID NO: 2, respectively.

Wherein, the cDNA sequence of the HEG1 gene mutant with the c.78_80delGCC mutation is SEQ ID NO: 3, the amino acid sequence (1380aa) of the protein with p.ala27del mutation is shown as SEQ ID NO: 4, respectively.

The cDNA sequence of the HEG1 gene mutant with c.2286_2303 dupCTCTTCCTCCTCCTCTC mutation is shown as SEQ ID NO: 5, and the amino acid sequence (1387aa) of the protein encoded by the protein with the p.Ser763_ Ser768dup mutation is shown as SEQ ID NO: and 6.

This example also relates to an isolated polypeptide having at least one mutation selected from the group consisting of p.ala27del and p.ser763_ Ser768dup, as compared to SEQ ID No. 2. The polypeptide is encoded by the isolated nucleic acid encoding a HEG1 mutant described above. Whether the biological sample is susceptible to dilated cardiomyopathy can be effectively detected by detecting whether the polypeptide is expressed in the biological sample, and whether the biological sample is susceptible to dilated cardiomyopathy can be effectively predicted by detecting the existence of the polypeptide in an organism.

The present embodiments also relate to a method of screening a biological sample for susceptibility to hypercholesterolemia. The method comprises the following steps:

s1, extracting a nucleic acid sample from the biological sample: the type of the biological sample is not particularly limited as long as a nucleic acid sample reflecting the presence or absence of a mutation in the biological sample HEG1 can be extracted from the biological sample; the biological sample may be at least one selected from human blood, skin, and subcutaneous tissue, and preferably peripheral blood. Therefore, the sampling and the detection can be conveniently carried out, and the efficiency of screening the biological samples susceptible to the dilated cardiomyopathy can be further improved. The term "nucleic acid sample" as used herein is to be understood in a broad sense and can be any sample that reflects the presence or absence of mutation in HEG1 in a biological sample, such as whole genomic DNA extracted directly from the biological sample, a portion of the whole genome that includes the HEG1 coding sequence, total RNA extracted from the biological sample, or mRNA extracted from the biological sample. Thus, the source range of the biological sample can be expanded, and various information of the biological sample can be determined at the same time, thereby improving the efficiency of screening a biological sample susceptible to hypercholesterolemia. In addition, for using RNA as a nucleic acid sample, extracting the nucleic acid sample from the biological sample further comprises: extracting an RNA sample from the biological sample, preferably the RNA sample is mRNA; and obtaining a cDNA sample by reverse transcription reaction based on the obtained RNA sample, the obtained cDNA sample constituting a nucleic acid sample. Thus, the efficiency of screening biological samples susceptible to dilated cardiomyopathy by using RNA as a nucleic acid sample can be further improved;

s2, after obtaining the nucleic acid sample, analyzing the nucleic acid sample to determine the nucleic acid sequence of the obtained nucleic acid sample; the method and apparatus for determining the nucleic acid sequence of the resulting nucleic acid sample are not particularly limited. The nucleic acid sequence of the nucleic acid sample can be determined by sequencing methods. The method and apparatus for sequencing is not particularly limited and may employ second generation sequencing techniques, as well as third and fourth generation or more advanced sequencing techniques; sequencing the nucleic acid sequence using at least one selected from the group consisting of hipseq 2000, solide, 454, ABI3730, and a single molecule sequencing device; therefore, by combining the latest sequencing technology, a higher sequencing depth can be achieved for a single site, and the detection sensitivity and accuracy are greatly improved, so that the characteristics of high throughput and deep sequencing of the sequencing devices can be utilized, the efficiency of detecting and analyzing the nucleic acid sample is further improved, and the accuracy and the precision of subsequent analysis of sequencing data can be improved; thus, determining the nucleic acid sequence of the nucleic acid sample may further comprise: firstly, aiming at the obtained nucleic acid sample, constructing a nucleic acid sequencing library; and sequencing the obtained nucleic acid sequence library so as to obtain a data result consisting of a plurality of sequencing data;

it should be noted that the term "nucleic acid sequence" used herein should be understood in a broad sense, and may be complete nucleic acid sequence information obtained by assembling sequencing data obtained by sequencing a nucleic acid sample, or may be nucleic acid sequences directly obtained by using sequencing data (reads) obtained by sequencing a nucleic acid sample, as long as the nucleic acid sequences contain a coding sequence corresponding to HEG 1.

S3, after determining the nucleic acid sequence of the nucleic acid sample, comparing the nucleic acid sequence of the obtained nucleic acid sample with the nucleic acid sequence of SEQ ID NO: 1, if there is a c.78_80delGCC and c.2286_2303 dupcttcctcctcctcctcctcctcctcctc complex heterozygous mutation in the resulting nucleic acid sequence, indicating that the biological sample is susceptible to dilated cardiomyopathy; thus, by the method of screening a biological sample susceptible to dilated cardiomyopathy according to the embodiment of the present invention, a biological sample susceptible to hypercholesterolemia can be effectively screened; wherein, the nucleotide sequence is similar to SEQ ID NO: 1 the method and apparatus for performing the alignment is not particularly limited and may be performed using any conventional software.

Unless otherwise specified, the technical means used in the examples are conventional means familiar to those skilled in the art, and can be carried out with reference to the third edition of molecular cloning, laboratory Manual, or related products, and the reagents and products used are also commercially available. Various procedures and methods not described in detail are conventional methods well known in the art, and the sources, trade names, and components of the reagents used are indicated at the time of first appearance, and the same reagents used thereafter are the same as those indicated at the first appearance, unless otherwise specified.

Example 2: determination of pathogenic gene and mutation site of dilated cardiomyopathy

1. Collecting samples:

the inventor collected 1 dilated cardiomyopathy family, as shown in fig. 1, the family members had 3 persons, 1 patient (proband) and 2 normal persons, according to the oral description of the patient. □ indicates normal males,. smallcircle indicates normal females,. ● indicates diseased females,. ▇ indicates diseased males, and. ↗ indicates probands. A total of 3 persons (proband their parents) participated in the present study, all family members participated in the present study signed informed consent. The inventor collects and obtains peripheral blood samples of patients in the family of the dilated cardiomyopathy patients and normal persons in the family.

2. Whole genome sequencing

The inventor utilizes The MGIEasy ^TM The DNA Library Prep Kit V1 is combined with BGISEQ-500 high-throughput sequencing technology to carry out whole genome sequencing on the patients and parents in the families, and the specific steps are as follows:

2.1 sample preparation

And (3) respectively taking peripheral blood of the patient and parents of the patient, and extracting the peripheral blood DNA by using an AllPrep DNA/RNA/miRNA universal kit. Quantification was performed using qubits, ensuring at least 2 μ g per DNA sample for whole genome sequencing.

2.2 library construction and sequencing

The DNA samples were randomly fragmented into 150-and 200-bp fragments using the E220 Covaris instrument, followed by selection of DNA fragment sizes using AMpure XP Beads according to the manufacturer's instructions, followed by end repair, phosphorylation and a-tail reactions. The BGISEQ-500 platform specific linker was ligated to the a-tail fragment, the ligated fragment was purified and amplified by PCR. Finally, cycle circularization is performed to generate single-stranded DNA circles. After quantitative identification, the library was sequenced.

3. Mutation detection, annotation, and database comparison

Whole genome sequencing was performed on proband its parents, the sequencing data were matched to HG19 genomic references using Burrows-Wheeler alignment tools and annotated using the snpEff 3 and dbSNP databases. Firstly, screening all identified variants through a dbSNP database, an ExAC, a HapMap database, 1000 genes and 100 local databases of Chinese healthy adults, deleting the variants with MAF larger than 0.01 of healthy people, and then comparing all the filtered variants with OMIM and CGD databases to determine the gene variation related to the disease phenotype.

Thus, the inventors found that c.78_80delGCC and c.2286_2303 existed in the HEG1 gene

dupCTCTTCCTCCTCCTCCTCC compound heterozygous mutation; further, by co-segregating the disease in the expanded cardiomyopathy patient family, the father of the patient carries the c.78_80delGCC heterozygous mutation, and the mother of the patient carries the c.2286_2303dupCTCTTCCTCCTCCTCCTC heterozygous mutation, i.e. the sequence and the phenotype appear to be co-segregated in the family. Therefore, the inventors preliminarily judged that the mutation is a causative site of hereditary dilated cardiomyopathy;

4. sequencing verification by Sanger method

The HEG1 genes of the patients in the family of the patients with the hereditary dilated cardiomyopathy described in example 2 and their parents (normal persons) were sequenced, respectively; the correlation between the c.78-80 delGCC and c.2286-2303 dupCTCTTCCTCCTCCTC complex heterozygous mutations of the HEG1 gene and hereditary dilated cardiomyopathy was verified by determining whether the sequence determination result belongs to the mutant type or the wild type. The method comprises the following specific steps:

1. DNA extraction

The peripheral blood genomic DNAs of the patients with dilated cardiomyopathy and their parents were extracted and prepared as described in example 1.

2. Primer design and PCR reaction

Specific primers aiming at the c.78-80 delGCC mutation site and having nucleotide sequences shown in SEQ ID NO. 7-8 and specific primers aiming at the c.2286-2303 dupCTCTTCCTCCTCCTC mutation site and having nucleotide sequences shown in SEQ ID NO. 9-10 are designed by referring to a human genome sequence database GRCh37.1/hg19, and the specific primers are specifically shown in the following table.

PCR reaction with the above specific primers was performed using the extracted DNA as a template according to a conventional method in the art, and the purified PCR product was sequenced.

3. Sequencing the PCR amplification products of the patients and their parents obtained in step 2 were subjected to DNA sequencing. Based on the sequencing result, the HEG1 gene coding sequence alignment is carried out on each sample. As a result, it was found that the patients carried the c.78-80 delGCC and c.2286-2303 dupCTCTTCCTCCTCCTC heterozygous mutations, whereas the mother of the patient who appeared normal carried only the c.2286-2303 dupCTCTTCCCTCCTCCTCC heterozygous mutation, and the father of the patient carried only the c.78-80 delGCC heterozygous mutation. Further, the normal examinee is taken as a control, the peripheral blood DNA is extracted according to the method and is subjected to PCR amplification, and the result of DNA sequencing of the PCR amplification product shows that the normal examinee does not have the two mutation sites. Thus, it was confirmed that the c.78-80 delGCC and c.2286-2303 dupCTCTTCCTCCTCCTCCTCC composite heterozygous mutation of the HEG1 gene is a causative mutation of dilated cardiomyopathy.

4. Functional verification of gene mutants

Based on the sequencing result, a lentivirus interference system is constructed, mouse cardiac muscle cells FMC84 cells are infected, and expression of HEG1 in the cells is interfered. On the basis of the reduction of the expression of HEG1, the expression of dilated cardiomyopathy marker genes Anp and Bnp in FMC84 cells on the transcription level is detected by using a real-time fluorescence quantitative technology. Lentiviral interference down-regulated HEG1 expression by 89% compared to the control group, while Anp and Bnp up-regulated by 0.6-fold and 2.9-fold, respectively (fig. 4). Therefore, the HEG1 gene mutation is further proved to be a pathogenic gene of the dilated cardiomyopathy.

Example 3: detection kit

A detection kit comprising primers suitable for HEG1 gene mutant (the HEG1 gene mutant has c.78_80delGCC and c.2286_2303dupCTCTTCCTCCTCCTCC complex heterozygous mutations compared with SEQ ID NO. 1) for screening biological samples susceptible to dilated cardiomyopathy is prepared, wherein the primers comprise HEG1 gene specific primers shown in SEQ ID NO.7-10

The method for screening the biological sample of the susceptible dilated cardiomyopathy by using the kit comprises the following specific steps: extracting DNA of a subject to be tested according to the method described in step 1 of example 2, performing PCR reaction with the specific primers using the extracted DNA as a template, purifying PCR products according to a conventional method in the art, sequencing the purified products, and then effectively detecting whether the subject is susceptible to dilated cardiomyopathy by observing whether the sequence obtained by sequencing has mutations of c.78_80delGCC and c.2286_2303dupCTCTTCCTCCTCCTC at the same time.

Sequence listing

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115 120 125

Asn Gln Glu Asp Phe Ser Thr Val Ser Ser Lys Glu Gly Val Met Val

130 135 140

Gln Thr Ser Gly Lys Ser His Ala Ala Ser Asp Ala Pro Glu Asn Leu

145 150 155 160

Thr Leu Leu Ala Glu Thr Ala Asp Ala Arg Gly Arg Ser Gly Ser Ser

165 170 175

Ser Arg Thr Asn Phe Thr Ile Leu Pro Val Gly Tyr Ser Leu Glu Ile

180 185 190

Ala Thr Ala Leu Thr Ser Gln Ser Gly Asn Leu Ala Ser Glu Ser Leu

195 200 205

His Leu Pro Ser Ser Ser Ser Glu Phe Asp Glu Arg Ile Ala Ala Phe

210 215 220

Gln Thr Lys Ser Gly Thr Ala Ser Glu Met Gly Thr Glu Arg Ala Met

225 230 235 240

Gly Leu Ser Glu Glu Trp Thr Val His Ser Gln Glu Ala Thr Thr Ser

245 250 255

Ala Trp Ser Pro Ser Phe Leu Pro Ala Leu Glu Met Gly Glu Leu Thr

260 265 270

Thr Pro Ser Arg Lys Arg Asn Ser Ser Gly Pro Asp Leu Ser Trp Leu

275 280 285

His Phe Tyr Arg Thr Ala Ala Ser Ser Pro Leu Leu Asp Leu Ser Ser

290 295 300

Ser Ser Glu Ser Thr Glu Lys Leu Asn Asn Ser Thr Gly Leu Gln Ser

305 310 315 320

Ser Ser Val Ser Gln Thr Lys Thr Met His Val Ala Thr Val Phe Thr

325 330 335

Asp Gly Gly Pro Arg Thr Leu Arg Ser Leu Thr Val Ser Leu Gly Pro

340 345 350

Val Ser Lys Thr Glu Gly Phe Pro Lys Asp Ser Arg Ile Ala Thr Thr

355 360 365

Ser Ser Ser Val Leu Leu Ser Pro Ser Ala Val Glu Ser Arg Arg Asn

370 375 380

Ser Arg Val Thr Gly Asn Pro Gly Asp Glu Glu Phe Ile Glu Pro Ser

385 390 395 400

Thr Glu Asn Glu Phe Gly Leu Thr Ser Leu Arg Trp Gln Asn Asp Ser

405 410 415

Pro Thr Phe Gly Glu His Gln Leu Ala Ser Ser Ser Glu Val Gln Asn

420 425 430

Gly Ser Pro Met Ser Gln Thr Glu Thr Val Ser Arg Ser Val Ala Pro

435 440 445

Met Arg Gly Gly Glu Ile Thr Ala His Trp Leu Leu Thr Asn Ser Thr

450 455 460

Thr Ser Ala Asp Val Thr Gly Ser Ser Ala Ser Tyr Pro Glu Gly Val

465 470 475 480

Asn Ala Ser Val Leu Thr Gln Phe Ser Asp Ser Thr Val Gln Ser Gly

485 490 495

Gly Ser His Thr Ala Leu Gly Asp Arg Ser Tyr Ser Glu Ser Ser Ser

500 505 510

Thr Ser Ser Ser Glu Ser Leu Asn Ser Ser Ala Pro Arg Gly Glu Arg

515 520 525

Ser Ile Ala Gly Ile Ser Tyr Gly Gln Val Arg Gly Thr Ala Ile Glu

530 535 540

Gln Arg Thr Ser Ser Asp His Thr Asp His Thr Tyr Leu Ser Ser Thr

545 550 555 560

Phe Thr Lys Gly Glu Arg Ala Leu Leu Ser Ile Thr Asp Asn Ser Ser

565 570 575

Ser Ser Asp Ile Val Glu Ser Ser Thr Ser Tyr Ile Lys Ile Ser Asn

580 585 590

Ser Ser His Ser Glu Tyr Ser Ser Phe Phe His Ala Gln Thr Glu Arg

595 600 605

Ser Asn Ile Ser Ser Tyr Asp Gly Glu Tyr Ala Gln Pro Ser Thr Glu

610 615 620

Ser Pro Val Leu His Thr Ser Asn Leu Pro Ser Tyr Thr Pro Thr Ile

625 630 635 640

Asn Met Pro Asn Thr Ser Val Val Leu Asp Thr Asp Ala Glu Phe Val

645 650 655

Ser Asp Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser

660 665 670

Gly Pro Pro Leu Pro Leu Pro Ser Val Ser Gln Ser His His Leu Phe

675 680 685

Ser Ser Ile Leu Pro Ser Thr Arg Ala Ser Val His Leu Leu Lys Ser

690 695 700

Thr Ser Asp Ala Ser Thr Pro Trp Ser Ser Ser Pro Ser Pro Leu Pro

705 710 715 720

Val Ser Leu Thr Thr Ser Thr Ser Ala Pro Leu Ser Val Ser Gln Thr

725 730 735

Thr Leu Pro Gln Ser Ser Ser Thr Pro Val Leu Pro Arg Ala Arg Glu

740 745 750

Thr Pro Val Thr Ser Phe Gln Thr Ser Thr Met Thr Ser Phe Met Thr

755 760 765

Met Leu His Ser Ser Gln Thr Ala Asp Leu Lys Ser Gln Ser Thr Pro

770 775 780

His Gln Glu Lys Val Ile Thr Glu Ser Lys Ser Pro Ser Leu Val Ser

785 790 795 800

Leu Pro Thr Glu Ser Thr Lys Ala Val Thr Thr Asn Ser Pro Leu Pro

805 810 815

Pro Ser Leu Thr Glu Ser Ser Thr Glu Gln Thr Leu Pro Ala Thr Ser

820 825 830

Thr Asn Leu Ala Gln Met Ser Pro Thr Phe Thr Thr Thr Ile Leu Lys

835 840 845

Thr Ser Gln Pro Leu Met Thr Thr Pro Gly Thr Leu Ser Ser Thr Ala

850 855 860

Ser Leu Val Thr Gly Pro Ile Ala Val Gln Thr Thr Ala Gly Lys Gln

865 870 875 880

Leu Ser Leu Thr His Pro Glu Ile Leu Val Pro Gln Ile Ser Thr Glu

885 890 895

Gly Gly Ile Ser Thr Glu Arg Asn Arg Val Ile Val Asp Ala Thr Thr

900 905 910

Gly Leu Ile Pro Leu Thr Ser Val Pro Thr Ser Ala Lys Glu Met Thr

915 920 925

Thr Lys Leu Gly Val Thr Ala Glu Tyr Ser Pro Ala Ser Arg Ser Leu

930 935 940

Gly Thr Ser Pro Ser Pro Gln Thr Thr Val Val Ser Thr Ala Glu Asp

945 950 955 960

Leu Ala Pro Lys Ser Ala Thr Phe Ala Val Gln Ser Ser Thr Gln Ser

965 970 975

Pro Thr Thr Val Ser Ser Ser Ala Ser Val Asn Ser Cys Ala Val Asn

980 985 990

Pro Cys Leu His Asn Gly Glu Cys Val Ala Asp Asn Thr Ser Arg Gly

995 1000 1005

Tyr His Cys Arg Cys Pro Pro Ser Trp Gln Gly Asp Asp Cys Ser Val

1010 1015 1020

Asp Val Asn Glu Cys Leu Ser Asn Pro Cys Pro Ser Thr Ala Met Cys

1025 1030 1035 1040

Asn Asn Thr Gln Gly Ser Phe Ile Cys Lys Cys Pro Val Gly Tyr Gln

1045 1050 1055

Leu Glu Lys Gly Ile Cys Asn Leu Val Arg Thr Phe Val Thr Glu Phe

1060 1065 1070

Lys Leu Lys Arg Thr Phe Leu Asn Thr Thr Val Glu Lys His Ser Asp

1075 1080 1085

Leu Gln Glu Val Glu Asn Glu Ile Thr Lys Thr Leu Asn Met Cys Phe

1090 1095 1100

Ser Ala Leu Pro Ser Tyr Ile Arg Ser Thr Val His Ala Ser Arg Glu

1105 1110 1115 1120

Ser Asn Ala Val Val Ile Ser Leu Gln Thr Thr Phe Ser Leu Ala Ser

1125 1130 1135

Asn Val Thr Leu Phe Asp Leu Ala Asp Arg Met Gln Lys Cys Val Asn

1140 1145 1150

Ser Cys Lys Ser Ser Ala Glu Val Cys Gln Leu Leu Gly Ser Gln Arg

1155 1160 1165

Arg Ile Phe Arg Ala Gly Ser Leu Cys Lys Arg Lys Ser Pro Glu Cys

1170 1175 1180

Asp Lys Asp Thr Ser Ile Cys Thr Asp Leu Asp Gly Val Ala Leu Cys

1185 1190 1195 1200

Gln Cys Lys Ser Gly Tyr Phe Gln Phe Asn Lys Met Asp His Ser Cys

1205 1210 1215

Arg Ala Cys Glu Asp Gly Tyr Arg Leu Glu Asn Glu Thr Cys Met Ser

1220 1225 1230

Cys Pro Phe Gly Leu Gly Gly Leu Asn Cys Gly Asn Pro Tyr Gln Leu

1235 1240 1245

Ile Thr Val Val Ile Ala Ala Ala Gly Gly Gly Leu Leu Leu Ile Leu

1250 1255 1260

Gly Ile Ala Leu Ile Val Thr Cys Cys Arg Lys Asn Lys Asn Asp Ile

1265 1270 1275 1280

Ser Lys Leu Ile Phe Lys Ser Gly Asp Phe Gln Met Ser Pro Tyr Ala

1285 1290 1295

Glu Tyr Pro Lys Asn Pro Arg Ser Gln Glu Trp Gly Arg Glu Ala Ile

1300 1305 1310

Glu Met His Glu Asn Gly Ser Thr Lys Asn Leu Leu Gln Met Thr Asp

1315 1320 1325

Val Tyr Tyr Ser Pro Thr Ser Val Arg Asn Pro Glu Leu Glu Arg Asn

1330 1335 1340

Gly Leu Tyr Pro Ala Tyr Thr Gly Leu Pro Gly Ser Arg His Ser Cys

1345 1350 1355 1360

Ile Phe Pro Gly Gln Tyr Asn Pro Ser Phe Ile Ser Asp Glu Ser Arg

1365 1370 1375

Arg Arg Asp Tyr Phe

1380

<210> 3

<211> 4143

<212> DNA

<213> Intelligent (Homo sapiens)

<400> 3

atggcctcgc cgcgcgcctc gcggtggccg ccgccgctcc tgctgctgtt gctgccgctg 60

ctgctgctgc cgccggcgcc cgggacgcgg gacccgccgc cttccccggc tcgccgcgcg 120

ctgagcctgg cgcccctcgc gggagcgggg ctggagctgc agctggagcg ccgcccggag 180

cgcgagccgc cgcccacgcc gccccgggag cgccgcgggc ccgcgacccc cggccccagc 240

tacagggccc ctgagccagg cgccgcgaca cagcggggac cctccggccg ggcccccaga 300

ggcgggagcg cggatgctgc ctggaaacat tggccagaaa gtaacactga ggcccatgta 360

gaaaacatca ccttctatca gaatcaagag gacttttcaa cagtgtcctc caaagagggc 420

gtgatggttc agacctctgg gaagagccat gctgcttcgg atgctccaga aaacctcact 480

ctactcgctg aaacagcaga tgctagagga aggagcggct cttcaagtag aacaaacttc 540

accattttgc ctgttgggta ctcactggag atagcaacag ctctgacttc ccagagtggc 600

aacttagcct cagaaagtct tcacctgcca tccagcagtt cagagttcga tgaaagaatt 660

gccgcttttc aaacaaagag tggaacagcc tcggagatgg gaacagagag ggcgatgggg 720

ctgtcagaag aatggactgt gcacagccaa gaggccacca cttcggcttg gagcccgtcc 780

tttcttcctg ctttggagat gggagagctg accacgcctt ctaggaagag aaattcctca 840

ggaccagatc tctcctggct gcatttctac aggacagcag cttcctctcc tctcttagac 900

ctttcctcat cttctgaaag tacagagaag cttaacaact ccactggcct ccagagctcc 960

tcagtcagtc aaacaaagac aatgcatgtt gccaccgtgt tcactgatgg tggcccgaga 1020

acgctgcgat ctttgacggt cagtctggga cctgtgagca agacagaagg cttccccaag 1080

gactccagaa ttgccacgac ttcatcctca gtccttcttt caccctctgc agtggaatcg 1140

agaagaaaca gtagagtaac tgggaatcca ggggatgagg aattcattga accatccaca 1200

gaaaatgaat ttggacttac gtctttgcgt tggcaaaatg attccccaac ctttggagaa 1260

catcagcttg ccagcagctc tgaggtgcaa aatggaagtc ccatgtctca gactgagact 1320

gtgtctaggt cagtcgcacc catgagaggt ggagagatca ctgcacactg gctcttgacc 1380

aacagcacaa catctgcaga tgtgacagga agctctgctt catatcctga aggtgtgaat 1440

gcttcagtgt tgacccagtt ctcagactct actgtacagt ctggaggaag tcacacagca 1500

ttgggagata ggagttattc agagtcttca tctacatctt cctcggaaag cttgaattca 1560

tcagcaccac gtggagaacg ttcgatcgct gggattagct acggtcaagt gcgtggcaca 1620

gctattgaac aaaggacttc cagcgaccac acagaccaca cctacctgtc atctactttc 1680

accaaaggag aacgggcgtt actgtccatt acagataaca gttcatcctc agacattgtg 1740

gagagctcaa cttcttatat taaaatctca aactcttcac attcagagta ttcctccttt 1800

tttcatgctc agactgagag aagtaacatc tcatcctatg acggggaata tgctcagcct 1860

tctactgagt cgccagttct gcatacatcc aaccttccgt cctacacacc caccattaat 1920

atgccgaaca cttcggttgt tctggacact gatgctgagt ttgttagtga ctcctcctcc 1980

tcctcttcct cctcctcctc ttcttcttct tcagggcctc ctttgcctct gccctctgtg 2040

tcacaatccc accatttatt ttcatcaatt ttaccatcaa ccagggcctc tgtgcatcta 2100

ctaaagtcta cctctgatgc atccacacca tggtcttcct caccatcacc tttaccagta 2160

tccttaacga catctacatc tgccccactt tctgtctcac aaacaacctt gccacagtca 2220

tcttctaccc ctgtcctgcc cagggcaagg gagactcctg tgacttcatt tcagacatca 2280

acaatgacat cattcatgac aatgctccat agtagtcaaa ctgcagacct taagagccag 2340

agcaccccac accaagagaa agtcattaca gaatcaaagt caccaagcct ggtgtctctg 2400

cccacagagt ccaccaaagc tgtaacaaca aactctcctt tgcctccatc cttaacagag 2460

tcctccacag agcaaaccct tccagccaca agcaccaact tagcacaaat gtctccaact 2520

ttcacaacta ccattctgaa gacctctcag cctcttatga ccactcctgg caccctgtca 2580

agcacagcat ctctggtcac tggccctata gccgtacaga ctacagctgg aaaacagctc 2640

tcgctgaccc atcctgaaat actagttcct caaatctcaa cagaaggtgg catcagcaca 2700

gaaaggaacc gagtgattgt ggatgctacc actggattga tccctttgac cagtgtaccc 2760

acatcagcaa aagaaatgac cacaaagctt ggcgttacag cagagtacag cccagcttca 2820

cgttccctcg gaacatctcc ttctccccaa accacagttg tttccacggc tgaagacttg 2880

gctcccaaat ctgccacctt tgctgttcag agcagcacac agtcaccaac aacagtgtcc 2940

tcttcagcct cagtcaacag ctgtgctgtg aacccttgtc ttcacaatgg cgaatgcgtc 3000

gcagacaaca ccagccgtgg ctaccactgc aggtgcccgc cttcctggca aggggatgat 3060

tgcagtgtgg atgtgaatga gtgcctgtcg aacccctgcc catccacagc catgtgcaac 3120

aatactcagg gatcctttat ctgcaaatgc ccggttgggt accagttgga aaaagggata 3180

tgcaatttgg ttagaacctt cgtgacagag tttaaattaa agagaacttt tcttaataca 3240

actgtggaaa aacattcaga cctacaagaa gttgaaaatg agatcaccaa aacgttaaat 3300

atgtgttttt cagcgttacc tagttacatc cgatctacag ttcacgcctc tagggagtcc 3360

aacgcggtgg tgatctcact gcaaacaacc ttttccctgg cctccaatgt gacgctattt 3420

gacctggctg ataggatgca gaaatgtgtc aactcctgca agtcctctgc tgaggtctgc 3480

cagctcttgg gatctcagag gcggatcttt agagcgggca gcttgtgcaa gcggaagagt 3540

cccgaatgtg acaaagacac ctccatctgc actgacctgg acggcgttgc cctgtgccag 3600

tgcaagtcgg gatactttca gttcaacaag atggaccact cctgccgagc atgtgaagat 3660

ggatataggc ttgaaaatga aacctgcatg agttgcccat ttggccttgg tggtctcaac 3720

tgtggaaacc cctatcagct tatcactgtg gtgatcgcag ccgcgggagg tgggctcctg 3780

ctcatcctag gcatcgcact gattgttacc tgttgcagaa agaataaaaa tgacataagc 3840

aaactcatct tcaaaagtgg agatttccaa atgtccccgt atgctgaata ccccaaaaat 3900

cctcgctcac aagaatgggg ccgagaagct attgaaatgc atgagaatgg aagtaccaaa 3960

aacctcctcc agatgacgga tgtgtactac tcgcctacaa gtgtaaggaa tccagaactt 4020

gaacgaaacg gactctaccc ggcctacact ggactgccag gatcacggca ttcttgcatt 4080

ttccccggac agtataaccc gtctttcatc agtgatgaaa gcagaagaag agactacttt 4140

taa 4143

<210> 4

<211> 1380

<212> PRT

<213> Intelligent (Homo sapiens)

<400> 4

Met Ala Ser Pro Arg Ala Ser Arg Trp Pro Pro Pro Leu Leu Leu Leu

1 5 10 15

Leu Leu Pro Leu Leu Leu Leu Pro Pro Ala Pro Gly Thr Arg Asp Pro

20 25 30

Pro Pro Ser Pro Ala Arg Arg Ala Leu Ser Leu Ala Pro Leu Ala Gly

35 40 45

Ala Gly Leu Glu Leu Gln Leu Glu Arg Arg Pro Glu Arg Glu Pro Pro

50 55 60

Pro Thr Pro Pro Arg Glu Arg Arg Gly Pro Ala Thr Pro Gly Pro Ser

65 70 75 80

Tyr Arg Ala Pro Glu Pro Gly Ala Ala Thr Gln Arg Gly Pro Ser Gly

85 90 95

Arg Ala Pro Arg Gly Gly Ser Ala Asp Ala Ala Trp Lys His Trp Pro

100 105 110

Glu Ser Asn Thr Glu Ala His Val Glu Asn Ile Thr Phe Tyr Gln Asn

115 120 125

Gln Glu Asp Phe Ser Thr Val Ser Ser Lys Glu Gly Val Met Val Gln

130 135 140

Thr Ser Gly Lys Ser His Ala Ala Ser Asp Ala Pro Glu Asn Leu Thr

145 150 155 160

Leu Leu Ala Glu Thr Ala Asp Ala Arg Gly Arg Ser Gly Ser Ser Ser

165 170 175

Arg Thr Asn Phe Thr Ile Leu Pro Val Gly Tyr Ser Leu Glu Ile Ala

180 185 190

Thr Ala Leu Thr Ser Gln Ser Gly Asn Leu Ala Ser Glu Ser Leu His

195 200 205

Leu Pro Ser Ser Ser Ser Glu Phe Asp Glu Arg Ile Ala Ala Phe Gln

210 215 220

Thr Lys Ser Gly Thr Ala Ser Glu Met Gly Thr Glu Arg Ala Met Gly

225 230 235 240

Leu Ser Glu Glu Trp Thr Val His Ser Gln Glu Ala Thr Thr Ser Ala

245 250 255

Trp Ser Pro Ser Phe Leu Pro Ala Leu Glu Met Gly Glu Leu Thr Thr

260 265 270

Pro Ser Arg Lys Arg Asn Ser Ser Gly Pro Asp Leu Ser Trp Leu His

275 280 285

Phe Tyr Arg Thr Ala Ala Ser Ser Pro Leu Leu Asp Leu Ser Ser Ser

290 295 300

Ser Glu Ser Thr Glu Lys Leu Asn Asn Ser Thr Gly Leu Gln Ser Ser

305 310 315 320

Ser Val Ser Gln Thr Lys Thr Met His Val Ala Thr Val Phe Thr Asp

325 330 335

Gly Gly Pro Arg Thr Leu Arg Ser Leu Thr Val Ser Leu Gly Pro Val

340 345 350

Ser Lys Thr Glu Gly Phe Pro Lys Asp Ser Arg Ile Ala Thr Thr Ser

355 360 365

Ser Ser Val Leu Leu Ser Pro Ser Ala Val Glu Ser Arg Arg Asn Ser

370 375 380

Arg Val Thr Gly Asn Pro Gly Asp Glu Glu Phe Ile Glu Pro Ser Thr

385 390 395 400

Glu Asn Glu Phe Gly Leu Thr Ser Leu Arg Trp Gln Asn Asp Ser Pro

405 410 415

Thr Phe Gly Glu His Gln Leu Ala Ser Ser Ser Glu Val Gln Asn Gly

420 425 430

Ser Pro Met Ser Gln Thr Glu Thr Val Ser Arg Ser Val Ala Pro Met

435 440 445

Arg Gly Gly Glu Ile Thr Ala His Trp Leu Leu Thr Asn Ser Thr Thr

450 455 460

Ser Ala Asp Val Thr Gly Ser Ser Ala Ser Tyr Pro Glu Gly Val Asn

465 470 475 480

Ala Ser Val Leu Thr Gln Phe Ser Asp Ser Thr Val Gln Ser Gly Gly

485 490 495

Ser His Thr Ala Leu Gly Asp Arg Ser Tyr Ser Glu Ser Ser Ser Thr

500 505 510

Ser Ser Ser Glu Ser Leu Asn Ser Ser Ala Pro Arg Gly Glu Arg Ser

515 520 525

Ile Ala Gly Ile Ser Tyr Gly Gln Val Arg Gly Thr Ala Ile Glu Gln

530 535 540

Arg Thr Ser Ser Asp His Thr Asp His Thr Tyr Leu Ser Ser Thr Phe

545 550 555 560

Thr Lys Gly Glu Arg Ala Leu Leu Ser Ile Thr Asp Asn Ser Ser Ser

565 570 575

Ser Asp Ile Val Glu Ser Ser Thr Ser Tyr Ile Lys Ile Ser Asn Ser

580 585 590

Ser His Ser Glu Tyr Ser Ser Phe Phe His Ala Gln Thr Glu Arg Ser

595 600 605

Asn Ile Ser Ser Tyr Asp Gly Glu Tyr Ala Gln Pro Ser Thr Glu Ser

610 615 620

Pro Val Leu His Thr Ser Asn Leu Pro Ser Tyr Thr Pro Thr Ile Asn

625 630 635 640

Met Pro Asn Thr Ser Val Val Leu Asp Thr Asp Ala Glu Phe Val Ser

645 650 655

Asp Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Gly

660 665 670

Pro Pro Leu Pro Leu Pro Ser Val Ser Gln Ser His His Leu Phe Ser

675 680 685

Ser Ile Leu Pro Ser Thr Arg Ala Ser Val His Leu Leu Lys Ser Thr

690 695 700

Ser Asp Ala Ser Thr Pro Trp Ser Ser Ser Pro Ser Pro Leu Pro Val

705 710 715 720

Ser Leu Thr Thr Ser Thr Ser Ala Pro Leu Ser Val Ser Gln Thr Thr

725 730 735

Leu Pro Gln Ser Ser Ser Thr Pro Val Leu Pro Arg Ala Arg Glu Thr

740 745 750

Pro Val Thr Ser Phe Gln Thr Ser Thr Met Thr Ser Phe Met Thr Met

755 760 765

Leu His Ser Ser Gln Thr Ala Asp Leu Lys Ser Gln Ser Thr Pro His

770 775 780

Gln Glu Lys Val Ile Thr Glu Ser Lys Ser Pro Ser Leu Val Ser Leu

785 790 795 800

Pro Thr Glu Ser Thr Lys Ala Val Thr Thr Asn Ser Pro Leu Pro Pro

805 810 815

Ser Leu Thr Glu Ser Ser Thr Glu Gln Thr Leu Pro Ala Thr Ser Thr

820 825 830

Asn Leu Ala Gln Met Ser Pro Thr Phe Thr Thr Thr Ile Leu Lys Thr

835 840 845

Ser Gln Pro Leu Met Thr Thr Pro Gly Thr Leu Ser Ser Thr Ala Ser

850 855 860

Leu Val Thr Gly Pro Ile Ala Val Gln Thr Thr Ala Gly Lys Gln Leu

865 870 875 880

Ser Leu Thr His Pro Glu Ile Leu Val Pro Gln Ile Ser Thr Glu Gly

885 890 895

Gly Ile Ser Thr Glu Arg Asn Arg Val Ile Val Asp Ala Thr Thr Gly

900 905 910

Leu Ile Pro Leu Thr Ser Val Pro Thr Ser Ala Lys Glu Met Thr Thr

915 920 925

Lys Leu Gly Val Thr Ala Glu Tyr Ser Pro Ala Ser Arg Ser Leu Gly

930 935 940

Thr Ser Pro Ser Pro Gln Thr Thr Val Val Ser Thr Ala Glu Asp Leu

945 950 955 960

Ala Pro Lys Ser Ala Thr Phe Ala Val Gln Ser Ser Thr Gln Ser Pro

965 970 975

Thr Thr Val Ser Ser Ser Ala Ser Val Asn Ser Cys Ala Val Asn Pro

980 985 990

Cys Leu His Asn Gly Glu Cys Val Ala Asp Asn Thr Ser Arg Gly Tyr

995 1000 1005

His Cys Arg Cys Pro Pro Ser Trp Gln Gly Asp Asp Cys Ser Val Asp

1010 1015 1020

Val Asn Glu Cys Leu Ser Asn Pro Cys Pro Ser Thr Ala Met Cys Asn

1025 1030 1035 1040

Asn Thr Gln Gly Ser Phe Ile Cys Lys Cys Pro Val Gly Tyr Gln Leu

1045 1050 1055

Glu Lys Gly Ile Cys Asn Leu Val Arg Thr Phe Val Thr Glu Phe Lys

1060 1065 1070

Leu Lys Arg Thr Phe Leu Asn Thr Thr Val Glu Lys His Ser Asp Leu

1075 1080 1085

Gln Glu Val Glu Asn Glu Ile Thr Lys Thr Leu Asn Met Cys Phe Ser

1090 1095 1100

Ala Leu Pro Ser Tyr Ile Arg Ser Thr Val His Ala Ser Arg Glu Ser

1105 1110 1115 1120

Asn Ala Val Val Ile Ser Leu Gln Thr Thr Phe Ser Leu Ala Ser Asn

1125 1130 1135

Val Thr Leu Phe Asp Leu Ala Asp Arg Met Gln Lys Cys Val Asn Ser

1140 1145 1150

Cys Lys Ser Ser Ala Glu Val Cys Gln Leu Leu Gly Ser Gln Arg Arg

1155 1160 1165

Ile Phe Arg Ala Gly Ser Leu Cys Lys Arg Lys Ser Pro Glu Cys Asp

1170 1175 1180

Lys Asp Thr Ser Ile Cys Thr Asp Leu Asp Gly Val Ala Leu Cys Gln

1185 1190 1195 1200

Cys Lys Ser Gly Tyr Phe Gln Phe Asn Lys Met Asp His Ser Cys Arg

1205 1210 1215

Ala Cys Glu Asp Gly Tyr Arg Leu Glu Asn Glu Thr Cys Met Ser Cys

1220 1225 1230

Pro Phe Gly Leu Gly Gly Leu Asn Cys Gly Asn Pro Tyr Gln Leu Ile

1235 1240 1245

Thr Val Val Ile Ala Ala Ala Gly Gly Gly Leu Leu Leu Ile Leu Gly

1250 1255 1260

Ile Ala Leu Ile Val Thr Cys Cys Arg Lys Asn Lys Asn Asp Ile Ser

1265 1270 1275 1280

Lys Leu Ile Phe Lys Ser Gly Asp Phe Gln Met Ser Pro Tyr Ala Glu

1285 1290 1295

Tyr Pro Lys Asn Pro Arg Ser Gln Glu Trp Gly Arg Glu Ala Ile Glu

1300 1305 1310

Met His Glu Asn Gly Ser Thr Lys Asn Leu Leu Gln Met Thr Asp Val

1315 1320 1325

Tyr Tyr Ser Pro Thr Ser Val Arg Asn Pro Glu Leu Glu Arg Asn Gly

1330 1335 1340

Leu Tyr Pro Ala Tyr Thr Gly Leu Pro Gly Ser Arg His Ser Cys Ile

1345 1350 1355 1360

Phe Pro Gly Gln Tyr Asn Pro Ser Phe Ile Ser Asp Glu Ser Arg Arg

1365 1370 1375

Arg Asp Tyr Phe

1380

<210> 5

<211> 4164

<212> DNA

<213> Intelligent (Homo sapiens)

<400> 5

atggcctcgc cgcgcgcctc gcggtggccg ccgccgctcc tgctgctgtt gctgccgctg 60

ctgctgctgc cgccggcggc ccccgggacg cgggacccgc cgccttcccc ggctcgccgc 120

gcgctgagcc tggcgcccct cgcgggagcg gggctggagc tgcagctgga gcgccgcccg 180

gagcgcgagc cgccgcccac gccgccccgg gagcgccgcg ggcccgcgac ccccggcccc 240

agctacaggg cccctgagcc aggcgccgcg acacagcggg gaccctccgg ccgggccccc 300

agaggcggga gcgcggatgc tgcctggaaa cattggccag aaagtaacac tgaggcccat 360

gtagaaaaca tcaccttcta tcagaatcaa gaggactttt caacagtgtc ctccaaagag 420

ggcgtgatgg ttcagacctc tgggaagagc catgctgctt cggatgctcc agaaaacctc 480

actctactcg ctgaaacagc agatgctaga ggaaggagcg gctcttcaag tagaacaaac 540

ttcaccattt tgcctgttgg gtactcactg gagatagcaa cagctctgac ttcccagagt 600

ggcaacttag cctcagaaag tcttcacctg ccatccagca gttcagagtt cgatgaaaga 660

attgccgctt ttcaaacaaa gagtggaaca gcctcggaga tgggaacaga gagggcgatg 720

gggctgtcag aagaatggac tgtgcacagc caagaggcca ccacttcggc ttggagcccg 780

tcctttcttc ctgctttgga gatgggagag ctgaccacgc cttctaggaa gagaaattcc 840

tcaggaccag atctctcctg gctgcatttc tacaggacag cagcttcctc tcctctctta 900

gacctttcct catcttctga aagtacagag aagcttaaca actccactgg cctccagagc 960

tcctcagtca gtcaaacaaa gacaatgcat gttgccaccg tgttcactga tggtggcccg 1020

agaacgctgc gatctttgac ggtcagtctg ggacctgtga gcaagacaga aggcttcccc 1080

aaggactcca gaattgccac gacttcatcc tcagtccttc tttcaccctc tgcagtggaa 1140

tcgagaagaa acagtagagt aactgggaat ccaggggatg aggaattcat tgaaccatcc 1200

acagaaaatg aatttggact tacgtctttg cgttggcaaa atgattcccc aacctttgga 1260

gaacatcagc ttgccagcag ctctgaggtg caaaatggaa gtcccatgtc tcagactgag 1320

actgtgtcta ggtcagtcgc acccatgaga ggtggagaga tcactgcaca ctggctcttg 1380

accaacagca caacatctgc agatgtgaca ggaagctctg cttcatatcc tgaaggtgtg 1440

aatgcttcag tgttgaccca gttctcagac tctactgtac agtctggagg aagtcacaca 1500

gcattgggag ataggagtta ttcagagtct tcatctacat cttcctcgga aagcttgaat 1560

tcatcagcac cacgtggaga acgttcgatc gctgggatta gctacggtca agtgcgtggc 1620

acagctattg aacaaaggac ttccagcgac cacacagacc acacctacct gtcatctact 1680

ttcaccaaag gagaacgggc gttactgtcc attacagata acagttcatc ctcagacatt 1740

gtggagagct caacttctta tattaaaatc tcaaactctt cacattcaga gtattcctcc 1800

ttttttcatg ctcagactga gagaagtaac atctcatcct atgacgggga atatgctcag 1860

ccttctactg agtcgccagt tctgcataca tccaaccttc cgtcctacac acccaccatt 1920

aatatgccga acacttcggt tgttctggac actgatgctg agtttgttag tgactcctcc 1980

tcctcctctt cctcctcctc ctcttcttct tcttcagggc ctcctttgcc tctgccctct 2040

gtgtcacaat cccaccattt attttcatca attttaccat caaccagggc ctctgtgcat 2100

ctactaaagt ctacctctga tgcatccaca ccatggtctt cctcaccatc acctttacca 2160

gtatccttaa cgacatctac atctgcccca ctttctgtct cacaaacaac cttgccacag 2220

tcatcttcta cccctgtcct gcccagggca agggagactc ctgtgacttc atttcagaca 2280

tcaacctctt cctcctcctc ctcaatgaca tcattcatga caatgctcca tagtagtcaa 2340

actgcagacc ttaagagcca gagcacccca caccaagaga aagtcattac agaatcaaag 2400

tcaccaagcc tggtgtctct gcccacagag tccaccaaag ctgtaacaac aaactctcct 2460

ttgcctccat ccttaacaga gtcctccaca gagcaaaccc ttccagccac aagcaccaac 2520

ttagcacaaa tgtctccaac tttcacaact accattctga agacctctca gcctcttatg 2580

accactcctg gcaccctgtc aagcacagca tctctggtca ctggccctat agccgtacag 2640

actacagctg gaaaacagct ctcgctgacc catcctgaaa tactagttcc tcaaatctca 2700

acagaaggtg gcatcagcac agaaaggaac cgagtgattg tggatgctac cactggattg 2760

atccctttga ccagtgtacc cacatcagca aaagaaatga ccacaaagct tggcgttaca 2820

gcagagtaca gcccagcttc acgttccctc ggaacatctc cttctcccca aaccacagtt 2880

gtttccacgg ctgaagactt ggctcccaaa tctgccacct ttgctgttca gagcagcaca 2940

cagtcaccaa caacagtgtc ctcttcagcc tcagtcaaca gctgtgctgt gaacccttgt 3000

cttcacaatg gcgaatgcgt cgcagacaac accagccgtg gctaccactg caggtgcccg 3060

ccttcctggc aaggggatga ttgcagtgtg gatgtgaatg agtgcctgtc gaacccctgc 3120

ccatccacag ccatgtgcaa caatactcag ggatccttta tctgcaaatg cccggttggg 3180

taccagttgg aaaaagggat atgcaatttg gttagaacct tcgtgacaga gtttaaatta 3240

aagagaactt ttcttaatac aactgtggaa aaacattcag acctacaaga agttgaaaat 3300

gagatcacca aaacgttaaa tatgtgtttt tcagcgttac ctagttacat ccgatctaca 3360

gttcacgcct ctagggagtc caacgcggtg gtgatctcac tgcaaacaac cttttccctg 3420

gcctccaatg tgacgctatt tgacctggct gataggatgc agaaatgtgt caactcctgc 3480

aagtcctctg ctgaggtctg ccagctcttg ggatctcaga ggcggatctt tagagcgggc 3540

agcttgtgca agcggaagag tcccgaatgt gacaaagaca cctccatctg cactgacctg 3600

gacggcgttg ccctgtgcca gtgcaagtcg ggatactttc agttcaacaa gatggaccac 3660

tcctgccgag catgtgaaga tggatatagg cttgaaaatg aaacctgcat gagttgccca 3720

tttggccttg gtggtctcaa ctgtggaaac ccctatcagc ttatcactgt ggtgatcgca 3780

gccgcgggag gtgggctcct gctcatccta ggcatcgcac tgattgttac ctgttgcaga 3840

aagaataaaa atgacataag caaactcatc ttcaaaagtg gagatttcca aatgtccccg 3900

tatgctgaat accccaaaaa tcctcgctca caagaatggg gccgagaagc tattgaaatg 3960

catgagaatg gaagtaccaa aaacctcctc cagatgacgg atgtgtacta ctcgcctaca 4020

agtgtaagga atccagaact tgaacgaaac ggactctacc cggcctacac tggactgcca 4080

ggatcacggc attcttgcat tttccccgga cagtataacc cgtctttcat cagtgatgaa 4140

agcagaagaa gagactactt ttaa 4164

<210> 6

<211> 1387

<212> PRT

<213> Intelligent (Homo sapiens)

<400> 6

Met Ala Ser Pro Arg Ala Ser Arg Trp Pro Pro Pro Leu Leu Leu Leu

1 5 10 15

Leu Leu Pro Leu Leu Leu Leu Pro Pro Ala Ala Pro Gly Thr Arg Asp

20 25 30

Pro Pro Pro Ser Pro Ala Arg Arg Ala Leu Ser Leu Ala Pro Leu Ala

35 40 45

Gly Ala Gly Leu Glu Leu Gln Leu Glu Arg Arg Pro Glu Arg Glu Pro

50 55 60

Pro Pro Thr Pro Pro Arg Glu Arg Arg Gly Pro Ala Thr Pro Gly Pro

65 70 75 80

Ser Tyr Arg Ala Pro Glu Pro Gly Ala Ala Thr Gln Arg Gly Pro Ser

85 90 95

Gly Arg Ala Pro Arg Gly Gly Ser Ala Asp Ala Ala Trp Lys His Trp

100 105 110

Pro Glu Ser Asn Thr Glu Ala His Val Glu Asn Ile Thr Phe Tyr Gln

115 120 125

Asn Gln Glu Asp Phe Ser Thr Val Ser Ser Lys Glu Gly Val Met Val

130 135 140

Gln Thr Ser Gly Lys Ser His Ala Ala Ser Asp Ala Pro Glu Asn Leu

145 150 155 160

Thr Leu Leu Ala Glu Thr Ala Asp Ala Arg Gly Arg Ser Gly Ser Ser

165 170 175

Ser Arg Thr Asn Phe Thr Ile Leu Pro Val Gly Tyr Ser Leu Glu Ile

180 185 190

Ala Thr Ala Leu Thr Ser Gln Ser Gly Asn Leu Ala Ser Glu Ser Leu

195 200 205

His Leu Pro Ser Ser Ser Ser Glu Phe Asp Glu Arg Ile Ala Ala Phe

210 215 220

Gln Thr Lys Ser Gly Thr Ala Ser Glu Met Gly Thr Glu Arg Ala Met

225 230 235 240

Gly Leu Ser Glu Glu Trp Thr Val His Ser Gln Glu Ala Thr Thr Ser

245 250 255

Ala Trp Ser Pro Ser Phe Leu Pro Ala Leu Glu Met Gly Glu Leu Thr

260 265 270

Thr Pro Ser Arg Lys Arg Asn Ser Ser Gly Pro Asp Leu Ser Trp Leu

275 280 285

His Phe Tyr Arg Thr Ala Ala Ser Ser Pro Leu Leu Asp Leu Ser Ser

290 295 300

Ser Ser Glu Ser Thr Glu Lys Leu Asn Asn Ser Thr Gly Leu Gln Ser

305 310 315 320

Ser Ser Val Ser Gln Thr Lys Thr Met His Val Ala Thr Val Phe Thr

325 330 335

Asp Gly Gly Pro Arg Thr Leu Arg Ser Leu Thr Val Ser Leu Gly Pro

340 345 350

Val Ser Lys Thr Glu Gly Phe Pro Lys Asp Ser Arg Ile Ala Thr Thr

355 360 365

Ser Ser Ser Val Leu Leu Ser Pro Ser Ala Val Glu Ser Arg Arg Asn

370 375 380

Ser Arg Val Thr Gly Asn Pro Gly Asp Glu Glu Phe Ile Glu Pro Ser

385 390 395 400

Thr Glu Asn Glu Phe Gly Leu Thr Ser Leu Arg Trp Gln Asn Asp Ser

405 410 415

Pro Thr Phe Gly Glu His Gln Leu Ala Ser Ser Ser Glu Val Gln Asn

420 425 430

Gly Ser Pro Met Ser Gln Thr Glu Thr Val Ser Arg Ser Val Ala Pro

435 440 445

Met Arg Gly Gly Glu Ile Thr Ala His Trp Leu Leu Thr Asn Ser Thr

450 455 460

Thr Ser Ala Asp Val Thr Gly Ser Ser Ala Ser Tyr Pro Glu Gly Val

465 470 475 480

Asn Ala Ser Val Leu Thr Gln Phe Ser Asp Ser Thr Val Gln Ser Gly

485 490 495

Gly Ser His Thr Ala Leu Gly Asp Arg Ser Tyr Ser Glu Ser Ser Ser

500 505 510

Thr Ser Ser Ser Glu Ser Leu Asn Ser Ser Ala Pro Arg Gly Glu Arg

515 520 525

Ser Ile Ala Gly Ile Ser Tyr Gly Gln Val Arg Gly Thr Ala Ile Glu

530 535 540

Gln Arg Thr Ser Ser Asp His Thr Asp His Thr Tyr Leu Ser Ser Thr

545 550 555 560

Phe Thr Lys Gly Glu Arg Ala Leu Leu Ser Ile Thr Asp Asn Ser Ser

565 570 575

Ser Ser Asp Ile Val Glu Ser Ser Thr Ser Tyr Ile Lys Ile Ser Asn

580 585 590

Ser Ser His Ser Glu Tyr Ser Ser Phe Phe His Ala Gln Thr Glu Arg

595 600 605

Ser Asn Ile Ser Ser Tyr Asp Gly Glu Tyr Ala Gln Pro Ser Thr Glu

610 615 620

Ser Pro Val Leu His Thr Ser Asn Leu Pro Ser Tyr Thr Pro Thr Ile

625 630 635 640

Asn Met Pro Asn Thr Ser Val Val Leu Asp Thr Asp Ala Glu Phe Val

645 650 655

Ser Asp Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser

660 665 670

Gly Pro Pro Leu Pro Leu Pro Ser Val Ser Gln Ser His His Leu Phe

675 680 685

Ser Ser Ile Leu Pro Ser Thr Arg Ala Ser Val His Leu Leu Lys Ser

690 695 700

Thr Ser Asp Ala Ser Thr Pro Trp Ser Ser Ser Pro Ser Pro Leu Pro

705 710 715 720

Val Ser Leu Thr Thr Ser Thr Ser Ala Pro Leu Ser Val Ser Gln Thr

725 730 735

Thr Leu Pro Gln Ser Ser Ser Thr Pro Val Leu Pro Arg Ala Arg Glu

740 745 750

Thr Pro Val Thr Ser Phe Gln Thr Ser Thr Ser Ser Ser Ser Ser Ser

755 760 765

Met Thr Ser Phe Met Thr Met Leu His Ser Ser Gln Thr Ala Asp Leu

770 775 780

Lys Ser Gln Ser Thr Pro His Gln Glu Lys Val Ile Thr Glu Ser Lys

785 790 795 800

Ser Pro Ser Leu Val Ser Leu Pro Thr Glu Ser Thr Lys Ala Val Thr

805 810 815

Thr Asn Ser Pro Leu Pro Pro Ser Leu Thr Glu Ser Ser Thr Glu Gln

820 825 830

Thr Leu Pro Ala Thr Ser Thr Asn Leu Ala Gln Met Ser Pro Thr Phe

835 840 845

Thr Thr Thr Ile Leu Lys Thr Ser Gln Pro Leu Met Thr Thr Pro Gly

850 855 860

Thr Leu Ser Ser Thr Ala Ser Leu Val Thr Gly Pro Ile Ala Val Gln

865 870 875 880

Thr Thr Ala Gly Lys Gln Leu Ser Leu Thr His Pro Glu Ile Leu Val

885 890 895

Pro Gln Ile Ser Thr Glu Gly Gly Ile Ser Thr Glu Arg Asn Arg Val

900 905 910

Ile Val Asp Ala Thr Thr Gly Leu Ile Pro Leu Thr Ser Val Pro Thr

915 920 925

Ser Ala Lys Glu Met Thr Thr Lys Leu Gly Val Thr Ala Glu Tyr Ser

930 935 940

Pro Ala Ser Arg Ser Leu Gly Thr Ser Pro Ser Pro Gln Thr Thr Val

945 950 955 960

Val Ser Thr Ala Glu Asp Leu Ala Pro Lys Ser Ala Thr Phe Ala Val

965 970 975

Gln Ser Ser Thr Gln Ser Pro Thr Thr Val Ser Ser Ser Ala Ser Val

980 985 990

Asn Ser Cys Ala Val Asn Pro Cys Leu His Asn Gly Glu Cys Val Ala

995 1000 1005

Asp Asn Thr Ser Arg Gly Tyr His Cys Arg Cys Pro Pro Ser Trp Gln

1010 1015 1020

Gly Asp Asp Cys Ser Val Asp Val Asn Glu Cys Leu Ser Asn Pro Cys

1025 1030 1035 1040

Pro Ser Thr Ala Met Cys Asn Asn Thr Gln Gly Ser Phe Ile Cys Lys

1045 1050 1055

Cys Pro Val Gly Tyr Gln Leu Glu Lys Gly Ile Cys Asn Leu Val Arg

1060 1065 1070

Thr Phe Val Thr Glu Phe Lys Leu Lys Arg Thr Phe Leu Asn Thr Thr

1075 1080 1085

Val Glu Lys His Ser Asp Leu Gln Glu Val Glu Asn Glu Ile Thr Lys

1090 1095 1100

Thr Leu Asn Met Cys Phe Ser Ala Leu Pro Ser Tyr Ile Arg Ser Thr

1105 1110 1115 1120

Val His Ala Ser Arg Glu Ser Asn Ala Val Val Ile Ser Leu Gln Thr

1125 1130 1135

Thr Phe Ser Leu Ala Ser Asn Val Thr Leu Phe Asp Leu Ala Asp Arg

1140 1145 1150

Met Gln Lys Cys Val Asn Ser Cys Lys Ser Ser Ala Glu Val Cys Gln

1155 1160 1165

Leu Leu Gly Ser Gln Arg Arg Ile Phe Arg Ala Gly Ser Leu Cys Lys

1170 1175 1180

Arg Lys Ser Pro Glu Cys Asp Lys Asp Thr Ser Ile Cys Thr Asp Leu

1185 1190 1195 1200

Asp Gly Val Ala Leu Cys Gln Cys Lys Ser Gly Tyr Phe Gln Phe Asn

1205 1210 1215

Lys Met Asp His Ser Cys Arg Ala Cys Glu Asp Gly Tyr Arg Leu Glu

1220 1225 1230

Asn Glu Thr Cys Met Ser Cys Pro Phe Gly Leu Gly Gly Leu Asn Cys

1235 1240 1245

Gly Asn Pro Tyr Gln Leu Ile Thr Val Val Ile Ala Ala Ala Gly Gly

1250 1255 1260

Gly Leu Leu Leu Ile Leu Gly Ile Ala Leu Ile Val Thr Cys Cys Arg

1265 1270 1275 1280

Lys Asn Lys Asn Asp Ile Ser Lys Leu Ile Phe Lys Ser Gly Asp Phe

1285 1290 1295

Gln Met Ser Pro Tyr Ala Glu Tyr Pro Lys Asn Pro Arg Ser Gln Glu

1300 1305 1310

Trp Gly Arg Glu Ala Ile Glu Met His Glu Asn Gly Ser Thr Lys Asn

1315 1320 1325

Leu Leu Gln Met Thr Asp Val Tyr Tyr Ser Pro Thr Ser Val Arg Asn

1330 1335 1340

Pro Glu Leu Glu Arg Asn Gly Leu Tyr Pro Ala Tyr Thr Gly Leu Pro

1345 1350 1355 1360

Gly Ser Arg His Ser Cys Ile Phe Pro Gly Gln Tyr Asn Pro Ser Phe

1365 1370 1375

Ile Ser Asp Glu Ser Arg Arg Arg Asp Tyr Phe

1380 1385

<210> 7

<211> 20

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<400> 7

cgctcctgct gctgttgctg 20

<210> 8

<211> 19

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<400> 8

gagggtcccc gctgtgtcg 19

<210> 9

<211> 24

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<400> 9

gggcctctgt gcatctacta aagt 24

<210> 10

<211> 21

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<400> 10

tggggtgctc tggctcttaa g 21

Claims (3)

1. Use of an agent for detecting a composite heterozygous mutation of c.78_80del and c.2286_2303dupCTCTTCCTCCTCCTC in the preparation of a kit for screening a biological sample susceptible to dilated cardiomyopathy, wherein the composite heterozygous mutation of c.78_80del and c.2286_2303dupCTCTTCCTCCTCCTC is indicative of the dilated cardiomyopathy susceptible to the biological sample; c.78 — 80del relative to SEQ ID NO: 1, 78 th to 80 th base deletion; c.2286 — 2303 dupCTCTTCCTCCTCCTCCTCCTC is relative to SEQ ID NO: CTCTTCCTCCTCCTCCTC repeats are inserted at position 2286 of 1.

2. Use of the reagent for detecting the complex heterozygous mutation of c.78_80del and c.2286_2303dupCTCTTCCTCCTCCTCC in the preparation of the kit for screening biological samples susceptible to dilated cardiomyopathy according to claim 1, wherein the reagent for detecting the complex heterozygous mutation of c.78_80del and c.2286_2303dupCTCTTCCTCCTCCTCC is a primer.

3. The use of the reagent for detecting the complex heterozygous mutation of c.78_80del and c.2286_2303 dupCTCTTCCTCCTCCTCCTCC according to claim 2 in the preparation of a kit for screening biological samples susceptible to dilated cardiomyopathy, wherein the primer sequences are shown as SEQ ID NO:7-8 for the c.78_80del mutation; aiming at c.2286-2303 dupCTCTTCCTCCTCCTCCTCCTC mutation, the primer sequence is shown as SEQ ID NO. 9-10.

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