US20040001832A1 - Alstroem syndrome gene, gene variants, expressed protein and methods of diagnosis for Alstroem syndrome - Google Patents

Alstroem syndrome gene, gene variants, expressed protein and methods of diagnosis for Alstroem syndrome Download PDF

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US20040001832A1
US20040001832A1 US10/292,576 US29257602A US2004001832A1 US 20040001832 A1 US20040001832 A1 US 20040001832A1 US 29257602 A US29257602 A US 29257602A US 2004001832 A1 US2004001832 A1 US 2004001832A1
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nucleic acid
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Gayle Collin
Jan Marshall
Mitchell Martin
Juergen Naggert
Patsy Nishina
W. So
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A01K67/0275—Genetically modified vertebrates, e.g. transgenic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/20—Screening for compounds of potential therapeutic value cell-free systems

Definitions

  • the present invention relates to a nucleic acid sequence (SEQ ID NO: 1) linked to Alström syndrome (ALMS1), variants of that nucleic acid sequence, the protein (SEQ ID NO: 2) encoded by that nucleic acid sequence and screening methods for testing individuals to determine if they are carriers of Alström syndrome.
  • Alström syndrome is a homogeneous autosomal recessive disorder that is characterized by childhood obesity associated with hyperinsulinemia, chronic hyperglycemia, and neurosensory deficits 3,4 .
  • the Alström locus is likely to interact with genetic modifiers as subsets of patients present with additional features such as dilated cardiomyopathy 5 , hepatic dysfunction 6 , hypothyroidism 7 , male hypogonadism, short stature and mild to moderate developmental delay and with secondary complications normally associated with type 2 diabetes, such as hyperlipidemia and atherosclerosis.
  • the locus for Alström syndrome was initially mapped to chromosome 2p13 in a large French Acadian kindred within a 14.9 cM region 8 and later to a refined interval of 6.1 cM 9,10 .
  • ALMS1 is a novel gene that is ubiquitously expressed at low levels and does not share significant sequence homology with any other genes reported thus far. Identification of the ALMS1 gene provides us with an entry point into a novel pathway leading toward the understanding of both Alström Syndrome and the common diseases that characterize it phenotypically, such as obesity, hyperinsulinemia and hyperglycemia.
  • the ALMS1 gene can be used to diagnose Alström Syndrome by genetic testing for mutations in the gene or testing for adequate production levels of the protein encoded by the gene in patient tissues. Identification of ALMS1 also enables screening of individuals to determine if they are carriers of Alström Syndrome by genetic testing.
  • FIG. 1 Fine resolution and physical maps of the ALMS1 region. Recombinations in an affected child from the French Acadian kindred (I) and a child from a small nuclear family (II) place the ALMS1 critical interval in ⁇ 2cM region. Eight overlapping BACs complete a 1.2 Mb contig. Locations of sixteen known and predicted genes derived from EST clusters are shown as darkened bars. Genes tested for mutation analysis are depicted with an asterisk. 1-16: SEC15 (AB023136), SPR (sepiapterin reductase), EMY1 (empty spiracle, drosophila homolog 1), THC529835 ( c.
  • elegans sre2 homolog PP75 (KIAA0857), EST (THC551446), a novel gene related to EMX homeobox protein, NN8-4AG (retinoic acid responsive), CCT7 (chaperonin containing TCP1, subunit 7), EST (THC530316), EST (AI014261), EGR4 (early growth response 4), EST (KIAA0328), DUSP11 (dual-specificity phosphatase 11), AMSH (STAM-associated molecule), and ACTG2 (actin, gamma-2, smooth muscle, enteric).
  • FIG. 2 Genomic structure and alternative splicing of the ALMS1 gene.
  • a Exon-intron structure of KIAA0328 (ALMS1) drawn to scale. The gene is comprised of 16 exons spanning >164 kb of genomic DNA. 5′ and 3′ UTR and exon regions are depicted by open and filled boxes, respectively. Introns for which there is incomplete sequence information are indicated by slash bars.
  • b Major alternative transcripts of human ALMS1 .
  • FIG. 3 Mutations in five unrelated families segregating for ALMS1. Mutations were observed in all affected subjects A1-A8. a-d, All mutations co-segregate with the disease in a homozygous state in affected individuals.
  • a Detection of a 19 bp insertion in exon 9 of KIAA0328 in a large consanguineous Acadian kindred (K1) 12 .
  • Chromatogram displays the sequence variation between a normal control and an affected individual. PCR-amplification of the 19 bp insertion from a nuclear family within the Acadian kindred is shown on the right.
  • the parents (1,2) are heterozygous for the mutation (carrier), the unaffected child (3) is homozygous for the normal allele (439 bp, non-carrier) and the affected child (4) is homozygous for the insertion (458 bp).
  • the transmission of the insertion is in full agreement with previously reported haplotypes (not shown).
  • b A 1582C>T nonsense mutation in exon 3 of an affected individual of Italian descent.
  • c 3808GA>T;3813G>A mutations in exon 9 resulting in a frameshift in all 3 affected siblings of French descent.
  • NS no sample.
  • d A 3974delC frameshift mutation in exon 9 in two kindreds. The genealogical relationship between these two has not been identified.
  • a premature termination signal results at codon 1330.
  • a second mutation (1594insA) was identified in A8 which results in a frameshift.
  • FIG. 4 Expression of ALMS1 in various adult human and mouse tissues.
  • a RT-PCR of human cDNA multiple tissue panel (CLONTECH).
  • b Mouse northern blot analysis of 5 ug polyA+RNA hybridized with a 490 bp cDNA fragment spanning exons 1-3 and ⁇ -actin as control.
  • ALMS1 expression in brain and muscle was not detected by human northern analysis, low expression was observed by RT-PCR.
  • FIG. 5 Amino acid similarity between human and mouse ALMS1 with mouse (AK016590) and macaque (AB055273) domains.
  • FIG. 6 ALMS1 ⁇ form cDNA sequence (SEQ ID NO: 1) with the predicted 1902 amino acid encoded protein.
  • FIG. 7 ALMS1 splice junctions.
  • FIG. 8 Primer pairs for ALMS1 mutation analysis.
  • One EST cluster containing the novel cDNA sequence KIAA0328 (AB002326), was composed of cDNA fragments expressed in many tissues affected in Alström patients and thus, was subjected to mutation analysis.
  • To obtain the full length coding sequence of the corresponding cDNA alignments were made between KIAA0328 and overlapping transcripts (Incyte Genomics, NCBI, and TIGR).
  • a total human cDNA sequence of 6,612 bp was derived with an open reading frame spanning 1902 amino acids (see FIG. 6).
  • a translation initiation site was identified at nucleotide 597 and two putative polyadenylation sites (AATAAA) was observed at positions 6389 and 6591, respectively. Alignment of the cDNA sequence with the genomic sequence identified 16 exons of varying lengths (45 through 1865 bp).
  • FIG. 2 a The exon-intron structure of the KIAA0328 gene, now referred to as ALMS1, is shown in FIG. 2 a.
  • ctd2005P16 and RPCI-582H21 AC069346 and AC074008
  • FIG. 2 b Two splice variants of ALMS1 have been identified from public and Incyte Genomics cDNA library databases. The relative abundance of the variants has been estimated from the number of GenBank clones representing the different sequences and the tissue distribution analysis reported in the Incyte Database.
  • the most abundant variant is the ⁇ form (TIGR, THC530050) that consists of 16 exons.
  • the carboxy terminal exons, 14 to 16, are not represented in the originally identified ⁇ transcript (GenBank, AB002326), which utilizes an alternate polyadenylation site in intron 14.
  • the predicted open reading frame of the ⁇ form terminates immediately after exon 14. Sequence analysis predicts that the ⁇ protein product (1902 aa) only differs from the ⁇ protein product (1855 aa) by a 47 aa extension at the C-terminus.
  • Intronic primers were designed to amplify and sequence the entire coding region in DNA from six unrelated individuals affected with Alström syndrome.
  • a 19 bp insertion was identified in exon 9 (FIG. 3 a ) which causes a frameshift resulting in early termination at codon 1263.
  • the insertion was present in a homozygous state in all five affected subjects in the kindred. Transmission of the insertion allele in unaffected carriers was consistent with previously reported haplotypes 8 . The insertion allele was not observed in 100 unrelated individuals from the general population. Five additional mutations were identified in five unrelated families of diverse ethnicity (FIGS. 3 b - e, Table 1).
  • a 3974delC mutation was observed in two unrelated young adults; a 19 year old male of British ancestry (K42, Subject A5) and a 21 year old male who traces his ancestry to England two centuries ago (K3, Subject A6). Both presented with infantile cardiomyopathy within the first two months of life and subsequently developed short stature, scoliosis, Type II diabetes mellitus, and renal insufficiency. However, these subjects differ in the course of their disease presentation. Subject K42 A5 experienced a sudden recurrence of dilated cardiomyopathy at age 18 and has no evidence of hepatic dysfunction.
  • Subject K3 A6 presented with severe hepatic failure at age 20 but has not had a recurrence of cardiomyopathy. This finding of different disease progression in individuals carrying the same mutation suggests that the phenotypic variability seen in many Alström patients may be the result of genetic or environmental modifiers interacting with the ALMS1 locus.
  • mouse Alms1 cDNA sequence (5.6 kb) from alignments of several EST sequences (GenBank & TIGR) as well as by aligning the human cDNA sequence with mouse genomic trace data (GenBank) and mouse genomic fragments (Celera).
  • the mouse cDNA sequence was confirmed by sequencing PCR-amplified mouse Alms1 cDNA in C57BL6/J mice (GenBank, AF425257). The deduced amino acid sequence is 67.3% identical to the human ALMS1 protein sequence.
  • Obesity and type 2 diabetes pervasive public health problems, are associated with increased risk of morbidity and mortality and affect a large percentage of the population 13 . Both diseases are influenced by environmental conditions but also by a strong genetic component 14,15 . Interestingly, most of the genes identified to date that lead to obesity and type 2 diabetes have been in the context of syndromic diseases such as Bardet-Biedl Syndrome 16,17,18 . The infantile obesity observed in Alström patients is most likely a primary consequence of the alteration of the Alström gene as they constitute an earlier (as early as 6 months of age) phenotype observed in all affected children.
  • ALMS1 may lie in the same or parallel pathway as obesity associated NIDDM. Determining the function of the ALMS1 gene will potentially provide insights into how this gene interacts with other genes to produce its pathological effects. Although it is unlikely that mutations within ALMS1 play a major role in common diseases in the general population, the real value of studying this gene lies in the access it may provide to novel metabolic and regulatory pathways involved in the etiology of obesity, type 2 diabetes, neurosensory diseases and related disorders. Many examples of this paradigm of identification of single gene mutations that have allowed for the identification of the upstream and downstream molecules in a biological pathway are available in the literature (i.e. leptin and the Jak/Stat kinase pathway in obesity 19 ).
  • vectors preferably expression vectors, containing a nucleic acid encoding an ALMS1 protein (or a portion thereof).
  • vector refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked.
  • plasmid refers to a circular double stranded DNA loop into which additional DNA segments can be ligated.
  • viral vector Another type of vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome.
  • Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors).
  • vectors e.g., non-episomal mammalian vectors
  • Other vectors are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome.
  • certain vectors are capable of directing the expression of genes to which they are operatively linked.
  • Such vectors are referred to as “expression vectors”.
  • expression vectors of utility in recombinant DNA techniques are often in the form of plasmids.
  • plasmid and vector can be used interchangeably as the plasmid is the most commonly used form of vector.
  • the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions.
  • a host cell of the invention such as a prokaryotic or eukaryotic host cell in culture, can be used to produce (i.e., espress) an ALMS1 protein.
  • the invention further provides methods for producing an ALMS1 protein using the host cells of the invention.
  • the method comprises culturing the host cell of the invention (into which, for example, a recombinant expression vector encoding an ALMS1 protein has been introduced) in a suitable medium such that an ALMS1 protein is produced.
  • the method further comprises isolating an ALMS1 protein from the medium or the host cell.
  • oligonucleotide primers for amplification of short tandem repeat polymorphisms were either obtained from Research Genetics or designed (MacVector 6.0) 21 and custom made (One Trick Pony). PCR amplification of STRPs was performed with 33 P-labeled oligonucleotides as previously described 22 . PCR products were separated on a 6% denaturing polyacrylamide gel and visualized by autoradiography.
  • Mouse Northern To generate the probe for northern analysis, mouse C57BL/6J retinal cDNA was PCR-amplified with exon 1-specific primers (forward: 5′-TTCAGACTCTCTTGATGGAAGC-3′ and reverse 5′-TTGTTGTCCCATGAGCAGC-3′) using the Expand Template system (Roche). The 394 bp product was purified and radiolabeled (Rediprime II labelling system, Amersham Pharmacia). Mouse multiple tissue blots 23 were pre-hybridized for one hour with Rapid Hyb buffer (Amersham Pharmacia) and hybridization was performed overnight. Membranes were washed and hybridized products were visualized by autoradiography following an 8 day exposure.
  • Blots were probed with ⁇ -actin as a control 23 .
  • Human Northern A human multiple tissue blot (FirstChoice Blot 1, Ambion) was hybridized with a 490 bp probe generated by PCR amplification of genomic DNA (Primers: for 5′-TATGGCACTGAAACGATGC-3′ and rev 5′-TTTATTCCCAATGGTTCCACT-3′). Hybridization was performed as above.
  • RT-PCR Human multiple tissue cDNA panel I (CLONTECH) was PCR-amplified using forward primer 5′-TGTACTGGAGCATCTGTGGG-3′ and reverse primer 5′-CAGTGATTTGGGGCTGACTG-3′ for 35 cycles at an annealing temperature of 56° C.
  • GenBank accession numbers Sequence data for human transcript KIAA0328, AB002326, mouse C57BL6/J cDNA, AF425257 and human BACs, AC069346 and AC074008.
  • the protein encoded by ALMS1 could be expressed and isolated and an antibody specific to that protein could be obtained by standard methods of biotechnology. The antibody would then be useful to detect the presence or absence of the ALMS1 protein in tissue samples from patients. Insufficient ALMS1 protein would implicate Alström Syndrome. All of the above methods can be practiced by those of skill in the art, once they know of the sequence of ALMS1 and the link between ALMS1 and Alström Syndrome.
  • hybridize under stringent conditions means that two nucleic acid fragments are capable of hybridization to one another under standard hybridization conditions described in Sambrook et al., Molecular Cloning: A Laboratory Manual (1989) Cold Spring Harbor Laboratory Press, New York, USA. More specifically, “stringent conditions” as used herein refer to hybridization at 65° C. in a hybridization buffer consisting of 250 mmol/l sodium phosphate buffer pH 7.2, 7% (w/v) SDS, 1% (w/v) BSA, 1 mmol/l EDTA and 0.1 mg/ml single-stranded salmon sperm DNA. A final wash is performed at 65° C. in 125 mmol/l sodium phosphate buffer pH 7.2, 1 mmol/l EDTA and 1% (w/v) SDS.

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