WO2014027615A1 - Procédé de détection de patients ou de porteurs déficients en complexe iii mitochondrial - Google Patents

Procédé de détection de patients ou de porteurs déficients en complexe iii mitochondrial Download PDF

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WO2014027615A1
WO2014027615A1 PCT/JP2013/071620 JP2013071620W WO2014027615A1 WO 2014027615 A1 WO2014027615 A1 WO 2014027615A1 JP 2013071620 W JP2013071620 W JP 2013071620W WO 2014027615 A1 WO2014027615 A1 WO 2014027615A1
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mutation
uqcrc2
gene
patient
detected
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直通 松本
紀子 三宅
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公立大学法人横浜市立大学
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention relates to a method for detecting a mitochondrial complex III deficiency patient or carrier.
  • Mitochondrial respiratory chain generates energy as adenosine triphosphate (ATP) by electron transport chain and oxidative phosphorylation system.
  • the mitochondrial respiratory chain present in the inner mitochondrial membrane is composed of five types of multimeric protein complexes, Complexes I to V. Among these, the complex III (CIII) (bc1 complex or ubiquinol cytochrome c reductase; EC 1.10.2.2) monomer is composed of 11 proteins (Non-patent Document 1). One protein is encoded by mitochondrial DNA (MTCYB) and the remaining 10 proteins are encoded by nuclear DNA.
  • CIII complex III
  • MTCYB mitochondrial DNA
  • nuclear DNA nuclear DNA
  • the latter is (1) core protein (encoded by UQCRC1 gene and UQCRC2 gene), (2) respiratory system protein (encoded by CYC1 gene and UQCRFS1 gene), (3) low molecular weight protein (UQCRH gene, UQCRB gene, UQCRQ gene, UCRC Gene, UQCR11 gene, and UQCRFS1 gene are coded).
  • core protein encoded by UQCRC1 gene and UQCRC2 gene
  • respiratory system protein encoded by CYC1 gene and UQCRFS1 gene
  • UQCRH gene, UQCRB gene, UQCRQ gene, UCRC Gene, UQCR11 gene, and UQCRFS1 gene are coded.
  • CIII monomers are rapidly converted to catalytically active homodimers and incorporated into respirasome along with complexes I and IV. This super complex functions as a single enzyme (Non-patent Document 2).
  • CIII deficiency MIM 124,000
  • MIM 124,000 Mitochondrial complex III deficiency
  • UQCRB NM_006294
  • UQCRQ NM_014402
  • BCS1L NM_004328
  • TTC19 NM_017775
  • UQCRB and UQCRQ encode components of complex III itself
  • BCS1L and TTC19 encode mitochondrial assembly factors.
  • the most common cause of CIII deficiency is the recessive BCS1L mutation.
  • BCS1L mutation results in several different phenotypes: Bjornstad syndrome, characterized by epilepsy deafness and torsion (MIM 262000, Non-Patent Document 6); fetal growth retardation, amino acid urine, cholestasis GRACILE syndrome (MIM 603358, Non-Patent Document 8) presenting with iron overload, lactic acidosis, and early death; and Leigh syndrome (MIMM 256000, Non-Patent Document 4).
  • a homozygous mutation of the TTC19 gene causes progressive neurodegenerative disease (Non-patent Document 9).
  • Non-patent Document 10 Homozygous 4 bp deletion of UQCRB gene results in hypoglycemia and lactic acidosis
  • Non-patent Document 11 homozygous missense mutation of UQCRQ gene results in severe psychomotor retardation, extrapyramidal signs, and dementia
  • Non-Patent Documents 3 to 8 the majority of genetic causes of CIII deficiency are still unknown.
  • the present invention is to provide a novel means useful for a definitive diagnosis of CIII deficiency in which the majority of genetic causes are still unknown.
  • the present invention detects a mitochondrial complex III deficiency patient or carrier comprising examining whether or not the subject has a mutation in the UQCRC2 gene using a sample isolated from the subject.
  • a method is provided wherein a patient is detected when the homozygous or compound heterozygous mutation is detected and a carrier is detected when the heterozygous mutation is detected.
  • a novel causative gene for CIII deficiency was identified, and a new index useful for definitive diagnosis of CIII deficiency was provided. This makes it possible to make a definitive diagnosis even in CIII deficient cases in which no mutation is found in the 4 genes that are already known to be involved in the disease. Prognosis can be estimated by confirming the diagnosis.
  • (A) It is a graph which shows the interaction energy change of the core protein homodimer by amino acid substitution in the 183rd residue computed using FoldX software.
  • (B) shows the crystal structure of bovine mitochondrial bcI (CIII) complex (PDB_code 2A06). The circle is residue 183 of the core protein.
  • (C-F) Detailed view of the core protein homodimer interface. C is a wild type (Arg), D is a mutant type (Trp), E is a SNP type (Gln), and F is an ortholog type (Lys) complex structure.
  • the UQCRC2 gene is a nuclear gene that encodes the core protein (ubiquinol-cytochrome c reductase core protein II, MIM 191329) among the components of the mitochondrial respiratory chain complex III (CIII).
  • the mRNA sequence of the UQCRC2 gene is registered in GenBank with an accession number of NM_003366.2. Sequence numbers 1 and 2 in the sequence listing are the base sequence of the cDNA coding region and the amino acid sequence of UQCRC2 protein.
  • SEQ ID NO: 3 is the mRNA sequence of the gene registered under the above accession number. In SEQ ID NOs: 4 to 16, the sequences of each exon and the nearby intron are shown in Table 1.
  • the inventors of the present application newly identified that the UQCRC2 gene is a causative gene of mitochondrial complex III deficiency (CIII deficiency).
  • CIII deficiency mitochondrial complex III deficiency
  • the pathogenic mutation present in the UQCRC2 gene is a pathogenic mutation for CIII deficiency. Patients with CIII deficiency have such mutations in the UQCRC2 gene in homo or compound hetero, and carriers with CIII deficiency have the mutation in hetero.
  • the term “complex hetero” means that both alleles of the UQCRC2 gene have different mutations.
  • CIII deficiency caused by abnormalities in UQCRC2 gene is slightly different from CIII deficiency caused by abnormalities in 4 previously reported genes (UQCRB, UQCRQ, BCS1L, TTC19). Symptom, ketonic acidosis, hyperammonemia.
  • the report by the present inventors is the first report in humans.
  • the mutation of the UQCRC2 gene to be detected in the present invention includes a nucleotide sequence that causes changes such as deletion of at least a part of the protein in addition to changes in a very small number of amino acids of the UQCRC2 protein encoded by the UQCRC2 gene. Mutations are included.
  • Such nucleotide sequence mutations include, for example, missense mutations, nonsense mutations, frameshift mutations, amino acid deletion mutations, splicing abnormality mutations due to base substitution, deletion, insertion, duplication, etc. in the exon or intron region. possible.
  • the cDNA sequence, genomic sequence, and amino acid sequence of UQCRC2 protein shown in the sequence table are typical examples of normal UQCRC2 sequences.
  • the presence / absence of mutation can be determined based on the sequence of UQCRC2 gene shown in the sequence listing and by comparison with this reference sequence.
  • a mutation in the UQCRC2 gene that causes a change in the amino acid sequence may be a pathogenic mutation that causes CIII deficiency, but among them, a genetic mutation that deletes an evolutionarily highly conserved amino acid, or this Mutations that change amino acids with different properties (for example, changing hydrophilic amino acids to hydrophobic amino acids) cannot function normally, such as UQCRC2 protein, for example, UQCRC2 protein that significantly reduces the enzymatic activity of CIII, and super complexes This is a typical example of a pathogenic mutation that has a high probability of producing UQCRC2 protein that cannot stably form CIII and causes CIII deficiency.
  • UQCRC2 protein sequences of various animals are known and registered in various databases such as GenBank.
  • the detected base mutation is a mutation that is not found in many healthy populations, or is not registered in a well-known database on nucleotide sequence diversity such as NCBI dbSNP or 1000NPGenomes Project. Even if it is a simple base mutation, there is a high possibility that it is a pathogenic mutation.
  • SIFT http://sift.jcvi.org/
  • PolyPhen http://genetics.bwh.harvard.edu/pph/
  • PolyPhen-2 http://genetics.bwh.harvard.edu/ pph2 /
  • Mutation Taster http://neurocore.charite.de/MutationTaster/index.html
  • Align GVGD http://agvgd.iarc.fr/agvgd_input.php
  • the mutation shown in Table 2 below is a pathogenic mutation of CIII deficiency identified from an inbred family in the examples, and is one of the specific examples of UQCRC2 mutation that serves as an index in the present invention.
  • This missense mutation is a rare mutation that is not registered in the database on the diversity of base sequences such as dbSNP and is hardly recognized in the healthy population.
  • the analysis using the above-mentioned various prediction tools strongly suggests that the mutation is a pathogenic mutation.
  • functional analysis using the mutant protein shows abnormalities in the enzyme activity and super complex formation of the CIII complex. It has also been confirmed that it will come.
  • the UQCRC2 mutation used as an index in the present invention is not limited to such specific examples, and UQCRC2 mutations that suggest pathogenicity are widely included in the scope of the present invention.
  • the 183rd amino acid a non-synonymous human SNP [rs4850 (c.548G> A, p.Arg183Gln)] to be substituted with Gln is known, but the mutation may not be a pathogenic variant. It has been confirmed by analysis using a prediction tool, functional analysis of p.Arg183Gln type UQCRC2 protein, and the like.
  • the mutation of UQCRC2 gene can be detected by analyzing the nucleotide sequence using a nucleic acid sample such as genomic DNA or RNA.
  • a nucleic acid sample such as genomic DNA or RNA.
  • genomic DNA can be easily prepared from peripheral blood, oral mucosa swabs, and the like by conventional methods.
  • various prenatal genetic testing methods are known, and it is possible to examine whether the UQCRC2 gene mutation is present in the fetus.
  • fetus For example, methods of collecting and examining cells from the fetus (using amniotic fluid, villi, umbilical cord blood), non-invasive testing methods of examining fetal genetic mutations using fetal cells mixed in maternal blood, in vitro
  • Various methods such as a method using one cell of a fertilized fertilized egg (pre-implantation diagnosis) are known.
  • the non-invasive test method the fetus is a “subject”, and the fetal cell sample contained in the maternal blood sample corresponds to the “sample separated from the subject”.
  • the method of the present invention uses the sample separated from the living body to It can be expressed as “check whether or not there is a mutation”.
  • the amino acid sequence of a protein can be affected not only by the exon region but also by mutations in the intron region.
  • the exon and its vicinity usually include several tens to several hundred bases, for example, an intron region of about 30 to 50 bases. It is common to inspect.
  • sequence analysis may be performed on exons and introns in the vicinity thereof.
  • Whether the mutation is homo or hetero can be confirmed from the waveform data of the sequence. If there is a heterozygous mutation, two types of signals will overlap at the same site. If there are two or more heterozygous mutations, the patient's parents are examined to determine whether the mutation is a complex heterogeneity (ie, whether the mutation is on different chromosomes), and the two mutations are derived from the father and mother, respectively. It can be confirmed by examining that.
  • heteroduplexes it is also effective to screen for mutations in the UQCRC2 gene by detecting heteroduplexes.
  • heterozygous or complex heterozygous mutations When heterozygous or complex heterozygous mutations are present, recombining the genomic DNA sample after heat denaturation results in heteroduplexes in which normal DNA and mutant DNA are hybridized.
  • Heteroduplexes (1) show different mobility in non-denaturing polyacrylamide gels, (2) mismatched bases are susceptible to cleavage by chemicals and enzymes, (3) different denaturation temperatures during denaturation It has the characteristic that shows.
  • Methods for detecting heteroduplexes using these characteristics are known in this field, and have been put into practical use as mutation testing methods. Specifically, for example, a method for detecting heteroduplexes using denaturing high performance liquid chromatography (dHPLC) and a High-Resolution-Melt method are known.
  • the High-Resolution-Melt method is a method for melting double-stranded DNA using fluorescent dyes (SYTO (registered trademark) 9, LC Green (registered trademark), EvaGreen (registered trademark), etc.) that bind to double-stranded DNA at high density.
  • This is a method of detecting heteroduplexes by treating the process of (thermal denaturation) as a change in fluorescence intensity. That is, when a double-stranded DNA is stained with a fluorescent dye that binds to the double-stranded DNA at a high density, when the double-stranded DNA is melted (thermally denatured), the fluorescent dye is drawn from the site where the double strand is dissociated.
  • heteroduplex detection can be performed quickly and with high sensitivity. It can be easily carried out using commercially available equipment and kits. If the mutation is homozygous, the detection sensitivity of the High resolution melt method is expected to be low (but not impossible to detect), but in autosomal recessive genetic disease, the compound heterozygous mutation first occurs in the absence of the relatives of the patient's parents. Therefore, heteroduplex detection such as High ⁇ Resolution Melt method can be an effective test method in the present invention.
  • the base sequence may be determined for all exons of UQCRC2 and nearby intron regions, and the presence or absence of mutation may be examined. In addition, for example, by narrowing down the region where the base sequence should be determined by detecting the heteroduplex, and then determining the base sequence of the target region, the inspection can be carried out more efficiently. If desired, the presence or absence of mutations in the four previously reported genes (UQCRB, UQCRQ, BCS1L, TTC19) may be examined.
  • a mutation that causes an amino acid sequence change can be determined as a pathogenic mutation of CIII deficiency. If necessary, refer to databases related to nucleotide sequence diversity such as NCBI dbSNP and 1000 Genomes Project, and check whether the mutation is a rare mutation without registration. You may check for it.
  • DNA and patient fibroblasts were collected after obtaining informed consent. DNA was extracted from peripheral blood leukocytes by a conventional method. As a control sample, DNA of 80 Mexican controls was purchased from Coriell Institute for Medical Research (Camden, NJ, USA). The experimental protocol was approved by the Yokohama City University Institutional Review Board.
  • Exome sequence 3 ⁇ g of genomic DNA was fragmented and captured using NimbleGen SeqCap EZ Exome library SR (Roche NimbleGen, Madison, Wis., USA) according to the manufacturer's instructions. Captured samples were sequenced on a next generation sequencer GAIIx (Illumina, San Diego, Calif., USA) using a 76 bp paired end. Image analysis and base calling were performed by sequence control software (SCS) real time analysis (Illumina) and CASAVA software v1.7 (Illumina).
  • SCS sequence control software
  • Illumina real time analysis
  • CASAVA software v1.7 Illumina
  • mouse anti-V5 antibody (1: 1000) (Invitrogen) and Alexa Fluor-488 goat anti-mouse IgG antibody (1: 1000) as secondary antibody (1: 1000) ( Molecular probe, Carlsbad, Calif., USA) was used to stain the C-terminal V5-6xHis-tagged UQCRC2 protein. Confocal microscope images were obtained using a FLUOVIEW FV1000-D microscope (Olympus, Tokyo, Japan).
  • Patient 1 (V: 2 in FIG. 1A) is a Latin American girl born as a child of a 26-year-old healthy woman (G2P2Ab0) and a 28-year-old healthy male who are also cousins. At 37 weeks of age, the patient was delivered by caesarean section due to abnormalities in the fetal heartbeat diagram. Weight at birth is 2,329 grams (5-10 percentile), height is 46 cm (5-10 percentile), and head circumference is 34 cm (25-50 percentile). Apgar score is 8 points after 1 minute, 9 points after 5 minutes, and 9 points after 10 minutes.
  • tachycardia 47 times / min
  • tachycardia (181 beats / min)
  • slight subcaval depression Levine II / VI systolic heart murmur, no organ hypertrophy, and poor sucking reflex Admitted.
  • the blood ammonia level was 126 ⁇ M (newborn reference range ⁇ 80 ⁇ M).
  • the girl patient responded quickly to symptomatic treatment, with blood lactate levels falling to 12.7 mM within 24 hours with intravenous glucose 10 mg / kg / min and sodium bicarbonate infusion.
  • the lactic acid level improved to 3.1 mM
  • the pyruvate level improved to 0.125 mM.
  • Abnormalities observed in urine organic acid analysis at admission were large amounts of lactic acid and pyruvate acidic urine, and ketone urine.
  • Plasma amino acids had particularly high alanine levels (1,519 ⁇ M; reference range 200-600 ⁇ M).
  • Magnetic resonance imaging tomography (MRI) of the brain revealed small infarcts in the right parietal region and temporal region.
  • Patient 1 is now 5 years old, normal growth, no signs of intellectual disability. Girls still needed urgent intravenous glucose treatment to prevent metabolic decompensation during comorbidities, but the frequency of hospitalization decreased.
  • Patient 2 (V: 3 in FIG. 1A) is Patient 1's younger brother. The boy was born by cesarean section at 39 weeks of gestation. Weight at birth is 2,658 g (5-10th percentile), height is 49 cm (25-50 percentile), and head circumference is 34.3 cm (25 percentile). Apgar score is 8 points after 1 minute and 9 points after 5 minutes. Due to hyperlactemia, Patient 2 developed tachypnea, examination, and poor feeding ability within a day. As a result of the first capillary blood gas analysis, pH was 7.05, pCO 2 was 25 mmHg, bicarbonate was 5.8 mmol / L, and excess base was -22 mEq / L.
  • patient 2 was intubated for 2 days and treated with intravenous glucose and bicarbonate. Eating high-carb, low-fat formula started within 10 days.
  • Patient 2 had an initial hospital stay of 1 month during which he was diagnosed with congenital lactemia and persistent hypoglycemia of unknown cause.
  • Patient 2 was treated with corticosteroids for 4 months, due to adrenal insufficiency, until normal results were obtained in the corticotropin (ACTH) stimulation test.
  • ACTH corticotropin
  • the patient had 5 episodes of generalized seizures associated with this episode, but the seizures disappeared after treatment with levetiracetam. No abnormalities were observed in brain MRI findings at 8 months of age.
  • the patient was hospitalized for 1 month and discharged without sequelae. The patient repeated hospitalization more than 10 times with similar episodes of lactic acidosis, hypoglycemia, hyperammonemia, and ketosis caused by concurrent disease. Developmental delay was pointed out once at the age of 4 months, and after physical and speech therapy, the growth was evaluated as normal at the age of 3 years.
  • Patient 2 is currently 4 years old, normal growth, no signs of intellectual disability. Physical examination revealed no external malformations or abnormal local neurological signs. The patient continues to take a low-fat, high-carbohydrate diet and fight hunger. Although the patient continues to require urgent intravenous glucose treatment to prevent metabolic decompensation during concomitant disease, the frequency of hospitalization has decreased. Laboratory tests for severe acute metabolic decompensation that occurred at the age of 16 months showed abnormalities in the following points: capillary blood gas pH 7.19, glucose 11 mg / dL, blood ammonia 348 ⁇ M, blood lactate 6.8 mM.
  • alanine was elevated to 440 ⁇ M (reference range was 23 to 410 ⁇ M).
  • the 19-month-old acylcarnitine profile which was mildly decompensated, showed a marked increase in C2 (48 nmol / mL [reference range 2.6 to 15.5 nmol / mL]) and 3-hydroxyacylcarnitine (C12 to C18). A moderate increase was observed.
  • Patient 3 (VI: 1 in FIG. 1A) is a girl who was born to a close-married parent who belongs to a branch in the same family as patients 1 and 2.
  • the fetal period was smaller than the gestational age, and was born by vaginal delivery from a 23-year-old mother at full gestation.
  • birth weight is 2,200 g. He had mild respiratory distress and was placed under supervision for one day more than usual. Due to vomiting, dehydration, and hypoglycemia, she experienced four hospitalizations by 18 months of age.
  • the blood glucose level was 17 mg / dL
  • the bicarbonate level was 8 mmol / L
  • the anion gap was 30 mmol / L.
  • Blood lactate and pyruvate levels were 26.3 mg / dL (reference range ⁇ 16.0 mg / dL) and 1.5 mg / dL (reference range ⁇ 1.5 mg / dL), respectively.
  • Brain MRI was performed because of developmental delay and microcephaly (2nd percentile). The results were normal.
  • Patient 3 spoke only two words, but was able to follow the two words. Walk at 15 months of age. She was 14 months old and underweight before starting occupational therapy. Outer surface malformation is not recognized. When he was healthy, his muscular strength and tone were normal, and he was able to climb, jump one leg and jump in an age-appropriate manner.
  • the UQCRC2 gene encodes ubiquinol-cytochrome c reductase core protein II (UQCRC2; MIM 191329, SEQ ID NO: 2), which is a CIII core protein. All three patients had homozygous p.Arg183Trp mutation in UQCRC2, but father (IV-2), mother (IV-1) and sister (V-1) (all unaffected) It was heterozygous (FIG. 1B). The mutation was not observed in 80 Mexican control alleles or 750 Japanese control alleles.
  • the amino acid 183 of UQCRC2 is a basic amino acid that is highly conserved among species from zebrafish to humans (for example, Arg in humans and cattle, and Lys in mice, see Fig. 1C).
  • a non-synonymous human SNP substituted for Gln [rs4850 (c.548G> A, p.Arg183Gln)] has been reported (FIG. 1C). Therefore, in addition to the substitution for Trp found in patients, the change in interaction energy due to substitution of Arg183 with Lys or Gln was also calculated.
  • the interaction energy change caused by substitution of Arg183 with Trp was calculated to be 10 kcal / mol, and the change caused by substitution with Lys or Gln was 2 kcal / mol or less (FIG. 2A, Table 3).
  • the substitution of Arg183 with Gln and Lys was both benign as predicted by the Polyphen-2 software.
  • BN-PAGE blue native polyacrylamide gel electrophoresis
  • mitochondria were solubilized with 0.5% (w / v) n-dodecyl- ⁇ -D-maltoside (DDM) ⁇ and used as supercomplexes (complexes I, III, and IV).
  • DDM n-dodecyl- ⁇ -D-maltoside
  • BN-PAGE immunoblotting was performed using a specific antibody against the respiratory chain complex (FIGS. 3C to F).

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Abstract

L'invention concerne un nouveau moyen utile pour le diagnostic définitif d'une déficience en CIII, dont la majorité des causes génétiques sont toujours inconnues. Ce procédé de détection de patients ou de porteurs de déficience en complexe III mitochondrial comprend la recherche de savoir si le sujet présente une mutation ou non dans le gène UQCRC2 à l'aide d'un échantillon isolé à partir du sujet. Dans ce procédé, un patient est détecté lorsque la mutation détectée est homozygote ou un composé hétérozygote, et un porteur est détecté lorsque la mutation détectée est hétérozygote. Une mutation du gène UQCRC2 est, par exemple, une mutation où l'acide aminé 183 de la protéine UQCRC2 est substitué par Trp.
PCT/JP2013/071620 2012-08-16 2013-08-09 Procédé de détection de patients ou de porteurs déficients en complexe iii mitochondrial WO2014027615A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
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JP2012085640A (ja) * 2003-01-28 2012-05-10 Cellectis カスタムメイドメガヌクレアーゼおよびその使用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012085640A (ja) * 2003-01-28 2012-05-10 Cellectis カスタムメイドメガヌクレアーゼおよびその使用

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
AGUILERA-AGUIRRE LEOPOLDO ET AL.: "Mitochondrial dysfunction increases allergic airway inflammation", THE JOURNAL OF IMMUNOLOGY, vol. 183, 2009, pages 5379 - 5387 *
BAREL ORTAL ET AL.: "Mitochondrial Complex III Deficiency Associated with a Homozygous Mutation in UQCRQ", THE AMERICAN JOURNAL OF HUMAN GENETICS, vol. 82, 2008, pages 1211 - 1216 *
HAUT SANDRINE ET AL.: "A deletion in the human QP-C gene causes a complex III deficiency resulting in hypoglycaemia and lactic acidosis", HUMAN GENETICS, vol. 113, 2003, pages 118 - 122 *
MIYAKE NORIKO ET AL.: "Mitochondrial Complex III Deficiency Caused by a Homozygous UQCRC2 Mutation Presenting with Neonatal-Onset Recurrent Metabolic Decompensation", HUMAN MUTATION, vol. 34, no. 3, 19 December 2012 (2012-12-19), pages 446 - 452 *

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