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PubMed1998

Point mutations of ornithine decarboxylase gene are an infrequent event in colorectal cancer but a missense mutation was found in a replication error positive patient with hMSH2 germline mutation.

BACKGROUND: Ornithine decarboxylase (ODC; EC 4.1.1.17) is the first rate-limiting enzyme in the biosynthesis of polyamines. ODC protein has a characteristic amino acid sequence, the PEST sequence, which is related to the enzyme's rapid degradation. ODC cDNA prepared from human hepatoma tissues has been reported to show nonsense or missense mutations. METHODS: We examined somatic mutations of ODC cDNA by RT-PCR-SSCP analysis and mRNA expressions by RT-PCR in 50 colorectal cancer tissues to investigate the involvement of ODC gene alterations in colorectal cancers. RESULTS: Increased expression of the ODC gene was observed in 36 cases (86%) out of the 42 examined by RT-PCR. In one case, a missense mutation was found in the cancer tissue but not in normal mucosa. The missense mutation from Asp to Asn at codon 424, in the PEST region, possibly stabilizes the ODC protein. In colorectal cancer, replication error and a germline mutation in hMSH2 gene were observed. CONCLUSIONS: The missense mutation at codon 424 is speculated to be a cause of stabilization and a passenger mutation owing to the mutator phenotype. Since only one of 50 colorectal cancers exhibited a missense mutation of the ODC gene, mutations in ODC gene are not frequent in colorectal cancer. The increased expression of the ODC gene was noted in 86% of colorectal cancer tissues by RT-PCR, however, it was not due to point mutations in ODC coding exons.

Colonic Neoplasms↗
PubMed1999

A functional and quantitative mutational analysis of p53 mutations in yeast indicates strand biases and different roles of mutations in DMBA- and BBN-induced tumors in rats.

In order to analyze the mutational events and to understand the biological significance of the p53 gene in chemical carcinogenesis, we applied a new yeast-based p53 functional assay to ovarian tumors induced by 7, 12-dimethylbenz[a]anthracene (DMBA), as well as to transitional cell carcinomas of the urinary bladder induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in rats. The assay demonstrated that 15 of 19 DMBA induced tumors harbored clonal p53 mutations, which is consistent with the expectations of the "clonal expansion" hypothesis. The majority of the mutations were purine (AG) to pyrimidine (CT) transversions (12/19) on the non-transcribed (sense) strand (NTS), which is likely to be due to depurination created by DMBA adduct formation on the NTS. In contrast, we found no pyrimidine to purine [corrected] transversion on the NTS. After cessation of BBN treatment, BBN-induced multifocal lesions in the bladder contained heterogeneous p53 mutations at an early stage. In the later stage, however, clonal p53 mutations were identified in 4 out of 7 bladders analyzed, conforming with the concept of "field cancerization". The observed base substitutions were G-->A (1/6) or C -->T transitions (2/6), and mutations at T (3/6) on the NTS in clonal mutations, together with non-clonal mutations, showing a preference of C-->T to G-->A (17 vs. 0). Thus, preferential repair was found in the transcribed strand of the p53 gene, whether modified by DMBA or by BBN carcinogens. Very similar mutation patterns were observed between clonal and non-clonal mutations in the DMBA- and BBN-induced tumors, indicating that the rat yeast p53 functional assay can be a potential tool for the characterization of in vivo mutation patterns of p53, when modified by chemical carcinogens.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1996

[Mutator genes of the yeast Saccharomyces cerevisiae. Interaction of mutations him and his with mutations blocking three principal pathways of repair of induced DNA damage].

During recent years, genes controlling mutation in higher eukaryotes have been found to be involved actively in carcinoma regeneration in cells. In this respect, studying the genetic control of mutagenesis becomes a key direction of research into mechanisms responsible for cancer generation. The results of studying interaction of mutations in the HIM and HSM genes, controlling spontaneous and induced mutagenesis in yeasts, and mutations impairing three known pathways of DNA damage repair in this microorganism, are described in this work. It was shown that mutation rev3 completely blocks UV-induced mutagenesis in all mutants studied. On the other hand, mutation rad2 synergistically interacts with mutations him1, hsm1, hsm3, hsm6, and hsm2, thus enhancing the frequency of UV-induced mutagenesis in double mutants multiple times. Mutations him2 and him3 manifested epistatic interaction with mutation rad2. With mutation rad54, the interaction was epistatic for mutations him1 and hsm2 and was additive for mutations hsm1, him2, and him3. On the basis of the data obtained, we developed a scheme for the appearance of mismatch bases in the process of repair of UV-induced DNA damage.

DNA Damage↗
PubMed2002

Screening of SLC25A13 mutations in early and late onset patients with citrin deficiency and in the Japanese population: Identification of two novel mutations and establishment of multiple DNA diagnosis methods for nine mutations.

We have recently identified SLC25A13 on chromosome 7q21.3 as the gene responsible for adult-onset type II citrullinemia (CTLN2) and found seven mutations in the SLC25A13 gene of CTLN2 patients. Most recently, the SLC25A13 mutations have been detected in neonatal/infantile patients with a type of neonatal hepatitis associated with cholestasis (NICCD). In the present study, we identified a novel mutation, E601X, in the SLC25A13 gene and established multiple DNA diagnosis methods for eight mutations by using a genetic analyzer with GeneScan and the single primer extension procedure (SNaPshot). An additional novel missense mutation (variation), E601K, was detected by SNaPshot analysis and was indistinguishable from the mutation E601X detected by the PCR/RFLP method. Multiple DNA diagnoses for the nine mutations revealed that 100 (male/female: 70/30) out of 115 CTLN2 and 38 (14/24) out of 45 NICCD patients tested were homozygotes or compound heterozygotes. The frequency of homozygotes carrying SLC25A13 mutations in both alleles is estimated to be minimally 1 in 21,000 from carrier detection (18 in 1,315 individuals tested) in the Japanese population. The differences in the gender ratio and in mutation types between CTLN2 and NICCD patients are significant. It is, however, unknown whether all homozygotes with mutated SLC25A13 in both alleles suffer from NICCD, CTLN2, both, or neither.

Age of Onset↗
PubMed1999

Evaluation of the protein truncation test and mutation detection in the NF1 gene: mutational analysis of 15 known and 40 unknown mutations.

The neurofibromatosis type 1 (NF1) gene located at 17q 11.2 contains 60 exons and spans 350 kb of genomic DNA. Mutation analysis has been hampered by the large size of the gene, the high rate of new mutations, a lack of mutational clustering and the presence of numerous homologous loci. Mutation detection methods based on the direct analysis of a gene's RNA transcript permit the rapid screening of large multi-exonic genes. However, the detection of frame-shift or nonsense mutations can be limited by instability of the mutant mRNA species due to nonsense-mediated decay. In order to determine the frequency of this allelic exclusion, total lymphocyte RNA was analysed from 15 NF1 patients with known truncating mutations and a panel of 40 NF1 patients with unknown mutations. The level of expression of the mutant message was greatly reduced in 2 of the 15 samples (13%), and 3 of the 18 informative samples from the panel of 40. A coupled reverse-transcription polymerase chain reaction and protein truncation test method was subsequently applied to screen RNA from the panel of 40 unrelated NF1 patients. Aberrant polypeptide bands were identified and characterised in 21 samples (53%). The mutations identified were 479del107;ins31, 495delTGTT, 1127delTGAT, R416X, R440X, 1446del 62, 1541delAG, 2252del 74, 2537insTG, 3456delACTC, R1276X, R1362X, 5749ins171, 6084del280, 6487insA, R2214X, 6791insA, 6858del141, 7458delC, 7676 2A-G and 8081delC. These mutations were uniformly distributed across the gene and 14 represent novel changes that contribute to the germline mutational spectrum of the NF1 gene.

Alleles↗
PubMed1999

Mutation rates in humans. II. Sporadic mutation-specific rates and rate of detrimental human mutations inferred from hemophilia B.

We estimated the rates per base per generation of specific types of mutations, using our direct estimate of the overall mutation rate for hemophilia B and information on the mutations present in the United Kingdom's population as well as those reported year by year in the hemophilia B world database. These rates are as follows: transitions at CpG sites 9.7x10-8, other transitions 7.3x10-9, transversions at CpG sites 5.4x10-9, other transversions 6.9x10-9, and small deletions/insertions causing frameshifts 3.2x10-10. By taking into account the ratio of male to female mutation rates, the above figures were converted into rates appropriate for autosomal DNA-namely, 1.3x10-7, 9.9x10-9, 7.3x10-9, 9.4x10-9, 6.5x10-10, where the latter is the rate for all small deletion/insertion events. Mutation rates were also independently estimated from the sequence divergence observed in randomly chosen sequences from the human and chimpanzee X and Y chromosomes. These estimates were highly compatible with those obtained from hemophilia B and showed higher mutation rates in the male, but they showed no evidence for a significant excess of transitions at CpG sites in the spectrum of Y-sequence divergence relative to that of X-chromosome divergence. Our data suggest an overall mutation rate of 2.14x10-8 per base per generation, or 128 mutations per human zygote. Since the effective target for hemophilia B mutations is only 1.05% of the factor IX gene, the rate of detrimental mutations, per human zygote, suggested by the hemophilia data is approximately 1.3.

Animals↗
PubMed1998

Variable penetrance of familial pheochromocytoma associated with the von Hipple Lindau gene mutation, S68W. Mutations in brief no. 150. Online.

Van Hippel-Lindau disease (VHL) is an autosomal dominantly inherited disorder, characterised by the development of clear cell renal carcinomas, CNS hemangioblastomas, retinal angiomas, pancreatic tumors, pheochromocytomas and hepatic cysts. Recently a number of families with dominant familial pheochromocytoma as the only clinical manifestation have been reported to carry mutations in the HVL gene. We describe a family in which a novel VHL S68W mutation was segregating and carrier individuals manifested with variable penetrance of isolated pheochromocytomas. Investigation of this kindred confirmed that a mutation in the VHL gene could produce isolated pheochromocytomas as the only clinical feature and was variably penetrant.

Genes, Tumor Suppressor↗
PubMed2002

Factor V gene G1691A mutation, prothrombin gene G20210A mutation, and MTHFR gene C677T mutation are not risk factors for pulmonary thromboembolism in Chinese population.

A mutation in coagulant factor V gene, a substitution in the 3' untranslated region of prothrombin gene, and a variant in 5,10-methylenetetrahydrofolate reductase (MTHFR) gene have been reported to be related to venous thromboembolism in Caucasians, but this relationship remains in debate in other populations. In this case-control study, we aimed to determine the prevalence of these three mutations in the Chinese population and investigate whether they are associated with pulmonary thromboembolism. The subjects consisted of 90 patients with pulmonary thromboembolism and 143 age- and sex-matched healthy controls. Traditional risk factors for venous thrombosis and pulmonary thromboembolism were investigated as well. We found that the frequencies of varicose vein, phlebitis, trauma, and surgery were significantly higher in cases than in controls. Of all subjects, none was a carrier of coagulant factor V gene G1691A mutation or prothrombin gene G 20210A mutation, which are common point mutations in Caucasians, while the frequency of MTHFR gene 677T allele exceeded 55% in cases (56.7%), controls (55.2%), and all subjects (55.8%) studied. The homozygous mutation rate of MTHFR gene was over 30% in both cases (33.3%) and controls (32.2%), but no significant difference was found in genotype distribution (chi(2)=0.100, P=0.951). Model fitting using logistic regression did not find that MTHFR gene C677T mutation was associated with pulmonary thromboembolism, consistent with the results of stratification analysis. In conclusion, coagulant factor V gene G1691A mutation and prothrombin G20210A mutation are very rare, while MTHFR C677T mutation is very common, and all of them are not associated with pulmonary thromboembolism in the Chinese population.

Case-Control Studies↗
PubMed1996

Mutation analysis of the RET proto-oncogene in Dutch families with MEN 2A, MEN 2B and FMTC: two novel mutations and one de novo mutation for MEN 2A.

Hereditary C-cell carcinoma is encountered in multiple endocrine neoplasia type 2A (MEN 2A), MEN 2B, and familial medullary thyroid carcinoma (FMTC). Mutations of the RET proto-oncogene are associated with all three diseases. To obtain an insight into the molecular heterogeneity of MEN 2 syndromes and FMTC in the Netherlands, probands of 20 MEN 2A families, two FMTC families, and seven MEN 2B families were analyzed by the polymerase chain reaction (PCR), DNA sequencing, and restriction enzyme digestion for abnormalities in the RET proto-oncogene. RET mutations were found in all cases. All MEN 2A families had a mutation involving one of five cysteine codons in exons 10 and 11 of RET. Two novel dinucleotide mutations and a de novo mutation were found. Both FMTC families had a mutation of the Cys at codon 618. All MEN 2B probands carried a Met to Thr mutation in exon 16. All mutations could be confirmed by restriction enzyme digestion of PCR amplicons. Identification of the RET mutation in the Dutch population with hereditary C-cell carcinoma facilitates genetic testing for families or individuals at risk for MEN 2A, FMTC, and MEN 2B.

Amino Acid Sequence↗
PubMed2002

The spectrum of PIG-A gene mutations in aplastic anemia/paroxysmal nocturnal hemoglobinuria (AA/PNH): a high incidence of multiple mutations and evidence of a mutational hot spot.

Paroxysmal nocturnal hemoglobinuria (PNH) may arise during long-term follow- up of aplastic anemia (AA), and many AA patients have minor glycosylphosphatidylinositol (GPI) anchor-deficient clones, even at presentation. PIG-A gene mutations in AA/PNH and hemolytic PNH are thought to be similar, but studies on AA/PNH have been limited to individual cases and a few small series. We have studied a large series of AA patients with a GPI anchor-deficient clone (AA/PNH), including patients with minor clones, to determine whether their pattern of PIG-A mutations was identical to the reported spectrum in hemolytic PNH. AA patients with GPI anchor-deficient clones were identified by flow cytometry and minor clones were enriched by immunomagnetic selection. A variety of methods was used to analyze PIG-A mutations, and 57 mutations were identified in 40 patients. The majority were similar to those commonly reported, but insertions in the range of 30 to 88 bp, due to tandem duplication of PIG-A sequences, and deletions of more than 10 bp were also seen. In 3 patients we identified identical 5-bp deletions by conventional methods. This prompted the design of mutation-specific polymerase chain reaction (PCR) primers, which were used to demonstrate the presence of the same mutation in an additional 12 patients, identifying this as a mutational hot spot in the PIG-A gene. Multiple PIG-A mutations have been reported in 10% to 20% of PNH patients. Our results suggest that the large majority of AA/PNH patients have multiple mutations. These data may suggest a process of hypermutation in the PIG-A gene in AA stem cells.

Anemia, Aplastic↗
PubMedDate not supplied

Mutation L210W of HIV-1 reverse transcriptase in patients receiving combination therapy. Incidence, association with other mutations, and effects on the structure of mutated reverse transcriptase.

Mutation L210W of HIV-1 reverse transcriptase (RT) is one of the six main mutations that confer in vivo resistance to zidovudine. Surprisingly, this mutation has received scant appraisal and its contribution to the genotypic resistance to nucleoside analogs is not well understood. The aim of this study was: (1) to study the frequency of mutation L210W in a large collection of HIV-1 sequences (2,049 samples, including 395 DNA and 1,654 RNA sequences) from patients receiving combination therapy, and (2) to analyze its association with the other mutations that confer resistance to zidovudine. A mutation at codon 210 (mainly L210W) was found in 647 (32%) of the 2,049 sequences analyzed. Only 43 (<7%) of these 647 genomes were also mutated at codon 70 (p < 10(-5)). In contrast, 98% of these 647 sequences were also mutated at codon 215 (essentially T215Y/F), and 94% at codon 41 (mainly M41L). These data showing a close association between L210W, T215Y/F, and M41L, and a mutual exclusion between K70R and L210W, were confirmed by analyzing the sequences stored in the HIV-1 sequences available through the Stanford HIV RT and Protease Database. Follow-up studies demonstrated that L210W appeared always after T215Y/F. This observation is consistent with crystallographic studies which suggested that the aromatic side chain of Trp 210 could stabilize the interaction of Phe/Tyr215 with the dNTP-binding pocket. This molecular cross-talk between amino acid chains occurs nearby the conserved Asp113 residue. Since the lateral chain of Arg70 may also interact with Asp113, this is likely to create a sterical hindrance around this residue. Thus, the R-->K reversion of codon 70 may represent a compensatory mechanism allowing a functional rearrangement of the dNTP-binding pocket in the mutated RT.

Amino Acid Sequence↗
PubMed1992

Differences in clinical expression of hypertrophic cardiomyopathy associated with two distinct mutations in the beta-myosin heavy chain gene. A 908Leu----Val mutation and a 403Arg----Gln mutation.

BACKGROUND: The disease gene for hypertrophic cardiomyopathy (HCM) has been identified as the beta-myosin heavy chain (beta-MHC) gene in some HCM families. We describe extensive clinical evaluations in two kindreds with two distinct point mutations in the beta-MHC gene. METHODS AND RESULTS: We used single-strand confirmation polymorphism (SSCP) gel analysis of polymerase chain reaction-amplified products capturing each of the 40 beta-MHC gene exons to identify distinct missense mutations in two HCM kindreds. Clinical, ECG, and echocardiographic studies were performed in the two kindreds: kindred 2755 with amino acid 908Leu----Val mutation and kindred 2002 with amino acid 403Arg----Gln mutation. The morphological appearances of HCM were similar in these two kindreds. However, the two kindreds differed with respect to disease penetrance, age of onset of disease, and incidence of premature sudden death. Twelve of 31 adults (greater than or equal to 17 years) with the disease gene in kindred 2755 did not have left ventricular hypertrophy (LVH), and only five of these had ECG abnormalities. Thus, the disease penetrance in adults with this mutation was only 61%. None of 11 children aged less than 16 years had LVH. The 908 mutation was associated with a low incidence of cardiac events: Only two sudden deaths and one syncope occurred in 46 individuals with the mutant allele. In contrast, LVH was present in all 11 adults in kindred 2002 with the 403 mutation (100% disease penetrance). In addition, three of four affected children were symptomatic and had clinical evidence of HCM. The disease in this kindred was severe and resulted in six premature sudden deaths. Seven additional patients had syncope or presyncope. CONCLUSIONS: In some kindreds, the HCM disease gene is more prevalent than indicated by echocardiography and ECG. Some point mutations may be associated with a more malignant prognosis. Preclinical identification of children with mutations associated with a high incidence of sudden death and syncope provides the opportunity to evaluate efficacy of early therapeutic interventions.

Adolescent↗
PubMed2002

The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations.

Mutations of c-KIT causing spontaneous activation of the KIT receptor kinase are associated with sporadic adult human mastocytosis (SAHM) and with human gastrointestinal stromal tumors. We have classified KIT-activating mutations as either "enzymatic site" type (EST) mutations, affecting the structure of the catalytic portion of the kinase, or as "regulatory" type (RT) mutations, affecting regulation of an otherwise normal catalytic site. Using COS cells expressing wild-type or mutant KIT, 2 compounds, STI571 and SU9529, inhibited wild-type and RT mutant KIT at 0.1 to 1 microM but did not significantly inhibit the Asp816Val EST mutant associated with SAHM, even at 10 microM. Using 2 subclones of the HMC1 mast cell line, which both express KIT with an identical RT mutation but which differ in that one also expresses the Asp816Val EST mutation, both compounds inhibited the RT mutant KIT, thereby suppressing proliferation and producing apoptosis in the RT mutant-only cell line. Neither compound suppressed activation of Asp816Val EST mutant KIT, and neither produced apoptosis or significantly suppressed proliferation of the cell line expressing the Asp816Val mutation. These studies suggest that currently available KIT inhibitors may be useful in treating neoplastic cells expressing KIT activated by its natural ligand or by RT activating mutations such as gastrointestinal stromal tumors but that neither compound is likely to be effective against SAHM. Furthermore, these results help establish a general paradigm whereby classification of mutations affecting oncogenic enzymes as RT or EST may be useful in predicting tumor sensitivity or resistance to inhibitory drugs.

Animals↗
PubMed1998

Novel compound heterozygous laminina2-chain gene (LAMA2) mutations in congenital muscular dystrophy. Mutations in brief no. 159. Online.

The laminina2-chain gene (LAMA2) encodes a basal lamina protein, laminina2, known to be deficient in one form of congenital muscular dystrophy (CMD). In a laminina2 deficient-CMD patient, we screened the entire LAMA2 cDNA (953bp) by reverse transcriptase polymerase chain reaction combined with single strand conformational polymorphism analysis. Direct sequencing of aberrant conformers in this patient revealed two loss-of-function mutations, consistent with autosomal recessive inheritance. The patient had two novel heterozygous mutations: 1) an exon 4 nonsense mutation caused by a G-->A substitution at cDNA position 547, changing the TGG codon for tryptophan into a TGA stop codon (W166X) in the N-terminus domain VI;ii) an exon 54 frameshift mutation due to a deletion of nucleotide 'C' at cDNA position 7707 (S2553Y), resulting in a premature stop codon (V2587X) in exon 55 in the globular G domain of laminina2 at the C-terminus. These mutations cause a disruption of the open reading frame of LAMA2. The absence of laminina2 observed in the patient's muscle biopsy could result from diminished levels of the LAMA2 transcript. Alternatively, the mutations might lead to translation of a truncated laminina2. By either mechanism the phenotype of congenital muscular dystrophy is believed to be the result of disruption of linkage between the extracellular matrix and the dystrophin glycoprotein complex.

DNA Mutational Analysis↗
PubMed1999

Three new mutations in the uroporphyrinogen decarboxylase gene in familial porphyria cutanea tarda. Mutation in brief no. 237. Online.

We have characterised three new mutations in the uroporphyrinogen decarboxylase gene in familial porphyria cutanea tarda. The first of these was a G to A substitution in the 5' splice junction of exon 4 which generated an mRNA that lacked exon 4. The second was a nonsense mutation in exon 5 which changed the arginine residue at position 142 to a stop codon, and the third mutation, also in exon 5, was a triple base substitution from nucleotide position 417 to 419. This mutation encompassed two codons but only changed the amino acid predicted from the second codon, resulting in the replacement of valine with glutamine at position 134. This missense mutation has been described previously by Meguro et al. 1994, on one allele in a compound heterozygote with hepatoerythropoietic porphyria. This is the third case of an hepatoerythropoietic porphyria mutation in an individual diagnosed with familial porphyria cutanea tarda.

Humans↗
PubMed1999

Carnitine transporter OCTN2 mutations in systemic primary carnitine deficiency: a novel Arg169Gln mutation and a recurrent Arg282ter mutation associated with an unconventional splicing abnormality.

Systemic primary carnitine deficiency (CDSP, MIM 212140) is a disorder of fatty acid oxidation manifesting in acute metabolic decompensation or in progressive cardiomyopathy and muscle weakness. Mutations in the plasmalemmal organic cation/carnitine transporter OCTN2 were recently identified in CDSP patients of diverse ethnic backgrounds. We have performed OCTN2 mutation analysis in two unrelated German patients with primary carnitine deficiency and identified three molecular abnormalities. On one of the four chromosomes analyzed, we detected an Arg169Gln missense mutation that affects an arginine residue absolutely conserved in the entire transporter superfamily to which OCTN2 belongs. On the three other chromosomes, we found an Arg282ter nonsense mutation in exon 5. This mutation is embedded into different haplotypes of closely spaced intragenic dimorphisms in our two patients and was recently described in a patient of Asiatic Indian background, so it appears to be a recurrent or ancient founder mutation that may account for more CDSP cases. Finally, we found that the Arg282ter nonsense mutation is associated with a splicing abnormality at the intron 6/exon 7 junction. However, no mutations are present in exon 6, intron 6, or exon 7, suggesting that defective splicing of exon 7 on the Arg282ter allele is due to an unconventional, long-distance mechanism.

Adolescent↗
PubMed1999

Expansion of CTG repeat in myotonin protein kinase gene on Alu(ins)-HinfI-I background in a myotonic dystrophy patient from India. Mutations in brief no. 210. Online.

To determine the founder of Indian myotonic dystrophy mutation, we have studied the expansion of CTG repeats in myotonin protein kinase gene and two intragenic linked loci Alu(ins) / Alu(del) and G/T intron 9 HinfI polymorphism in ten unrelated DM patients from eastern India. Out of these ten patients, reconstruction of haplotype was possible for five patients unambiguously. In the other five cases, haplotype for the normal allele was assumed to be the most common haplotype found in normal individuals from Indian populations. Such analysis showed that in nine cases, the expansion of CTG repeats took place on Alu(ins)-HinfI-2 background indicating common founder with other DM mutation published. However, in one case we observed a different haplotype [Alu(ins)-HinfI-1] which could be a new mutation or due to admixture.

Deoxyribonucleases, Type II Site-Specific↗
PubMed2001

A deletion mutation in GJB6 cooperating with a GJB2 mutation in trans in non-syndromic deafness: A novel founder mutation in Ashkenazi Jews.

A deletion of at least 140 kb starting approximately 35kb upstream (telomeric) to the GJB2 (CX26) gene was identified in 7 patients from 4 unrelated Jewish Ashkenazi families with non-syndromic hearing loss. These patients were heterozygous for one of the common mutations 167delT or 35delG in the GJB2 gene in trans to the deletion. The deletion started at 5' side of the GJB6 (CX30) gene including the first exon and it did not affect the integrity of the GJB2 gene. The deletion mutation segregated together with the hearing loss, and was not found in a control group of 100 Ashkenazi individuals. We suggest that the deletion is a recessive mutation causing hearing loss in individuals that are double heterozygous for the deletion and for a mutation in the GJB2 gene. The effect of the deletion mutation could be due to a digenic mode of inheritance of GJB2 and GJB6 genes that encode two different connexins; connexin 26 and connexin 30, or it may abolish control elements that are important in the expression of the GJB2 gene in the cochlea. Regardless which of the options is valid, it is apparent that the deletion mutation provides a new insight into connexin function in the auditory system. The deletion mutation was on the same haplotypic background in all the families, and therefore is a founder mutation that increases the impact of GJB2 in the etiology of prelingual recessive non-syndromic hearing loss in the Ashkenazi population.

Alleles↗