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ABSTRACT: ALR/Lt, a mouse strain with strong resistance to type 1 diabetes, is closely related to autoimmune type 1 diabetes-prone NOD/Lt mice. ALR pancreatic beta cells are resistant to the beta cell toxin alloxan, combinations of cytotoxic cytokines, and diabetogenic NOD T-cell lines. Reciprocal F1 hybrids between either ALR and NOD or ALR and NON/Lt, showed that alloxan resistance was transmitted to F1 progeny only when ALR was the maternal parent. Here we show that the mitochondrial genome (mtDNA) of ALR mice contributes resistance to diabetes.
When F1 progeny from reciprocal outcrosses between ALR and NOD were backcrossed to NOD, a four-fold lower frequency of spontaneous type 1 diabetes development occurred when ALR contributed the mtDNA. Because of the apparent interaction between nuclear and mtDNA, the mitochondrial genomes were sequenced.
An ALR-specific sequence variation in the mt-Nd2 gene producing a leucine to methionine substitution at amino acid residue 276 in the NADH dehydrogenase 2 was discovered. An isoleucine to valine mutation in the mt-Co3 gene encoding COX3 distinguished ALR and NOD from NON and ALS. All four strains were distinguished by variation in a mt-encoded arginyl tRNA polyadenine tract. Shared alleles of mt-Co3 and mt-Tr comparing NOD and ALR allowed for exclusion of these two genes as candidates, implicating the mt-Nd2 variation as a potential ALR-derived type 1 diabetes protective gene.
The unusual resistance of ALR mice to both ROS-mediated and autoimmune type 1 diabete stresses reflects an interaction between the nuclear and mt genomes. The latter contribution is most likely via a single nucleotide polymorphism in mt-Nd2.
Diabetologia 03/2005; 48(2):261-7. · 6.81 Impact Factor
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ABSTRACT: Presbycusis, an age-related hearing loss, is accompanied by histopathological cochlear changes including variable amounts of degeneration of the auditory receptors, neurons and the stria vascularis. The causes of degeneration are unknown, although acoustic trauma and exposure to ototoxic agents are certainly contributors to the cellular degeneration. Acquired mitochondrial DNA defects are postulated as important determinants of aging in neuromuscular tissues. The cochlear neurons are highly metabolic and are, therefore, likely to be affected by mitochondrial DNA defects. Sequence analysis has demonstrated a significant number of acquired mutations in the cytochrome oxidase gene in the neurons from aged human cochleas. The current study used immunohistochemical labeling of cytochrome oxidase in the neuronal cell bodies in archival celloidin sections to evaluate relationships among label density, hearing loss, number of neurons and mitochondrial DNA changes within individual cochleas. Label density was less in many aged temporal bones, but not all. There was no relationship among any other variables. It is concluded that while there may be a decrease in the amount of cytochrome oxidase expression in aged spiral ganglion cell bodies, there are many other factors that contribute to hearing loss and cellular degeneration.
Hearing Research 08/2001; 157(1-2):93-9. · 2.70 Impact Factor
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ABSTRACT: The pathogenetic mechanism of the human mitochondrial 12S rRNA gene mutation at position 1555, associated with non-syndromic deafness and aminoglycoside-induced deafness, has been investigated in 33 transformants obtained by transferring mitochondria from lymphoblastoid cell lines into human mitochondrial DNA (mtDNA)-less (rho *206) cells. In this nearly constant nuclear background, 15 transformants derived from five symptomatic individuals from a large Arab-Israeli family, carrying this mutation in homoplasmic form, exhibited significant decreases compared with nine control transformants in the rate of growth in a medium containing galactose instead of glucose, as well as in the rates of mitochondrial protein synthesis and of substrate-dependent respiration. Most significantly, these decreases were very similar to those observed in nine transformants derived from three asymptomatic members of the family. This result in transmitochondrial cybrids is in contrast to the differences in the same parameters previously demonstrated between the original lymphoblastoid cell lines derived from the symptomatic and asymptomatic members of the Arab-Israeli family. In addition, the intragroup variability in biochemical dysfunction among the lymphoblastoid cell lines from different symptomatic or asymptomatic or control individuals was significantly reduced in the derived mitochondrial transformants carrying the same nuclear background. These observations provide strong genetic and biochemical evidence in support of the idea that the nuclear background plays a determinant role in the phenotypic manifestation of the non-syndromic deafness associated with the A1555G mutation.
Human Molecular Genetics 04/2001; 10(6):573-80. · 7.64 Impact Factor
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ABSTRACT: The pathophysiologic pathways and clinical expression of mitochondrial DNA (mtDNA) mutations are not well understood. This is mainly the result of the heteroplasmic nature of most pathogenic mtDNA mutations and of the absence of clinically relevant animal models with mtDNA mutations. mtDNA mutations predisposing to hearing impairment in humans are generally homoplasmic, yet some individuals with these mutations have severe hearing loss, whereas their maternal relatives with the identical mtDNA mutation have normal hearing. Epidemiologic, biochemical and genetic data indicate that nuclear genes are often the main determinants of these differences in phenotype. To identify a mouse model for maternally inherited hearing loss, we screened reciprocal backcrosses of three inbred mouse strains, A/J, NOD/LtJ and SKH2/J, with age-related hearing loss (AHL). In the (A/J x CAST/Ei) x A/J backcross, mtDNA derived from the A/J strain exerted a significant detrimental effect on hearing when compared with mtDNA from the CAST/Ei strain. This effect was not seen in the (NOD/LtJ x CAST/Ei) x NOD/LtJ and (SKH2/J x CAST/Ei) x SKH2/J backcrosses. Genotyping revealed that this effect was seen only in mice homozygous for the A/J allele at the Ahl locus on mouse chromosome 10. Sequencing of the mitochondrial genome in the three inbred strains revealed a single nucleotide insertion in the tRNA-Arg gene (mt-Tr) as the probable mediator of the mitochondrial effect. This is the first mouse model with a naturally occurring mtDNA mutation affecting a clinical phenotype, and it provides an experimental model to dissect the pathophysiologic processes connecting mtDNA mutations to hearing loss.
Nature Genetics 03/2001; 27(2):191-4. · 35.53 Impact Factor
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ABSTRACT: It has been proposed that splice-variants of proteins involved in mitochondrial RNA processing and translation may be involved in the tissue specificity of mitochondrial DNA disease mutations (Fischel-Ghodsian, 1998. Mol. Genet. Metab. 65, 97-104). To identify and characterize the structural components of mitochondrial RNA processing and translation, the Mammalian Mitochondrial Ribosomal Consortium has been formed. The 338 amino acid (aa) residues long MRP-L5 was identified (O'Brien et al., 1999. J. Biol. Chem. 274, 36043-36051), and its transcript was screened for tissue specific splice-variants. Screening of the EST databases revealed a single putative splice-variant, due to the insertion of an exon consisting of 89 nucleotides prior to the last exon. Screening of multiple cDNA libraries revealed this inserted exon to be present only in heart tissue, in addition to the predominant MRP-L5 transcript. Sequencing of this region confirmed the EST sequence, and showed in the splice-variant a termination triplet at the beginning of the last exon. Thus the inserted exon replaces the coding sequence of the regular last exon, and creates a new 353 aa long protein (MRP-L5V1). Sequence analysis and 3D modeling reveal similarity between MRP-L5 and threonyl-t-RNA synthetases, and a likely RNA binding site within MRP-L5, with the C-terminus in proximity to the RNA binding site. Sequence analysis of MRP-L5V1 also suggests a likely transmembrane domain at the C-terminus. Thus it is possible that the MRP-L5V1 C-terminus could interfere with RNA binding and may have gained a transmembrane domain. Further studies will be required to elucidate the functional significance of MRP-L5V1.
Gene 01/2001; 261(2):229-34. · 2.34 Impact Factor
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ABSTRACT: The A1555 G mutation in mitochondrial 12S rRNA has been found to be associated with non-syndromic deafness and aminoglycoside-induced deafness. The sensitivity to the aminoglycoside paromomycin has been analyzed in lymphoblastoid cell lines derived from five deaf individuals and five hearing individuals from an Arab-Israeli family carrying the A1555G mutation, and three married-in controls from the same family. Exposure to a high concentration of paromomycin (2 mg/ml), which caused an 8% average increase in doubling time (DT) in the control cell lines, produced higher average DT increases (49 and 47%) in the A1555G mutation-carrying cell lines derived from symptomatic and asymptomatic individuals, respectively. The ratios of translation rates in the presence and absence of paromomycin, which reflected the effect of the drug on mitochondrial protein synthesis, were significantly decreased in the cell lines derived from symptomatic and asymptomatic individuals (by 30 and 28% on average, respectively), compared with the ratios in the control cell lines. These ratios showed, in both groups of mutant cell lines, a significant negative correlation with the ratios of DTs in the presence and absence of the antibiotic. These results have provided the first direct evidence that the mitochondrial 12S rRNA carrying the A1555G mutation is the main target of aminoglycosides. They suggest that these antibiotics exert their detrimental effect through an alteration of mitochondrial protein synthesis, which exacerbates the inherent defect caused by the mutation, reducing the overall translation rate down to and below the minimal level required for normal cellular function (40-50%).
Human Molecular Genetics 08/2000; 9(12):1787-93. · 7.64 Impact Factor
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ABSTRACT: Mitochondrial ribosomal proteins (MRPs) are required for the translation of all 13 mitochondrial encoded genes in humans. It has been speculated that mutations and polymorphisms in the human MRPs may be a primary cause of some oxidative phosphorylation disorders or modulate the severity and tissue specificity of pathogenic mitochondrial DNA mutations. Although the sequences of most of the yeast MRPs are known, only very few mammalian and nearly no human MRPs have been completely characterized. MRPs differ greatly in sequence, and sometimes biochemical properties, between different species, not allowing easy recognition by sequence homology. Therefore, the Mammalian Mitochondrial Ribosomal Consortium is using a direct approach of purifying individual mammalian (bovine) MRPs, determining their N-terminal and/or internal peptide sequences using different protein sequencing techniques, and using the resulting sequence information for screening expressed sequence tags and genomic data bases to determine human, mouse, and rat homologues of the bovine proteins. Two proteins of the large and three proteins of the small ribosomal subunit have been analyzed in this manner. Three of them represent "new," i.e. formerly unknown mammalian mitochondrial ribosomal protein classes. Only one of these three different MRPs shows significant sequence similarities to known ribosomal proteins. In one case, the corresponding human genomic DNA sequences were found in the data bases, and the exon/intron structure was determined.
Journal of Biological Chemistry 07/2000; 275(24):18153-9. · 4.77 Impact Factor
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ABSTRACT: Maternally inherited deafness associated with the A1555G mutation in the mitochondrial 12S ribosomal RNA (rRNA) gene appears to require additional environmental or genetic changes for phenotypic expression. Aminoglycosides have been identified as one such environmental factor. In one large Arab-Israeli pedigree with congenital hearing loss in some of the family members with the A1555G mutation and with no exposure to aminoglycosides, biochemical evidence has suggested the role of nuclear modifier gene(s), but a genomewide search has indicated the absence of a single major locus having such an effect. Thus it has been concluded that the penetrance of the mitochondrial mutation appears to depend on additive effects of several nuclear genes. We have now investigated 10 multiplex Spanish and Italian families with 35 members with the A1555G mutation and sensorineural deafness. Parametric analysis of a genomewide screen again failed to identify significant evidence for linkage to a single autosomal locus. However, nonparametric analysis supported the role of the chromosomal region around marker D8S277. The combined maximized allele-sharing LOD score of 3.1 in Arab-Israeli/Spanish/Italian families represents a highly suggestive linkage result. We suggest that this region should be considered a candidate for containing the first human nuclear modifier gene for a mitochondrial DNA disorder. The locus operates in Arab-Israeli, Spanish, and Italian families, resulting in the deafness phenotype on a background of the mitochondrial A1555G mutation. No obvious candidate genes are located in this region.
The American Journal of Human Genetics 07/2000; 66(6):1905-10. · 10.60 Impact Factor
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A Mimouni,
N Magal,
N Stoffman,
T Shohat,
A Minasian,
M Krasnov,
G J Halpern,
J I Rotter, N Fischel-Ghodsian,
Y L Danon,
M Shohat
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ABSTRACT: The gene causing familial Mediterranean fever (FMF)-an autosomal recessive disease characterized by recurrent short episodes of fever associated most commonly with peritonitis, pleuritis, and arthritis-has recently been found and several mutations identified. The most severe complication of the disease is amyloidosis, which can lead to renal failure. The aim of this study was to investigate the role of genetic versus nongenetic factors on the phenotype as well as on the development of amyloidosis in FMF in a large and heterogeneous group of patients.
We studied 382 patients from 4 ethnic origins living in different environments: North African Jews, other Jews, Turks, Armenians living in the United States, and Armenians from Yerevan, Armenia. Information regarding amyloidosis was available for 371 patients. We examined the association between the mutation M694V and the development of amyloidosis, and we also compared the clinical characteristics of the inflammatory attacks in patients from different ethnic origins, while controlling for the type of mutation.
A significant association was found between amyloidosis and the most common mutation in exon 10 of the FMF gene (MEFV), M694V (for M694V homozygotes, relative risk = 1.77; 95% CI = 1.16-2.71). Amyloidosis was present in 44 of 171 homozygous FMF patients (25.7%), in 22 of 143 compound heterozygous FMF patients (15.4%), and in 7 of 57 patients carrying other mutations (12.3%). In homozygotes for M694V who had not been treated with colchicine before 20 years of age, the risk of amyloidosis developing before this age was 61.0%. In our series, there were no cases of amyloidosis in 16 patients carrying the common mutation E148Q. We found that the type and severity of the FMF inflammatory symptoms were associated with both the genotype and the country of residence of the patient.
In the light of the high frequency of amyloidosis in homozygotes for the mutation M694V, colchicine treatment should be given to this group irrespective of the severity of the inflammatory attacks to prevent the development of amyloidosis. Our findings also suggest that factors other than genotype, such as environment or genes other than MEFV, play a role in the determination of the severity of the inflammatory attacks in FMF. amyloidosis, specific mutation, phenotype-genotype correlation, ethnicity.
PEDIATRICS 06/2000; 105(5):E70. · 4.47 Impact Factor
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ABSTRACT: The biological function of pyrin, the protein mutated in Familial Mediterranean Fever (FMF), has not been elucidated. Based on sequence homology, a transcription factor activity was proposed for this neutrophil-specific protein. In a yeast two-hybrid assay, neither transcription activation activity nor any self interaction was detected for pyrin. Screening of an expression cDNA library of peripheral blood leukocytes using as bait the carboxyl portion of pyrin (amino acids 557-781), which contains most of the FMF mutations, led to the identification of P/M-IP1 (pyrin/marenostrin interacting protein 1). A splice variant of P/M-IP1, GTC-90, had previously been described as a component of the 13S hetero-oligomeric protein complex that stimulates in vitro Golgi transport. We have now shown that P/M-IP1 colocalizes with pyrin in the perinuclear cytoplasm of Cos-7 cells and that the interaction between these two proteins is impaired by FMF causing mutations in pyrin. These data suggest that, at some stage of its functional pathway, pyrin resides in the cytoplasm and might be involved in, or impacted by, cellular protein sorting by the Golgi apparatus. The data also imply that P/M-IP1 may be involved in the abnormal inflammatory response that occurs in patients with FMF.
Proceedings of The Society for Experimental Biology and Medicine 06/2000; 224(1):32-40.
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ABSTRACT: Familial Mediterranean fever (FMF) is a recessively inherited disorder characterized by recurrent, self-limited attacks of fever and serositis and by infiltration of affected tissues by large numbers of neutrophils. A candidate gene for FMF was identified by positional cloning and named "MEFV." The corresponding protein was named "pyrin." To elucidate the currently unknown function of pyrin, we characterized its tissue distribution, regulation of expression during hematopoietic differentiation, and subcellular localization. Reverse transcription-polymerase chain reaction analysis, followed by hybridization with an internal oligonucleotide, demonstrated expression of MEFV in different populations of peripheral blood cells. Among hematopoietic cell lines, MEFV was almost exclusively expressed in cells of the myeloid lineage. Furthermore, MEFV messenger RNA was strongly expressed within 24 hours of dimethyl sulfoxide-induced granulocytic differentiation of HL-60 cells. Analysis of complementary DNA from human solid tumor-derived cell lines revealed expression of MEFV in several cell lines derived from colon and prostate cancers. Expression of MEFV fused to enhanced green fluorescent protein showed that pyrin localized in distinct patches in the cytoplasm, forming a perinuclear cap. Taken together, MEFV is predominantly expressed in myeloid cells and upregulated during myeloid differentiation, and the corresponding protein, pyrin, is expressed in the cytoplasm. (Blood. 2000;95:1451-1455)
Blood 03/2000; 95(4):1451-5. · 9.90 Impact Factor
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N Fischel-Ghodsian
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ABSTRACT: Ototoxicity is the major irreversible toxicity of aminoglycosides, and occurs both in a dose-dependent and idiosyncratic fashion. The idiosyncratic pathway is presumably due to genetic predispositions, and in 1993 we identified an inherited mutation that predisposes to aminoglycoside ototoxicity, the A1555G mutation in the mitochondrial 12S ribosomal RNA gene. Seventeen-33% of patients with aminoglycoside ototoxicity carry this mutation. In a search for additional susceptibility mutations, a dual strategy of yeast genetics and candidate genes was employed. Through yeast genetics 8 genes that by overexpression prevent aminoglycoside toxicity were identified. The human homologues of these genes may harbor aminoglycoside susceptibility mutations. Another candidate gene is the mitochondrial ribosomal protein S12, which interacts with the ribosomal RNA gene and in bacteria can harbor aminoglycoside resistance mutations. Analysis of this gene in 41 patients with aminoglycoside ototoxicity did not reveal any mutations in the coding regions. However, an Italian family with five maternally related family members who went deaf after aminoglycosides led to the identification of the second susceptibility mutation in the mitochondrial 12S ribosomal RNA gene, delta T961Cn. While these findings have immediate clinical implications for prevention of aminoglycoside-induced ototoxicity, they have not yet led to a clear understanding of the pathophysiology of aminoglycoside toxicity or the development of therapeutic options after the onset of symptoms.
Annals of the New York Academy of Sciences 12/1999; 884:99-109. · 3.15 Impact Factor
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ABSTRACT: Chronic inflammatory bowel disease (IBD) presents as two major clinical forms, Crohn's disease (CD) and ulcerative colitis (UC). Genetic epidemiological studies and animal models suggest that inherited factors play significant roles in the susceptibility to both forms of IBD. From four genome-wide scans, putative susceptibility loci on chromosome 16 (IBD1 for CD), and on chromosomes 1, 3, 4, 6, 7, 10, and 12 for IBD, have been identified. Several other groups, including ours, have confirmed linkage to the loci on chromosomes 12 and 16. The aim of this study is to identify other potential susceptibility loci for CD with a genome-wide search approach. In our sample of 222 individuals from 46 families (20 Jewish and 26 non-Jewish), with a total of 65 sibpairs diagnosed with CD, we observed a novel locus with suggestive linkage [multipoint logarithm of the odds score (Mlod) > 2] at chromosome 14q11.2 (Mlod = 2.8, p = 0.0002). In addition, suggestive linkage was observed in our Jewish families at chromosome 17q21-q23 (Mlod = 2.1, p = 0.01) and chromosome 5q33-q35 (Mlod = 2.2, p = 0.0003). The syntenic regions of the latter locus are mapped within two putative loci on mouse chromosomes 11 and 18, which were identified in a mouse IBD model induced by dextran sulfate sodium (29). Our preliminary results provide potential evidence for several susceptibility loci contributing to the risk of CD. The observation of man-mouse synteny may accelerate the identification of CD susceptibility gene(s) on human chromosome 5.
Inflammatory Bowel Diseases 11/1999; 5(4):271-8. · 4.86 Impact Factor
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R A Friedman,
Y Bykhovskaya,
C M Sue,
S DiMauro,
R Bradley,
R Fallis-Cunningham,
N Paradies,
M L Pensak,
R J Smith,
J Groden,
X C Li, N Fischel-Ghodsian
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ABSTRACT: In this study we characterized clinically and evaluated molecularly a large family with maternally inherited hearing impairment. Relatives were evaluated audiologically and clinically, the most likely pattern of inheritance was deduced, and molecular DNA analysis for the known mitochondrial mutations associated with hearing impairment was performed. Clinical examination of several relatives showed a normal general state of health, but in 14 of the members tested variable degrees of sensorineural hearing loss were noted. The pedigree was established and demonstrated a clear pattern of maternal inheritance, with 34 of 38 offspring of deaf mothers being hearing impaired, but none of 22 offspring of deaf fathers having any hearing impairment. Since by far the most likely explanation of such a maternal inheritance pattern is a mitochondrial mutation, molecular testing for the three known mitochondrial mutations, A1555G, A7445G, and Cins7472, was performed on 27 of the relatives. All of the individuals tested had the normal sequence at the sites tested. This family with nonsyndromic sensorineural hearing loss has an inheritance pattern strongly suggestive of a mitochondrial mutation. However, molecular testing for the three known mitochondrial mutations associated with nonsyndromic hearing impairment was negative, implying that additional molecular defects can lead to the same phenotype. The search for this novel molecular defect is underway.
American Journal of Medical Genetics 07/1999; 84(4):369-72.
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C M Sue,
K Tanji,
G Hadjigeorgiou,
A L Andreu,
I Nishino,
S Krishna,
C Bruno,
M Hirano,
S Shanske,
E Bonilla, N Fischel-Ghodsian,
S DiMauro,
R Friedman
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ABSTRACT: Thirty-six of 43 maternally related members of a large African American family experienced hearing loss. A muscle biopsy specimen from the proband showed cytochrome c oxidase (COX)-deficient fibers but no ragged-red fibers; biochemical analysis showed marked reduction of COX activity. A novel T7511C point mutation in the tRNA(Ser(UCN)) gene was present in almost homoplasmic levels (>95%) in the blood of 18 of 20 family members, and was also found in lower abundance in the other two. Single-fiber PCR showed that the mutational load was greater in COX-deficient muscle fibers. The tRNA(ser(UCN)) gene may be a "hot spot" for mutations associated with maternally transmitted hearing loss.
Neurology 06/1999; 52(9):1905-8. · 8.31 Impact Factor
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M Shohat,
N Magal,
T Shohat,
X Chen,
T Dagan,
A Mimouni,
Y Danon,
R Lotan,
G Ogur,
A Sirin,
M Schlezinger,
G J Halpern,
A Schwabe,
D Kastner,
J I Rotter, N Fischel-Ghodsian
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ABSTRACT: Familial Mediterranean fever (FMF) is an autosomal recessive disease characterised by recurrent attacks of inflammation of serosal membranes. Amyloidosis is the most severe complication of the disease. The aim of this study was to investigate the genotype-phenotype correlation and specifically the association between amyloidosis and the four common mutations in exon 10 of the gene causing FMF (MEFV) in a total of 83 FMF families from three ethnic groups: North African Jews, Armenians and Turks. A significant association was found between amyloidosis and the specific mutation at the MEFV gene: Met694Val (RR = 1.41, P = 0.02). Amyloidosis was present in 18 out of 87 homozygous FMF patients (20.7%) and in only two out of the 41 compound heterozygous FMF patients (4.9%). No patients carrying other mutations had amyloidosis. There was no significant association between the various mutations and the type or severity of the FMF symptoms. This finding underscores the importance of performing molecular studies on all suspect FMF patients. In addition to providing accurate diagnosis, these tests allow identification of presymptomatic genetically affected individuals, detection of carriers and assessment of the risk for amyloidosis in later life.
European Journal of HumanGenetics 05/1999; 7(3):287-92. · 4.40 Impact Factor
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ABSTRACT: There is evidence for genetic susceptibility to Crohn's disease, and a tentative association with tumour necrosis factor (TNF) and HLA class II alleles.
To examine the potential of genetic linkage between Crohn's disease and the MHC region on chromosome 6p.
TNF microsatellite markers and, for some families, additional HLA antigens were typed for 323 individuals from 49 Crohn's disease multiplex families to generate informative haplotypes. Non-parametric linkage analysis methods, including sib pair and affected relative pair methods, were used.
Increased sharing of haplotypes was observed in affected sib pairs: 92% (48/52) shared one or two haplotypes versus an expected 75% if linkage did not exist (p=0.004). After other affected relative pairs were included, the significance level reached 0.001. The mean proportion of haplotype sharing was increased for both concordant affected (pi=0.60, p=0.002) and unaffected sib pairs (pi=0.58, p=0. 031) compared with the expected value (pi=0.5). In contrast, sharing in discordant sib pairs was significantly decreased (pi=0.42, p=0. 007). Linear regression analysis using all three types of sib pairs yielded a slope of -0.38 at p=0.00003. It seemed that the HLA effect was stronger in non-Jewish families than in Jewish families.
All available analytical methods support linkage of Crohn's disease to the MHC region in these Crohn's disease families. This region is estimated to contribute approximately 10-33% of the total genetic risk to Crohn's disease.
Gut 05/1999; 44(4):519-26. · 10.11 Impact Factor
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ABSTRACT: We initiated a clinical and genetic linkage study on members of a large Venezuelan family with hereditary hearing loss. A medical history and a physical examination were performed on 30 family members. Audiometry was carried out in 25 subjects, and in 2 additional children auditory brainstem responses were obtained. Additional testing (site-of-lesion, electronystagmography and computed tomography) was also obtained in a few subjects. DNA was extracted from blood samples from 25 family members. The type of deafness in this family is neurosensorial, non-syndromic and postlingual. The average age of onset of deafness is 7 years and there is a rapid progression leading to profound deafness. Deafness is possibly of cochlear origin and there is no associated vestibular pathology. Analysis of the pedigree discloses a maternal pattern of inheritance with a significant female predominance, compatible with a mutation of the mitochondrial DNA. The molecular DNA analysis for the known mitochondrial mutations are discussed.
Acta Oto-Laryngologica 04/1999; 119(2):158-62. · 1.08 Impact Factor
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ABSTRACT: During our search for the familial Mediterranean fever (FMF) gene, we identified by cDNA selection a 1.2 kb cDNA fragment representing a novel human gene that is expressed in a wide variety of tissues. This gene spans approx. 8.0 kb genomic DNA and has seven exons. Its 3' untranslated region contains a long tandem repeat that gives rise to a polymorphism with two alleles of approx. 1.1 kb and 1.0 kb, with the 1.1 kb allele in strong linkage disequilibrium with FMF in patients of different ethnic backgrounds. However, both genetic and mutational analyses have excluded this gene as the one responsible for FMF. The predicted 424 amino acid protein, designated ZNF213, contains three C2H2 zinc fingers, a Kruppel associated A box and a leucine rich motif (LeR domain/SCAN box), strongly suggestive of a transcription factor.
Biochimica et Biophysica Acta 03/1999; 1444(2):218-30. · 4.66 Impact Factor
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N Fischel-Ghodsian
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ABSTRACT: The first molecular defect for nonsyndromic hearing loss was identified in 1993, and was a mitochondrial mutation. Since then a number of inherited mitochondrial DNA (mtDNA) mutations have been implicated in hearing loss, and acquired mtDNA mutations have been proposed as one of the causes of the hearing loss associated with aging, presbyacusis. These molecular findings have raised as many questions as they have answered, however, since the pathophysiology between the mutations and the clinical phenotype remains poorly understood. This mini-review will, after a short background review of mitochondrial genetics, (1) outline the different mtDNA mutations associated with inherited syndromic, nonsyndromic, and ototoxic hearing loss, (2) summarize the data on acquired mtDNA mutations and their possible association with presbyacusis, (3) describe the biochemical consequences of the inherited mtDNA mutations, (4) suggest the clinical implications of the identification of these mutations, and (5) discuss the penetrance and tissue specificity of the hearing associated mtDNA mutations.
Human Mutation 02/1999; 13(4):261-70. · 5.69 Impact Factor
