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Minxin Guan - One of the best experts on this subject based on the ideXlab platform.
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human trmu encoding the mitochondrial 5 methylaminomethyl 2 thiouridylate methyltransferase is a putative nuclear Modifier Gene for the phenotypic expression of the deafness associated 12s rrna mutations
Biochemical and Biophysical Research Communications, 2006Co-Authors: Qingfeng Yan, Yelena Bykhovskaya, Xavier Estivill, Mordechai Shohat, Minxin Guan, Emebet Mengesha, Nathan FischelghodsianAbstract:Nuclear Modifier Genes have been proposed to modulate the phenotypic manifestation of human mitochondrial 12S rRNA A1491G mutation associated with deafness in many families world-wide. Here we identified and characterized the putative nuclear Modifier Gene TRMU encoding a highly conserved mitochondrial protein related to tRNA modification. A 1937 bp TRMU cDNA has been isolated and the genomic organization of TRMU has been elucidated. The human TRMU Gene containing 11 exons encodes a 421 residue protein with a strong homology to the TRMU-like proteins of bacteria and other homologs. TRMU is ubiquitously expressed in various tissues, but abundantly in tissues with high metabolic rates including heart, liver, kidney, and brain. Immunofluorescence analysis of human 143B cells expressing TRMU-GFP fusion protein demonstrated that the human Trmu localizes and functions in mitochondrion. Furthermore, we show that in families with the deafness-associated 12S rRNA A1491G mutation there is highly suggestive linkage and linkage disequilibrium between microsatellite markers adjacent to TRMU and the presence of deafness. These observations suggest that human TRMU may modulate the phenotypic manifestation of the deafness-associated mitochondrial 12S rRNA mutations.
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isolation and characterization of the putative nuclear Modifier Gene mto1 involved in the pathoGenesis of deafness associated mitochondrial 12 s rrna a1555g mutation
Journal of Biological Chemistry, 2002Co-Authors: Xinhua Lin, Minxin GuanAbstract:Abstract The human mitochondrial 12 S rRNA A1555G mutation has been found to be associated with aminoglycoside-induced and non-syndromic deafness. However, putative nuclear Modifier Gene(s) have been proposed to regulate the phenotypic expression of this mutation. In yeast, the mutant alleles of MTO1, encoding a mitochondrial protein, manifest respiratory-deficient phenotype only when coupled with the mitochondrial 15 S rRNA PR 454 mutation corresponding to human A1555G mutation. This suggests that the MTO1-like Modifier Gene may influence the phenotypic expression of human A1555G mutation. Here we report the identification of full-length cDNA and elucidation of genomic organization of the human MTO1 homolog. Human Mto1 is an evolutionarily conserved protein that implicates a role in the mitochondrial tRNA modification. Functional conservation of this protein is supported by the observation that isolated humanMTO1 cDNA can complement the respiratory deficient phenotype of yeast mto1 cells carrying PR 454 mutation. MTO1 is ubiquitously expressed in various tissues, but with a markedly elevated expression in tissues of high metabolic rates including cochlea. These observations suggest that human MTO1 is a structural and functional homolog of yeast MTO1. Thus, it may play an important role in the pathoGenesis of deafness-associated A1555G mutation in 12 S rRNA Gene or mutations in tRNA Genes.
Michael Sendtner - One of the best experts on this subject based on the ideXlab platform.
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early onset of severe familial amyotrophic lateral sclerosis with a sod 1 mutation potential impact of cntf as a candidate Modifier Gene
American Journal of Human Genetics, 2002Co-Authors: Ralf Giess, Bettina Holtmann, Massimiliano Braga, Tiemo Grimm, Klaus V. Toyka, Bertram Mullermyhsok, Michael SendtnerAbstract:Mutations in the copper/zinc superoxide dismutase 1 (SOD-1) Gene are found in ∼20% of patients with familial amyotrophic lateral sclerosis (FALS), or amyotrophic lateral sclerosis 1. Here we describe a 25-year-old male patient who died from FALS after a rapid disease course of 11 mo. Sequencing of the SOD-1 Gene revealed a heterozygous T→G exchange at position 1513 within exon 5, coding for a V→G substitution at position 148 of the mature protein. Genetic analysis of this family revealed the same mutation in both his healthy 35-year-old sister and his mother, who did not develop the disease before age 54 years. Screening for candidate Modifier Genes that might be responsible for the early onset and severe course of the disease in the 25-year-old patient revealed an additional homozygous mutation of the CNTF Gene not found in his yet unaffected sister. hSOD-1G93A mice were crossbred with CNTF−/− mice and were investigated with respect to disease onset and duration, to test the hypothesis that CNTF acts as a candidate Modifier Gene in FALS with mutations in the SOD-1 Gene. Such hSOD-1G93A/CNTF-deficient mice develop motoneuron disease at a significantly earlier stage than hSOD-1G93A/CNTF-wild-type mice. Linkage analysis revealed that the SOD-1 Gene was solely responsible for the disease. However, disease onset as a quantitative trait was regulated by the allelic constitution at the CNTF locus. In addition, patients with sporadic amyotrophic lateral sclerosis who had a homozygous CNTF Gene defect showed significantly earlier disease onset but did not show a significant difference in disease duration. Thus, we conclude that CNTF acts as a Modifier Gene that leads to early onset of disease in patients with FALS who have SOD-1 mutations, in patients with sporadic amyotrophic lateral sclerosis, and in the hSOD-1G93A mouse model.
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Early Onset of Severe Familial Amyotrophic Lateral Sclerosis with a SOD-1 Mutation: Potential Impact of CNTF as a Candidate Modifier Gene
American journal of human genetics, 2002Co-Authors: Ralf Giess, Bettina Holtmann, Massimiliano Braga, Tiemo Grimm, Bertram Müller-myhsok, Klaus V. Toyka, Michael SendtnerAbstract:Mutations in the copper/zinc superoxide dismutase 1 (SOD-1) Gene are found in approximately 20% of patients with familial amyotrophic lateral sclerosis (FALS), or amyotrophic lateral sclerosis 1. Here we describe a 25-year-old male patient who died from FALS after a rapid disease course of 11 mo. Sequencing of the SOD-1 Gene revealed a heterozygous T-->G exchange at position 1513 within exon 5, coding for a V-->G substitution at position 148 of the mature protein. Genetic analysis of this family revealed the same mutation in both his healthy 35-year-old sister and his mother, who did not develop the disease before age 54 years. Screening for candidate Modifier Genes that might be responsible for the early onset and severe course of the disease in the 25-year-old patient revealed an additional homozygous mutation of the CNTF Gene not found in his yet unaffected sister. hSOD-1G93A mice were crossbred with CNTF(-/-) mice and were investigated with respect to disease onset and duration, to test the hypothesis that CNTF acts as a candidate Modifier Gene in FALS with mutations in the SOD-1 Gene. Such hSOD-1G93A/CNTF-deficient mice develop motoneuron disease at a significantly earlier stage than hSOD-1G93A/CNTF-wild-type mice. Linkage analysis revealed that the SOD-1 Gene was solely responsible for the disease. However, disease onset as a quantitative trait was regulated by the allelic constitution at the CNTF locus. In addition, patients with sporadic amyotrophic lateral sclerosis who had a homozygous CNTF Gene defect showed significantly earlier disease onset but did not show a significant difference in disease duration. Thus, we conclude that CNTF acts as a Modifier Gene that leads to early onset of disease in patients with FALS who have SOD-1 mutations, in patients with sporadic amyotrophic lateral sclerosis, and in the hSOD-1G93A mouse model.
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Potential role of LIF as a Modifier Gene in the pathoGenesis of amyotrophic lateral sclerosis.
Neurology, 2000Co-Authors: Ralf Giess, Marcus Beck, R. Goetz, Robert Nitsch, Kv Toyka, Michael SendtnerAbstract:Leukemia inhibitory factor (lif) is a potent survival factor for motoneurons in cell culture and in vivo. The authors screened 104 patients with ALS and 338 control subjects for mutations in the LIF Gene. In four ALS patients, but in no control subject, a G-to-A point mutation at position 3400 was identified, which leads to an amino acid exchange of valine to methionine at position 64 of the mature lif protein. This region of the lif protein (AB loop) interacts with the lif receptor. The authors suggest that LIF could act as a Modifier Gene which, in combination with other Genetic predispositions, might lead to motoneuron disease.
Ralf Giess - One of the best experts on this subject based on the ideXlab platform.
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early onset of severe familial amyotrophic lateral sclerosis with a sod 1 mutation potential impact of cntf as a candidate Modifier Gene
American Journal of Human Genetics, 2002Co-Authors: Ralf Giess, Bettina Holtmann, Massimiliano Braga, Tiemo Grimm, Klaus V. Toyka, Bertram Mullermyhsok, Michael SendtnerAbstract:Mutations in the copper/zinc superoxide dismutase 1 (SOD-1) Gene are found in ∼20% of patients with familial amyotrophic lateral sclerosis (FALS), or amyotrophic lateral sclerosis 1. Here we describe a 25-year-old male patient who died from FALS after a rapid disease course of 11 mo. Sequencing of the SOD-1 Gene revealed a heterozygous T→G exchange at position 1513 within exon 5, coding for a V→G substitution at position 148 of the mature protein. Genetic analysis of this family revealed the same mutation in both his healthy 35-year-old sister and his mother, who did not develop the disease before age 54 years. Screening for candidate Modifier Genes that might be responsible for the early onset and severe course of the disease in the 25-year-old patient revealed an additional homozygous mutation of the CNTF Gene not found in his yet unaffected sister. hSOD-1G93A mice were crossbred with CNTF−/− mice and were investigated with respect to disease onset and duration, to test the hypothesis that CNTF acts as a candidate Modifier Gene in FALS with mutations in the SOD-1 Gene. Such hSOD-1G93A/CNTF-deficient mice develop motoneuron disease at a significantly earlier stage than hSOD-1G93A/CNTF-wild-type mice. Linkage analysis revealed that the SOD-1 Gene was solely responsible for the disease. However, disease onset as a quantitative trait was regulated by the allelic constitution at the CNTF locus. In addition, patients with sporadic amyotrophic lateral sclerosis who had a homozygous CNTF Gene defect showed significantly earlier disease onset but did not show a significant difference in disease duration. Thus, we conclude that CNTF acts as a Modifier Gene that leads to early onset of disease in patients with FALS who have SOD-1 mutations, in patients with sporadic amyotrophic lateral sclerosis, and in the hSOD-1G93A mouse model.
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Early Onset of Severe Familial Amyotrophic Lateral Sclerosis with a SOD-1 Mutation: Potential Impact of CNTF as a Candidate Modifier Gene
American journal of human genetics, 2002Co-Authors: Ralf Giess, Bettina Holtmann, Massimiliano Braga, Tiemo Grimm, Bertram Müller-myhsok, Klaus V. Toyka, Michael SendtnerAbstract:Mutations in the copper/zinc superoxide dismutase 1 (SOD-1) Gene are found in approximately 20% of patients with familial amyotrophic lateral sclerosis (FALS), or amyotrophic lateral sclerosis 1. Here we describe a 25-year-old male patient who died from FALS after a rapid disease course of 11 mo. Sequencing of the SOD-1 Gene revealed a heterozygous T-->G exchange at position 1513 within exon 5, coding for a V-->G substitution at position 148 of the mature protein. Genetic analysis of this family revealed the same mutation in both his healthy 35-year-old sister and his mother, who did not develop the disease before age 54 years. Screening for candidate Modifier Genes that might be responsible for the early onset and severe course of the disease in the 25-year-old patient revealed an additional homozygous mutation of the CNTF Gene not found in his yet unaffected sister. hSOD-1G93A mice were crossbred with CNTF(-/-) mice and were investigated with respect to disease onset and duration, to test the hypothesis that CNTF acts as a candidate Modifier Gene in FALS with mutations in the SOD-1 Gene. Such hSOD-1G93A/CNTF-deficient mice develop motoneuron disease at a significantly earlier stage than hSOD-1G93A/CNTF-wild-type mice. Linkage analysis revealed that the SOD-1 Gene was solely responsible for the disease. However, disease onset as a quantitative trait was regulated by the allelic constitution at the CNTF locus. In addition, patients with sporadic amyotrophic lateral sclerosis who had a homozygous CNTF Gene defect showed significantly earlier disease onset but did not show a significant difference in disease duration. Thus, we conclude that CNTF acts as a Modifier Gene that leads to early onset of disease in patients with FALS who have SOD-1 mutations, in patients with sporadic amyotrophic lateral sclerosis, and in the hSOD-1G93A mouse model.
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Potential role of LIF as a Modifier Gene in the pathoGenesis of amyotrophic lateral sclerosis.
Neurology, 2000Co-Authors: Ralf Giess, Marcus Beck, R. Goetz, Robert Nitsch, Kv Toyka, Michael SendtnerAbstract:Leukemia inhibitory factor (lif) is a potent survival factor for motoneurons in cell culture and in vivo. The authors screened 104 patients with ALS and 338 control subjects for mutations in the LIF Gene. In four ALS patients, but in no control subject, a G-to-A point mutation at position 3400 was identified, which leads to an amino acid exchange of valine to methionine at position 64 of the mature lif protein. This region of the lif protein (AB loop) interacts with the lif receptor. The authors suggest that LIF could act as a Modifier Gene which, in combination with other Genetic predispositions, might lead to motoneuron disease.
Melanie Lafleur - One of the best experts on this subject based on the ideXlab platform.
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X chromosome transmission ratio distortion in Cftr +/- intercross-derived mice.
BMC Genetics, 2007Co-Authors: Christina K. Haston, Daryl G. Humes, Melanie LafleurAbstract:Background Cystic fibrosis (CF) mice, created with a Genetically engineered mutation in the Cystic fibrosis transmembrane conductance regulator (Cftr) Gene, may develop intestinal plugs which limit their survival past weaning. In a studied population of Genetically mixed CF mice differences in allelic ratios at particular loci, between surviving CF mice and mice with the lethal intestinal defect, were used to map cystic fibrosis Modifier Gene one, Cfm1. Using this approach, we previously identified an X chromosome locus which may influence the survival to weaning of C57BL/6J × BALB/cJ F2 CF mice. We also detected two regions of transmission ratio distortion, independent of Cftr genotype, in a limited dataset. To investigate these findings, in this study we have genotyped 1208 three-week old F2 mice, and 186 day E15.5 embryos, derived from a congenic (C57BL/6J × BALB/cJ) F1 Cftr +/- intercross, for the putative distortion regions.
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x chromosome transmission ratio distortion in cftr intercross derived mice
BMC Genetics, 2007Co-Authors: Christina K. Haston, Daryl G. Humes, Melanie LafleurAbstract:Background Cystic fibrosis (CF) mice, created with a Genetically engineered mutation in the Cystic fibrosis transmembrane conductance regulator (Cftr) Gene, may develop intestinal plugs which limit their survival past weaning. In a studied population of Genetically mixed CF mice differences in allelic ratios at particular loci, between surviving CF mice and mice with the lethal intestinal defect, were used to map cystic fibrosis Modifier Gene one, Cfm1. Using this approach, we previously identified an X chromosome locus which may influence the survival to weaning of C57BL/6J × BALB/cJ F2 CF mice. We also detected two regions of transmission ratio distortion, independent of Cftr genotype, in a limited dataset. To investigate these findings, in this study we have genotyped 1208 three-week old F2 mice, and 186 day E15.5 embryos, derived from a congenic (C57BL/6J × BALB/cJ) F1 Cftr +/- intercross, for the putative distortion regions.
Joachim Füllekrug - One of the best experts on this subject based on the ideXlab platform.
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Genetic analysis of BIRC4/XIAP as a putative Modifier Gene of Wilson disease.
Journal of inherited metabolic disease, 2010Co-Authors: Karl Heinz Weiss, Heiko Runz, Barbara Noe, Daniel Nils Gotthardt, Uta Merle, Peter Ferenci, Wolfgang Stremmel, Joachim FüllekrugAbstract:Wilson disease (WD) is an autosomal-recessive copper overload disorder caused by mutations in the copper-transporting adenosine triphosphatase (ATPase) ATP7B. It presents with a highly variable clinical phenotype ranging from asymptomatic to fulminant hepatic failure or progressive neurological involvement. No clear genotype-phenotype correlation has been established. Thus, variants in Modifier Genes could have an impact on WD manifestation and severity. Recently, the antiapoptotic protein baculoviral IAP repeat-containing protein 4 BIRC4/XIAP has been suggested as a regulator of copper-induced cell death. With the aim of investigating a putative role of BIRC4/XIAP as Modifier Gene in individuals with copper overload, we analyzed a WD patient cohort (n = 98) for sequence variants at the BIRC4/XIAP locus. When compared with clinical data, the previously described coding single nucleotide polymorphisms (SNPs) at the BRIC4/XIAP locus (rs28382721, rs28382722, rs28382723, rs5956583, rs28382740, rs12838858, rs28382741) did not correlate with age of onset or clinical presentation in our collective. However, three previously unreported variants in the BIRC4/XIAP Gene were identified (c.1-26 T > G; c.1408A > T; p.T470S; c.1019A > G; p.N340S). The two patients with variants leading to amino acid exchanges in the BIRC4/XIAP protein showed a remarkably early disease onset at the age of 5 years. Furthermore, one of these patients was only heterozygous for disease-causing mutations in the ATP7B Gene. In summary, these data emphasize the need to further elucidate a role of BIRC4/XIAP variants as putative pathoGenetic factors in copper overload disorders.
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Genetic analysis of birc4 xiap as a putative Modifier Gene of wilson disease
Journal of Inherited Metabolic Disease, 2010Co-Authors: Karl Heinz Weiss, Heiko Runz, Barbara Noe, Daniel Nils Gotthardt, Uta Merle, Peter Ferenci, Wolfgang Stremmel, Joachim FüllekrugAbstract:Wilson disease (WD) is an autosomal-recessive copper overload disorder caused by mutations in the copper-transporting adenosine triphosphatase (ATPase) ATP7B. It presents with a highly variable clinical phenotype ranging from asymptomatic to fulminant hepatic failure or progressive neurological involvement. No clear genotype–phenotype correlation has been established. Thus, variants in Modifier Genes could have an impact on WD manifestation and severity. Recently, the antiapoptotic protein baculoviral IAP repeat-containing protein 4 BIRC4/XIAP has been suggested as a regulator of copper-induced cell death. With the aim of investigating a putative role of BIRC4/XIAP as Modifier Gene in individuals with copper overload, we analyzed a WD patient cohort (n = 98) for sequence variants at the BIRC4/XIAP locus. When compared with clinical data, the previously described coding single nucleotide polymorphisms (SNPs) at the BRIC4/XIAP locus (rs28382721, rs28382722, rs28382723, rs5956583, rs28382740, rs12838858, rs28382741) did not correlate with age of onset or clinical presentation in our collective. However, three previously unreported variants in the BIRC4/XIAP Gene were identified (c.1-26 T > G; c.1408A > T; p.T470S; c.1019A > G; p.N340S). The two patients with variants leading to amino acid exchanges in the BIRC4/XIAP protein showed a remarkably early disease onset at the age of 5 years. Furthermore, one of these patients was only heterozygous for disease-causing mutations in the ATP7B Gene. In summary, these data emphasize the need to further elucidate a role of BIRC4/XIAP variants as putative pathoGenetic factors in copper overload disorders.