Background & Aims: The role of the mismatch repair gene PMS2 in hereditary nonpolyposis colorectal carcinoma (HNPCC) is not fully clarified. To date, only 7 different heterozygous truncating PMS2 mutations have be...Background & Aims: The role of the mismatch repair gene PMS2 in hereditary nonpolyposis colorectal carcinoma (HNPCC) is not fully clarified. To date, only 7 different heterozygous truncating PMS2 mutations have been reported in HNPCC-suspected families. Our aim was to further assess the role of PMS2 in HNPCC. Methods: We performed Southern blot analysis in 112 patients from MLH1- , MSH2- , and MSH6- negative HNPCC-like families. A subgroup (n = 38) of these patients was analyzed by denaturing gradient gel electrophoresis (DGGE). In a second study group consisting of 775 index patients with familial colorectal cancer,we performed immunohistochemistry using antibodies against MLH1,MSH2, MSH6, and PMS2 proteins. In 8 of 775 tumors, only loss of PMS2 expression was found. In these cases, we performed Southern blot analysis and DGGE. Segregation analysis was performed in the families with a (possibly) deleterious mutation. Results: Seven novel mutations were identified: 4 genomic rearrangements and 3 truncating point mutations. Three of these 7 families fulfill the Amsterdam II criteria. The pattern of inheritance is autosomal dominant with a milder phenotype compared with families with pathogenic MLH1 or MSH2 mutations. Microsatellite instability and immunohistochemical analysis performed in HNPCC-related tumors from proven carriers showed a microsatellite instability high phenotype and loss of PMS2 protein expression in all tumors. Conclusions: We show that heterozygous truncatingmutations in PMS2 do play a role in a small subset of HNPCC-like families. PMS2 mutation analysis is indicated in patients diagnosed with a colorectal tumor with Absent staining for the PMS2 protein.展开更多
Hailey-Hailey disease(HHD;MIM 16960)is a rare autosomal dominant hereditary disorder characterized by recurrent eruption of vesicles and bullae,predominantly involving the body folds.It is caused by heterozygous mutat...Hailey-Hailey disease(HHD;MIM 16960)is a rare autosomal dominant hereditary disorder characterized by recurrent eruption of vesicles and bullae,predominantly involving the body folds.It is caused by heterozygous mutations in the ATP2C1 gene,encoding the human secretory pathway Ca2+/Mn-ATPase protein 1(hSPCA1).When we studied Chinese patients with HHD,we found two different heterozygous mutations,Q506X and G353V,the former previously reported ina Hungarian patient,and the latter being a novel mutation.In a 38-year-old patient from a four-generation pedigree with a3-year history of severe recurrent blisters,we identified a C →T transition at nucleotide 1696,c(1696C →T),in exon 17 of ATP2C1,resulting in a nonsenes mutation,Gln506X,which resultedin a premature termination codon.In the second patient,who represented a occurrence of sporadic Hailey-Hailey disease,a G →T transversion of nucleotide,c(G1238T),in exon13 of ATP2C1 was detected,which resulted in a Gly353 →Val amino acid substitution(G353V).Our molecular findings further demonstrate that the mutational events in the human ATP2C1 gene encoding the hSPCA1 pump play an important role in the pathogenesis of HHD.展开更多
Benign familial chronic pemphigus (Hailey-Hailey disease,HHD) is a rare hereditary condition characterized by development of blisters at sites of friction and in the intertriginous areas. Mutations in the ATP2C1 gene,...Benign familial chronic pemphigus (Hailey-Hailey disease,HHD) is a rare hereditary condition characterized by development of blisters at sites of friction and in the intertriginous areas. Mutations in the ATP2C1 gene, which encodes the human secretory pathway calcium ATPase 1 (hSPCA1), have been identified as possible causative mutations. Studying Hungarian patients with HHD, we found two novel, distinct, heterozygous mutations. In a 65-year-old man with a 41-year history of severe recurrent symptoms, a single nucleotide insertion,1085insA, was detected. In a patient whose symptoms were induced by environmental contact allergens, we found a nonsense mutation, Q506X, in exon 17. Our study further illustrates the diversity of mutational events in the pathogenesis of HHD.展开更多
文摘Background & Aims: The role of the mismatch repair gene PMS2 in hereditary nonpolyposis colorectal carcinoma (HNPCC) is not fully clarified. To date, only 7 different heterozygous truncating PMS2 mutations have been reported in HNPCC-suspected families. Our aim was to further assess the role of PMS2 in HNPCC. Methods: We performed Southern blot analysis in 112 patients from MLH1- , MSH2- , and MSH6- negative HNPCC-like families. A subgroup (n = 38) of these patients was analyzed by denaturing gradient gel electrophoresis (DGGE). In a second study group consisting of 775 index patients with familial colorectal cancer,we performed immunohistochemistry using antibodies against MLH1,MSH2, MSH6, and PMS2 proteins. In 8 of 775 tumors, only loss of PMS2 expression was found. In these cases, we performed Southern blot analysis and DGGE. Segregation analysis was performed in the families with a (possibly) deleterious mutation. Results: Seven novel mutations were identified: 4 genomic rearrangements and 3 truncating point mutations. Three of these 7 families fulfill the Amsterdam II criteria. The pattern of inheritance is autosomal dominant with a milder phenotype compared with families with pathogenic MLH1 or MSH2 mutations. Microsatellite instability and immunohistochemical analysis performed in HNPCC-related tumors from proven carriers showed a microsatellite instability high phenotype and loss of PMS2 protein expression in all tumors. Conclusions: We show that heterozygous truncatingmutations in PMS2 do play a role in a small subset of HNPCC-like families. PMS2 mutation analysis is indicated in patients diagnosed with a colorectal tumor with Absent staining for the PMS2 protein.
文摘Hailey-Hailey disease(HHD;MIM 16960)is a rare autosomal dominant hereditary disorder characterized by recurrent eruption of vesicles and bullae,predominantly involving the body folds.It is caused by heterozygous mutations in the ATP2C1 gene,encoding the human secretory pathway Ca2+/Mn-ATPase protein 1(hSPCA1).When we studied Chinese patients with HHD,we found two different heterozygous mutations,Q506X and G353V,the former previously reported ina Hungarian patient,and the latter being a novel mutation.In a 38-year-old patient from a four-generation pedigree with a3-year history of severe recurrent blisters,we identified a C →T transition at nucleotide 1696,c(1696C →T),in exon 17 of ATP2C1,resulting in a nonsenes mutation,Gln506X,which resultedin a premature termination codon.In the second patient,who represented a occurrence of sporadic Hailey-Hailey disease,a G →T transversion of nucleotide,c(G1238T),in exon13 of ATP2C1 was detected,which resulted in a Gly353 →Val amino acid substitution(G353V).Our molecular findings further demonstrate that the mutational events in the human ATP2C1 gene encoding the hSPCA1 pump play an important role in the pathogenesis of HHD.
文摘Benign familial chronic pemphigus (Hailey-Hailey disease,HHD) is a rare hereditary condition characterized by development of blisters at sites of friction and in the intertriginous areas. Mutations in the ATP2C1 gene, which encodes the human secretory pathway calcium ATPase 1 (hSPCA1), have been identified as possible causative mutations. Studying Hungarian patients with HHD, we found two novel, distinct, heterozygous mutations. In a 65-year-old man with a 41-year history of severe recurrent symptoms, a single nucleotide insertion,1085insA, was detected. In a patient whose symptoms were induced by environmental contact allergens, we found a nonsense mutation, Q506X, in exon 17. Our study further illustrates the diversity of mutational events in the pathogenesis of HHD.
