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Cloning of the Gene for CMT2L and Mutation Analysis of the SIMPLE, RAB7, LMNA and MTMR2 Genes in Chinese CMT Patients

Author: ZhaoGuoHua
Tutor: TangBeiSha
School: Central South University
Course: Neurology
Keywords: Charcot-Marie-Tooth disease Candidate gene Mutation analysis Heat-shock protein 22 SIMPLE gene RAB7 gene LMNA gene MTMR2 gene
CLC: R746
Type: PhD thesis
Year: 2006
Downloads: 110
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Abstract


PARTI Cloning of the gene for CMT2LCharcot-Marie-Tooth disease (CMT) is the most common inherited motor and sensory neuropathy and is genetically heterogeneous. We previously reported a large Chinese family with CMT linked to chromosome 12q24 (CMT2L), over a 6.8-cM interval between markers D12S1720 and D12S1611. After excluding 11 genes as the cause for CMT2L, another 15 genes in this interval were screened in the CMT2L family by direct sequencing: SIRT4, CABP1, KSR2, ABCB9, RNF34, HM74, MONDOA, MSI1, PLA2G1B, SFRS9, RFC5, EIF2B1, Hsp22, GTF2H and P2RX7. A novel 423G→T (Lys141Asn) missense mutation of Hsp22 in the CMT2L family was identified and co-segregated perfectly with the CMT2 phenotype, but not in 100 normal control individuals. Our studies strongly suggest that the Lys141Asn amid acid change that is caused by the 423G→T mutation in Hsp22 is responsible for CMT2L. We also detected following polymorphisms: 2498A→G in KSR2; IVS8-6A→G, IVS9+52A→C and IVS10-22A→G in RFC5; 227T→C, 463T→C, IVS6-5C→G and 1267G→A in P2RX7, in which IVS9+52A→C in RFC5 and 1267G→A in P2RX7 were not reported previously. No disease-causing mutation in Hsp22 gene was identified in another set of 116 CMT families. The rate of Hsp22 mutation in Chinese CMT patients may be low (0.9%).PARTⅡMutation analysis of the SIMPLE, RAB7, LMNA and MTMR2 genes in Chinese CMT patientsIn order to investigate the mutation characteristics of the SIMPLE, RAB7, LMNA and MTMR2 genes in Chinese patients with Charcot-Marie-Tooth disease, mutation analysis of SIMPLE gene was performed in 6 autosomal dominant families and 27 sporadic patients by using PCR and direct sequencing. Mutation analysis of RAB7 gene was done in 6 autosomal dominant families and 27 sporadic patients and mutation analysis of LMNA and MTMR2 genes was done in 14 autosomal recessive families and 27 sporadic patients by PCR-SSCP and direct sequencing. Each family was tested negative for PMP22 duplication, point mutations of PMP22、MPZ、EGR2, Cx32, NEFL、GDAP1、Hsp22 and Hsp27 genes. Each new variant identified was analyzed in 100 controls to determine whether the variant is a common polymorphism or a rare mutation. Two nucleotide variations 269G→A and 274A→G in the SIMPLE gene were identified in two different sporadic patients and they were proved as polymorphisms and the 269G→A was not reported previously. 1243G→A and 1910 C→T were identified in the LMNA gene and they were proved as polymorphisms and were not reported previously too. No sequence variations were found in the RAB7 and MTMR2 genes. Our study showed that the rates of mutation in SIMPLE, RAB7, LMNA and MTMR2 genes may be rare in Chinese CMT patients.

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