Screening for mutations in the peripheral myelin genes PMP22, MPZ and Cx32 (GJB1) in Russian Charcot-Marie-Tooth neuropathy patients

Abstract

Charcot-Marie-Tooth disease (CMT) and related inherited peripheral neuropathies, including Dejerine-Sottas syndrome, congenital hypomyelination, and hereditary neuropathy with liability to pressure palsies (HNPP), are caused by mutations in three myelin genes: PMP22, MPZ and Cx32 (GJB1). The most common mutations are the 1.5 Mb CMT1A tandem duplication on chromosome 17p11.2-p12 in CMT1 patients and the reciprocal 1.5 Mb deletion in HNPP patients. We performed a mutation screening in 174 unrelated CMT patients and three HNPP families of Russian origin. The unrelated CMT patients included 108 clinically and electrophysiologically diagnosed CMT1 cases, 32 CMT2 cases, and 34 cases with unspecified CMT. Fifty-nine CMT1A duplications were found, of which 58 belonged to the CMT1 patient group. We found twelve distinct mutations in Cx32, six mutations in MPZ, and two mutations in PMP22. Of these respectively, eight, five, and two lead to a CMT1 phenotype. Eight mutations (Cx32: Ile20Asn/Gly21Ser, Met34Lys, Leu90Val, and Phe193Leu; MPZ: Asp134Gly, Lys138Asn, and Thr139Asn; PMP22: ValSer25-26del) were not reported previously. Phenotype-genotype correlations were based on nerve conduction velocity studies and mutation type.

X‐linked dominant Charcot‐Marie‐Tooth disease with connexin 32 (Cx32) mutations in Koreans

“…It is important to take this into account because Cx32 is the second most frequently affected gene. The frequency of Korean CMTX patients with a Cx32 mutation (5.3%) was lower than that reported in Europeans (13.0-21.3%) (8,9,19,20) but similar to that found in the Japanese (5.6-5.7%) (10,21) and Chinese (10.8%) (11). Therefore, it appears that Cx32 mutations are less frequent in Asian CMT patients than in European CMT patients.…”

“…Although more than 300 different mutations in Cx32 have been reported as the underlying cause of CMTX1 in the Inherited Peripheral Neuropathies Mutation Database (http://www.molgen.ua.ac. be/CMTMutations/Mutations/) and recent reports, Cx32 mutation analysis of CMTX patients has been performed mainly in various Western populations (4,8,9) and few studies have been performed in Asians (10,11). Despite the remarkable advancements in molecular analysis methods, there is only one study on Cx32 mutations in Korean CMTX patients (12).…”

Median nerve motor conduction velocity is concordant with myelin protein zero gene mutation

“…In the literature, seven reports were found of Arg98His mutation [13][14][15][16][17][18][19], six were of Arg98Cys [8,14,15,[20][21][22], two of Ser63Phe [23,24], one of Thr65Ile [25], and one of Ser233fs [26]. Eleven reports provided electrophysiological information.…”

An Algorithm for Genetic Testing of Serbian Patients with Demyelinating Charcot-Marie-Tooth

“…17p11.2 duplication/deletion screening was performed by polymerase chain reaction (PCR)/EcoRI restriction digestion (Stronach et al, 1999) and by microsatellite analysis using six polymorphic markers located in the involved region (Mersiyanova et al, 2000). The coding regions, exon-adjacent sequences, and some promoters of GJB1, MPZ, PMP22, EGR2, and LITAF/SIMPLE were amplified using PCR, and then sequenced.…”

“…To date, about 30 genes and 50 loci have been associated with CMT (Inherited Peripheral Neuropathies Mutation Database -IPNMD, 2011). Among them, mutations in the PMP22, MPZ, and GJB1 genes are responsible for the vast majority of patients with CMT, while mutations in other genes are often present in rare, even individual cases (Mersiyanova et al, 2000;Mostacciuolo et al, 2001;Numakura et al, 2002;Keckarevic Markovic et al, 2009).…”