Mutational analysis of the MPZ, PMP22 and Cx32 genes in patients of Spanish ancestry with Charcot-Marie-Tooth disease and hereditary neuropathy with liability to pressure palsies

Abstract

Charcot-Marie-Tooth disease (CMT) and hereditary neuropathy with liability to pressure palsies (HNPP) are two inherited peripheral neuropathies. The most prevalent mutations are a reciprocal 1.5-Mb duplication and 1.5-Mb deletion, respectively, at the CMT1A/HNPP locus on chromosome 17p11.2. Point mutations in the coding region of the myelin genes, peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ) or connexin 32 (Cx32) have been reported in CMT patients, including CMT type 1 (CMT1), CMT type 2 (CMT2) and Déjérine-Sottas neuropathy (DS) patients, and only in the coding region of PMP22 in HNPP families lacking a deletion. We have investigated point and small mutations in the MPZ, PMP22 and Cx32 genes in a series of patients of Spanish ancestry: 47 CMT patients without duplications, and 5 HNPP patients without deletions. We found 15 different mutations in 16 CMT patients (34%). Nine different mutations in ten patients were detected in the Cx32 gene, this being the most frequently involved gene in this series, whereas five mutations involved the MPZ gene and only one the PMP22 gene. Six out of nine nucleotide substitutions in the Cx32 gene involved two codons encoding arginine at positions 164 and 183, suggesting that these two codons may constitute two Cx32 regions prone to mutate in the Spanish population. Analysis of HNPP patients revealed a 5' splicing mutation in intron 1 of the PMP22 gene in a family with autosomal dominance, which confirms allelic heterogeneity in HNPP. Ectopic mRNA analysis on leukocytes suggests that this mutation might behave as a null allele.

Mutational analysis ofPMP22, MPZ, GJB1, EGR2 andNEFL in Korean Charcot-Marie-Tooth neuropathy patients

“…In the pedigree analysis, the mutation was well segregated to 4 affected persons. A similar c.449-1G>C mutation was previously described in a CMT1 patient (Bort et al, 1997). The p.Lys236Glu missense mutation was found in an isolated CMT2 patient.…”

“…The mutation frequency in GJB1 (7.1%) in this study was considerably lower than in several European groups, i.e., Spain 21.3% (Bort et al, 1997), Finland 19.0% (Silander et al, 1998), Russia 13.0% (Mersiyanova et al, 2000b), Italy 16.7% (Mostacciuolo et al, 2001) and Germany 11.9% (Huehne et al, 2003), but similar to that of the Japanese 5.6-5.7% (Yoshihara et al, 2000;Numakura et al, 2002). It appears that mutations in GJB1 are less frequent in East Asian CMT patients than in European patients.…”

“…However the frequency is higher than the level of 31.2% in Japanese CMT1 patients (Ikegami et al, 1997). Mersiyanova et al, 2000bHuehne et al, 2003Bort et al, 1997Silander et al, 1998Jordanova et al, 2003Mostacciuolo et al, 2001 Patients with the CMT1A duplication were excluded. b Patients neither CMT1A duplication nor causative mutation in PMP22, MPZ and GJB1.…”

“…This mutation causes the replacement of a basic by an acidic amino acid, and was therefore considered as the causative mutation. The c.600G>A (p.Gly200Gly) variation was not considered as a causative mutation, as it was reported as a polymorphism (Bort et al, 1997).…”

The Role of Gap Junctions in Charcot-Marie-Tooth Disease

“…Moreover, CMT1X mutations have been increasingly associated with clinical CNS phenotypes. Signs of chronic corticospinal tract dysfunction such as spasticity, extensor plantar responses and hyperactive reflexes have been reported in patients with the A39V (Marques et al, 1999), T55I (Panas et al, 1998), M93V (Bell et al, 1996), R164Q (Panas et al, 1998), R183H (Bort et al, 1997), T191 frameshift (Lee et al, 2002), and L143P mutations. Duplication of amino acids 55-61 is associated with progressive cerebellar ataxia, dysarthria, and delayed central somatosensory responses (Kawakami et al, 2002).…”