Clinical and molecular analysis of X‐linked Charcot‐Marie‐Tooth disease type 1 in Spanish population

Abstract

From 1995 to 2004, 979 families with hereditary peripheral neuropathy were referred to the Genetic Diagnosis Center. Using single-strand conformation analysis (SSCA), the connexin 32 gene was analysed in all the patients from 498 families with sporadic or dominant inheritance with no male-to-male transmission and absence of the 17p2 duplication or deletion. Affected males had pes cavus, distal leg weakness, muscular distal atrophy, areflexia and distal sensory loss. The 106 families in which SSCA revealed abnormal migration electrophoresis were directly sequenced. We found 34 families (59 patients) with mutations in connexin 32 gene. In electrophysiological studies, 58.8% families presented slow and 14.7% intermediate nerve conduction velocities. Molecular findings revealed that codon 164 (29.4 +/- 15.3%) and the second extracellular (EC2) domain (44.1 +/- 16.6%) were the most frequently affected codon and domain of the connexin 32. Six novel mutations, Leu39fs, Glu47Gly, His153fs, Cys179Tyr, Cys201Phe and Ser211fs, were found in our study.

Gap junction beta 1 (GJB1) gene mutations in Italian patients with X-linked Charcot-Marie-Tooth disease

“…Twenty-two mutations have been identified, including eight novel mutations. The EC2 domain was the most affected, as also shown in a large study that described 34 Spanish families with mutations in the GJB1 gene (31.8 vs. 36.8%) (Casasnovas et al 2006). …”

“…The X-linked form of CMT (CMTX) is the second most frequent form of CMT (Ionasescu et al 1995;Nelis et al 1996;Mersiyanova et al 2000;Mostacciuolo et al 2001;Hattori et al 2003;Casasnovas et al 2006) and is associated with a large number of mutations in the gap junction beta 1 (GJB1) gene on chromosome Xq13 encoding the gap junction protein Connexin 32 (Cx32) (Bergoffen et al 1993;Shy et al 2007). Cx32 is expressed by Schwann cells and oligodendrocytes.…”

Phenotypic spectrum of MFN2 mutations in the Spanish population

“…(C) Oxygen consumption measured in permeabilised cells in the presence of complex I-dependent substrates (5 mM malate and 5 mM pyruvate) or complex II-dependent substrate (10 mM succinate), and rotenone (10 μM) and 1.5 mM ADP. MP, malate and pyruvate; SR, succinate and rotenone; MPS, malate, pyruvate and succinate; patient, patient with Arg468His change reported in this study; Mfn2, respiratory parameters found in previously reported patients with Mfn2 mutations20 24; controls, controls with no mutations in Mfn2; *, statistical significance applied to controls and Mfn2 groups: p<0.05. (D) Ratios of malate-pyruvate-dependent respiration rate to the succinate-rotenone-dependent respiration rate (MP/SR) ratio was calculated as the ratio of the malate–pyruvate-dependent respiration rate to the succinate–rotenone-dependent respiration rate.…”

Six New Gap Junction Beta 1 Gene Mutations and Their Phenotypic Expression in Czech Patients with Charcot-Marie-Tooth Disease

“…There was another amino acid substitution (Val63Ile) described affecting the same codon of GJB1 (Fairweather et al, 1994;Bone et al, 1997;Matsuyama et al, 2001;Takashima et al, 2003;Casasnovas et al, 2006). Both extracellular domains of the GJB1 gene have the role of connexon-connexon interactions, and therefore the pathology of this mutation can be in the malfunction of these interactions.…”

“…The X-linked CMT (CMTX1) is the second most frequent form of CMT (Ionasescu, 1995;Nelis et al, 1996;Casasnovas et al, 2006) with mutations in the gap junction beta 1 (GJB1) gene coding for connexin 32. Nerve conduction velocities in most of the affected males with GJB1 mutations are intermediate and range between 25 and 40 m=s in upper limb motor nerves (Nicholson and Nash, 1993).…”