Elsevier

Neuromuscular Disorders

Volume 12, Issue 9, November 2002, Pages 869-873
Neuromuscular Disorders

A novel homozygous missense mutation in the myotubularin-related protein 2 gene associated with recessive Charcot–Marie–Tooth disease with irregularly folded myelin sheaths

https://doi.org/10.1016/S0960-8966(02)00046-9Get rights and content

Abstract

Mutations in the myotubularin-related protein 2 gene on chromosome 11q22 are known to cause autosomal recessive Charcot–Marie–Tooth disease with irregularly folded myelin sheaths. We screened the coding region of the myotubularin-related protein 2 gene in a Turkish consanguineous Charcot–Marie–Tooth disease family compatible with linkage to chromosome 11q22. A homozygous cytosine to thymine missense mutation at nucleotide position 847, resulting in an amino acid substitution of arginine to tryptophan at codon 283, was detected in exon 9 of the MTMR2 gene. This is the second homozygous missense mutation associated with recessive Charcot–Marie–Tooth disease with focally folded myelin sheaths.

Introduction

Charcot–Marie–Tooth disease (CMT), or hereditary motor and sensory neuropathy (HMSN) is the most common form of the inherited peripheral neuropathies. The disease is characterized by distal muscle weakness and atrophy, predominantly involving the legs. CMT is clinically and genetically heterogeneous. Autosomal dominant (AD), autosomal recessive (AR) as well as X-linked forms are described. Molecular genetic analyses have identified 34 genetic loci and 17 genes for inherited peripheral neuropathies, of which 17 loci and 5 genes are for recessive types (http://molgen-www.uia.ac.be/CMTMutations) [1].

The first AR demyelinating CMT locus on chromosome 8q13–q21 was described in 1993 [2] (CMT4A, MIM 214400). Very recently, mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) were found to be associated with CMT4A [3]. In a single Italian inbred CMT1 family, the disease locus was located on 11q22 by homozygosity mapping (CMT4B.1, MIM 601382) [4]. The myotubularin-related protein 2 gene (MTMR2) was shown to be mutated in CMT4B.1 patients [5]. A second locus for AR CMT with myelin outfoldings (CMT4B.2, MIM 604563) was mapped to 11p15 in a Tunisian pedigree [6]. A fourth locus on 5q31–q33 was found in consanguineous Algerian CMT1 families with early onset and severe scoliosis (CMT4 (5q31–q33), MIM 601596) [7]. In Bulgarian Gypsies with recessive HMSN I and deafness, the gene was located on 8q24 (HMSN-Lom, MIM 601455) [8]. A single homozygous nonsense mutation in the N-myc downstream-regulated gene 1 (NDRG1) was found in the HMSN-Lom patients [9]. Recently, two more loci for recessive CMT1 were mapped: HMSN-Russe (MIM 605285) on 10q23.2 in Gypsies [10], and CMT4F (MIM 145900) on 19q13.1–q13.3 in a Lebanese family [11]. CMT4F was subsequently shown to be caused by a mutation in the periaxin gene (PRX) [12]. PRX mutations can also cause AR Dejerine–Sottas syndrome [12], [13].

The first locus for the autosomal recessive axonal form of CMT (CMT2B1, MIM 605588) was mapped on 1q21.2–q21.3 in a consanguineous Moroccan family [14]. A homozygous missense mutation in lamin A/C (LMNA) was recently shown to cause CMT2B1 [15]. A second locus on 19q13.3 for an axonal form of autosomal recessive CMT, designated CMT2B2 (MIM 605589), was identified in an inbred Costa Rican family [16]. Recently mutations in GDAP1 were shown to underlie AR axonal CMT with vocal cord paresis [17]. It is of interest that mutations in this gene also result in a AR demyelinating CMT phenotype (CMT4A). Finally, in a Tunisian inbred family, a third locus for AR-CMT2 was assigned to 8q21.3 [18], overlapping with the CMT4A locus. Mutation screening of GDAP1 in this family has not yet been reported, leaving open the possibility that CMT4A, CMT2 with vocal cord paresis and AR CMT2 linked to 8q21.3 are actually allelic and due to GDAP1 mutations.

Here, we describe a novel missense mutation in MTMR2 causing recessive demyelinating CMT with irregularly folded myelin sheaths (CMT4B.1).

Section snippets

Patients and methods

Family CMT-116 is a consanguineous family of Turkish origin diagnosed with recessive CMT (Fig. 1A). Two siblings, a 10-year-old boy (CMT-116.2) and his 16-year-old sister (CMT-116.3) are affected, while the consanguineous parents, second degree relatives, are unaffected. The age at onset was 2 years. The patients are able to walk unassisted, but with light weight orthoses. Examination of the nerve conduction velocities (NCV) revealed a severe demyelinating neuropathy. Motor median NCV of

Missense mutation

We have previously screened a set of autosomal recessive CMT families with markers of the CMT4A, CMT4B.1 and CMT4 (5q23–q33) regions. In one family, CMT-116, the haplotype of the chromosome 11q22 markers was compatible with linkage to the CMT4B.1 locus [22], harboring the MTMR2 gene. We screened the consanguineous unaffected parents and the two affected siblings of CMT-116 by direct PCR sequencing for the presence of mutations in the MTMR2 gene.

In family CMT-116, sequence analysis of MTMR2 exon

Discussion

Homozygosity mapping of autosomal recessive CMT families revealed a Turkish family, CMT-116, compatible with linkage to the CMT4B.1 locus [22]. Since mutations in MTMR2 were recently identified in CMT4B.1 families [5], we screened the coding region of MTMR2 in CMT-116. A missense mutation in exon 9 (c.847C>T/R283W) was detected in the homozygous state in the two affected siblings, and in the heterozygous state in the unaffected consanguineous parents. The mutation was not detected in 168 normal

Acknowledgements

This work was in part funded by the Fund for Scientific Research (FWO-Flanders), the University of Antwerp (UIA) and the Geneeskundige Stichting Koningin Elisabeth (GSKE), Belgium. E.N. and V.T. are postdoctoral fellows of the FWO. H.T. has been supported by the Association Française contre les Myopathies (AFM, France).

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