Novel mutation in the myelin protein zero gene in a family with intermediate hereditary motor and sensory neuropathy

Abstract

Objectives-To determine the molecular basis for autosomal dominant intermediate hereditary motor and sensory neuropathy (HMSN) in a four generation family. The gene defects in families with intermediate HMSN are not known, but it has been suggested that most have X linked HMSN. Methods-All participating family members were examined clinically. Genomic DNA was obtained from 10 aVected and seven unaVected members. Linkage analysis for the known HMSN loci was first performed. Mutations in the peripheral myelin protein zero gene (PMP0) were sought in two aVected members, using one unaVected member for comparison, by amplification of the six exons of the gene followed by single strand conformation polymorphism (SSCP) analysis, dideoxy fingerprinting (ddF), and sequencing. Subsequently, the mutation was screened for in all aVected and unaVected members in the family using Alu I digestion and in 100 unrelated control subjects using "snap back" SSCP analysis. Sequencing of cDNA from a sural nerve biopsy from an aVected member was also performed. Results-The clinical phenotype was of variable severity, with motor nerve conduction velocities in the intermediate range. Linkage to PMP0 was demonstrated. Analysis of genomic DNA and cDNA for PMP0 identified a novel codon 35 GAC to TAC mutation. The mutation produces an inferred amino acid change of aspartate to tyrosine at codon six of the processed protein (Asp6Tyr) in the extracellular domain and was present in all aVected family members but not in 100 unrelated controls. Conclusions-The present findings further extend the range of phenotypes associated with PMP0 mutations and indicate that families with "intermediate" HMSN need not necessarily be X-linked as previously suggested. (J Neurol Neurosurg Psychiatry 1999;67:174-179)

Autonomic and respiratory dysfunction in Charcot–Marie–Tooth disease due to Thr124Met mutation in the myelin protein zero gene

“…Abnormal or abolished pupillary reflex may be the first sign of CMT disease associated with MPZ mutation, since asymptomatic carriers may present pupillary abnormalities before they reach the age of onset (De Jonghe et al, 1999). Deafness was an additional phenotypic feature in previously reported families (Chapon et al, 1999;Misu et al, 2000;Mastaglia et al, 1999;De Jonghe et al, 1999). Although seldom described in CMT patients, involvement of the cochlear nerve has been reported in different forms of CMT, whether demyelinating or axonal (Pareyson et al, 1995).…”

“…In this respect, the serine palmitoyltransferase long chain base subunit-1 gene was recently associated with an autosomal dominant form of hereditary sensory and autonomic neuropathy (Bejaoui et al, 2001;Dawkins et al, 2001), which does not however, share the electrophysiological features of the affected individuals of our family, who had significantly reduced motor conduction velocities. Indeed, several CMT families carrying an MPZ gene mutation and showing an axonal phenotype with late onset have been described (Marrosu et al, 1998;Chapon et al, 1999;Mastaglia et al, 1999;De Jonghe et al, 1999;Misu et al, 2000). On the basis of this new phenotype, this form of CMT with MPZ gene mutation has been classified in the group of axonal form or CMT2 (Gemignani and Marbini, 2001).…”

“…Three clinical and electrophysiological phenotypes have been associated with MPZ gene mutations: CMT1B, which is characterized by slow MNCV (, 25 m/s) and onset in the first two decades of life, Dejerine -Sottas syndrome with onset in infancy and extremely reduced MNCV (, 10 m/s), and congenital hypomyelination (Warner et al, 1996). However, several axonopathies in CMT disease have been associated with a mutation in the MPZ gene (Marrosu et al, 1998;Chapon et al, 1999;Mastaglia et al, 1999;Misu et al, 2000;Senderek et al, 2000;Young et al, 2001). Recently, a family with a distinct clinical phenotype characterized by marked sensory abnormalities, deafness, pupillary abnormalities and variable slowing of MNCV was reported to carry a new mutation (Thr124Met) in the MPZ gene (De Jonghe et al, 1999).…”

A novel LRSAM1 mutation is associated with autosomal dominant axonal Charcot-Marie-Tooth disease

“…3,4 Intermediate types of CMT are characterized by median MNCVs in the range of 25-45 m/s. 5 Inheritance of CMT can be autosomal dominant (AD) that is the most common, 6 X-linked, 7 or autosomal recessive (AR). 8 This diversity results from a large number of mutations in multiple causative genes that are expressed either by myelinating Schwann cells, axons or both.…”

Μοριακή γενετική μελέτη της κληρονομικής πολυνευροπάθειας Charcot - Marie - Tooth (CMT)

“…Πρόσφατα περιγράφηκε και ο μικτός τύπος ο οποίος είναι ένας συνδυασμός απομυελινωτικού και αξονικού τύπου με ενδιάμεσες ταχύτητες αγωγής νεύρου (Mastaglia et al 1999). …”