Two novel missense mutations in the myelin protein zero gene causes Charcot-Marie-Tooth type 2 and Déjérine-Sottas syndrome

Geir J Braathen,Jette C Sand,Michael B Russell

doi:10.1186/1756-0500-3-99

Geir J Braathen, Jette C Sand + Show 1 more

Open Access

https://doi.org/10.1186/1756-0500-3-99

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Abstract

BackgroundThe Charcot-Marie-Tooth (CMT) phenotype caused by mutation in the myelin protein zero (MPZ) gene varies considerably, from early onset and severe forms to late onset and milder forms. The mechanism is not well understood. The myelin protein zero (P0) mediates adhesion in the spiral wraps of the Schwann cell's myelin sheath. The crystalline structure of the extracellular domain of the myelin protein zero (P0ex) is known, while the transmembrane and intracellular structure is unknown.FindingsOne novel missense mutation caused a milder late onset CMT type 2, while the second missense mutation caused a severe early onset phenotype compatible with Déjérine-Sottas syndrome.ConclusionsThe phenotypic variation caused by different missense mutations in the MPZ gene is likely caused by different conformational changes of the MPZ protein which affects the functional tetramers. Severe changes of the MPZ protein cause dysfunctional tetramers and predominantly uncompacted myelin, i.e. the severe phenotypes congenital hypomyelinating neuropathy and Déjérine-Sottas syndrome, while milder changes cause the phenotypes CMT type 1 and 2.

Highlights

The Charcot-Marie-Tooth (CMT) phenotype caused by mutation in the myelin protein zero (MPZ) gene varies considerably, from early onset and severe forms to late onset and milder forms
The phenotypic variation caused by different missense mutations in the MPZ gene is likely caused by different conformational changes of the MPZ protein which affects the functional tetramers
The most frequent autosomal recessive form of CMT is caused by mutation in the glioside-induced differentiation-associated protein-1 (GDAP1) gene, which is located in the mitochondrial outer membrane and expressed in both neurons and Schwann cells [5]

Summary

Introduction

The Charcot-Marie-Tooth (CMT) phenotype caused by mutation in the myelin protein zero (MPZ) gene varies considerably, from early onset and severe forms to late onset and milder forms. Charcot-Marie-Tooth (CMT) disease is characterized by distal muscle wasting and weakness, sensory loss with reduced tendon reflexes and foot deformities [1,2]. It is the most common inherited disorder of the peripheral nervous system with an estimated prevalence of 1 in 2,500 [3]. The most frequent autosomal recessive form of CMT is caused by mutation in the glioside-induced differentiation-associated protein-1 (GDAP1) gene, which is located in the mitochondrial outer membrane and expressed in both neurons and Schwann cells [5]

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