Myelin Protein Zero Mutations In Inherited Neuropathies: The Recurrent Thr124Met IS Associated With A Distinct Phenotype
Mutations in the myelin protein zero gene (MPZ) were found associated with different forms of inherited peripheral neuropathies, both demyelinating (Charcot-Marie-Tooth type 1, congenital hypomyelination) and axonal (Charcot-Marie-Tooth type 2). Six mutations were reported in patients with Charcot-Marie-Tooth type 2 (CMT2); in particular, the Thr124Met variant is supposed to be a recurrent mutation. We describe a family with three subjects in which Thr124Met segregates with the disease. The index case was a 41-year-old woman with a severe impairment at the four limbs. Motor nerve conduction velocities were reduced at lower limbs and relatively conserved at upper limbs. The sural nerve biopsy showed mild to severe loss of myelinated fibres with relative sparing of small fibres. Several clusters of small regenerating fibres and few thinly myelinated fibres were observed. Direct sequencing of the MPZ coding sequence revealed a C/T transition resulting in a Thr/Met substitution at codon 124. The same variant was found in the affected aunt of the patient. The mutation seems to occur on a different genetic background with respect to the haplotypes to date associated with the disease. The position of the amino acid replaced by the mutation in the extracellular domain suggests that the substitution could act by affecting the interactions between the two facing molecules extending from opposite membrane layers. The complex relationship between the molecular damage induced by the protein zero mutations and the clinicopathological features of the related diseases will be addressed, and discussed in the light of the current pathophysiological models. Partially granted by MURST and Ateneo to FA, Ministero della Sanità to PM. The laboratory is a member of the European CMT Consortium.
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Document Type: Abstract
Affiliations: Dept. of Oncology, Biology and Genetics, University of Genova
Publication date: March 1, 2001