CMT 1B and HSMN 3: Clinical and in silico evidence for and against pathogenicity

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Clin Genet. 2010 Apr 20

Clinical and in silico evidence for and against pathogenicity of 11 new

mutations in the MPZ gene.

Brožková D, Mazanec R, Haberlová J, Sakmaryová I, Seeman P.

DNA Laboratory, Department of Child Neurology, University 2nd Medical

School and University Hospital Motol, V Uvalu 84, 15006 Prague, Czech Republic.

Abstract:

Clinical and in silico evidence for and against pathogenicity of 11 new

mutations in the MPZ gene. Mutations in the myelin protein zero (MPZ) gene are

one of the frequent causes of Charcot-Marie-Tooth (CMT) hereditary neuropathies.

Because the mutation rate of MPZ gene is rather high and some mutations are

reported as polymorphisms, the proper clinical, electrophysiological examination

and the segregation of the new mutation in larger families are crucial for the

correct interpretation of the pathogenic or non-pathogenic character of each

novel mutation.

We examined 11 families with novel MPZ mutations. Eight of the mutations (L48Q,

T65N, E97fs, G103W, P132T, T143R, V146G, c.645+1G> T) seem to be pathogenic on

the basis of perfect segregation with the CMT phenotype and two (G213R and

D246N), on the contrary, seem to be non-pathogenic/rare polymorphisms because

they are present in healthy relatives.

The character of the V46M mutation is difficult to interpret definitely; it may

cause a sensory neuropathy or may also be a rare polymorphism. Phenotypes

associated with each of the new mutations include severe hereditary motor and

sensory neuropathy type III (HMSN III), and mild phenotype CMT1B presented

mostly with only decreased or absent reflexes, foot deformities and mild or even

absent atrophies in the lower limbs.

Our report and careful family investigations with genotype-phenotype

correlations should help to improve genetic counselling and correct

interpretation of DNA testing results in further isolated patients or smaller

families worldwide where these novel mutations might be found.