CMT 4C: L239F founder mutation in GDAP1 is associated with a mild CMT phenotype

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Neurogenetics. 2010 Mar 16.

L239F founder mutation in GDAP1 is associated with a mild Charcot-Marie-Tooth

type 4C4 (CMT4C4) phenotype.

Kabziñska D, Strugalska-Cynowska H, Kostera-Pruszczyk A, Ryniewicz B, Posmyk R,

Midro A, Seeman P, Báranková L, Zimoñ M, Baets J, Timmerman V, Guergueltcheva V,

Tournev I, Sarafov S, De Jonghe P, Jordanova A, Hausmanowa-Petrusewicz I,

Kochañski A.

Neuromuscular Unit, Mossakowski Medical Research Centre, Polish Academy of

Sciences, Pawiñskiego 5, 02-106, Warsaw, Poland.

Over 40 mutations in the GDAP1 gene have been shown to segregate with

Charcot-Marie-Tooth disease (CMT). Among these, only two mutations, i.e., S194X

and Q163X have been reported in a sufficient number of CMT families to allow for

the construction of reliable phenotype-genotype correlations. Both the S194X and

Q163X mutations have been shown to segregate with an early-onset and severe

neuropathy resulting in loss of ambulance at the beginning of the second decade

of life.

In this study, we identified the L239F mutation in the GDAP1 gene in one

Bulgarian and five Polish families. We hypothesized that the L239F mutation may

result from a founder effect in the European population since this mutation has

previously been reported in Belgian, Czech, and Polish patients. In fact, we

detected a common disease-associated haplotype within the 8q13-q21 region in the

Polish, German, Italian, Czech, and Bulgarian CMT families. Like the previously

detected " regional " S194X and Q163X mutations, respectively present in Maghreb

countries and in patients of Spanish descent, the L239F mutation seems to be the

most common GDAP1 pathogenic variant in the Central and Eastern European

population.

Given the likely presence of a common ancestor harboring the L239F mutation, we

decided to compare the phenotypes of the CMT (L239F) patients collected in this

study with those of previously reported cases. In contrast to CMT4A caused by

the S194X and Q163X mutations, the CMT phenotype resulting from the L239F

substitution represents a milder clinical entity with a long-preserved period of

ambulance at least until the end of the second decade of life.