CMT Type 4: The p.R1109X mutation in SH3TC2 gene is predominant in Spanish Gypsi

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Clin Genet. 2007 Apr;71(4):343-9.

The p.R1109X mutation in SH3TC2 gene is predominant in Spanish

Gypsies with Charcot-Marie-Tooth disease type 4.

Claramunt R, Sevilla T, Lupo V, Cuesta A, Millan J, Vilchez J, Palau

F, Espinos C.

Instituto de Biomedicina, Consejo Superior de Investigaciones

Cientificas (CSIC), Valencia, Spain.

Charcot-Marie-Tooth (CMT) disease type 4 (CMT4) is the name given to

autosomal recessive forms of hereditary motor and sensory neuropathy

(HMSN). When we began this study, three genes or loci associated

with inherited peripheral neuropathies had already been identified

in the European Gypsy population: HMSN-Lom (MIM 601455), HMSN-Russe

(MIM 605285) and the congenital cataracts facial dysmorphism

neuropathy syndrome (MIM 604168).

We have carried out genetic analyses in a series of 20 Spanish Gypsy

families diagnosed with a demyelinating CMT disease compatible with

an autosomal recessive trait.

We found the p.R148X mutation in the N-myc downstream-regulated gene

1 gene to be responsible for the HMSN-Lom in four families and also

possible linkage to the HMSN-Russe locus in three others. We have

also studied the CMT4C locus because of the clinical similarities

and showed that in 10 families, the disease is caused by mutations

located on the SH3 domain and tetratricopeptide repeats 2 (SH3TC2)

gene: p.R1109X in 20 out of 21 chromosomes and p.C737_P738delinsX in

only one chromosome.

Moreover, the SH3TC2 p.R1109X mutation is associated with a

conserved haplotype and, therefore, may be a private founder

mutation for the Gypsy population.

Estimation of the allelic age revealed that the SH3TC2 p.R1109X

mutation may have arisen about 225 years ago, probably as the

consequence of a bottleneck.