title: The p.R1109X mutation in SH3TC2 gene is predominant in Spanish Gypsies with Charcot-Marie-Tooth disease type 4.
abstract: 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.
authors.affiliation: Instituto de Biomedicina, Consejo Superior de Investigaciones Científicas, Valencia, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Claramunt
authors.forename: T
authors.initials: T
authors.lastname: Sevilla
authors.forename: V
authors.initials: V
authors.lastname: Lupo
authors.forename: A
authors.initials: A
authors.lastname: Cuesta
authors.forename: J M
authors.initials: JM
authors.lastname: Millán
authors.forename: J J
authors.initials: JJ
authors.lastname: Vílchez
authors.forename: F
authors.initials: F
authors.lastname: Palau
authors.forename: C
authors.initials: C
authors.lastname: Espinós
mesh_terms: D002607:Charcot-Marie-Tooth Disease / Q000145:classification / Q000235:genetics*; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D019143:Evolution, Molecular; D005260:Female; D018703:Founder Effect; D005808:Genes, Recessive; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D010375:Pedigree; D017354:Point Mutation; D011506:Proteins / Q000235:genetics*; D006178:Romani People / Q000235:genetics; D013030:Spain
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C488620:SH3TC2 protein, human