Hereditary motor and sensory neuropathy (HMSN) type X1 in an Argentinean family reveals independent GJB1/Cx32 mutations at the identical nucleotide position.

X-linked Charcot-Marie-Tooth disease (CMT Type X1, OMIM: 302800) represents a frequent cause of hereditary peripheral motor and sensory neuropathies and is associated with mutations in GJB1 encoding the gap junction beta 1 protein connexin 32 (Cx32). Studying an Argentinean family of Italian origin with seven affected males in three generations exhibiting clinical signs of CMT, eight obligate female carriers were identified genealogically. DNA sequencing of exon 2 and adjacent regions of the GJB1 gene in two symptomatic males whose respective maternal grandfathers, both affected, were brothers, revealed mutations in GJB1/Cx32. Surprisingly, each of the two affected patients had a different mutation in hemizygous state at the same nucleotide position: c.383C>T (p.S128L) and c.383C>A (p.S128X). In both cases, the identified mutation was present in heterozygous state in the corresponding maternal genomic DNA. Furthermore, X-chromosomal microsatellite analysis showed identical marker alleles in both patients. Together with the genealogical information, these molecular data imply that a primarily mutated allele mutated for a second time. In conclusion, two different mutations at the same nucleotide position in this Argentinean family represent a finding with a very low probability of occurrence.