SCREENING FOR CONNEXIN-32 MUTATIONS IN CHARCOT-MARIE-TOOTH-DISEASE FAMILIES WITH POSSIBLE X-LINKED INHERITANCE

The X-linked dominant form of Charcot-Marie-Tooth disease (CMTX) is as sociated with mutations in a gene coding for the gap-junction protein connexin 32 (Cx32). We screened 32 CMT families with a pedigree patter n suggestive of X-linked inheritance for the presence of mutations in the coding region of Cx32 by direct sequencing. Five of the families h ad a CMT1 diagnosis, 24 had a CMT2 diagnosis and 3 patients had an uns pecified CMT. Eight families with a Cx32 point mutation were detected. Five different mutations (four of them published previously) were fou nd in six CMT2 families and one mutation was found in a sporadic CMT1 male patient. One of the mutations, Met194Val, is among the first desc ribed in the fourth transmembrane domain of Cx32. Two CMT2 families an d the sporadic CMT1 patient had the same mutation, Arg22Gln. An additi onal, previously unpublished mutation, Arg75Trp. was found in a male p atient with unspecified CMT, who subsequently was verified to have a v ariant Klinefelter syndrome with 48,XXYY karyotype. Our findings show the difficulty in distinguishing CMTX patients from CMT1 and CMT2 pati ents, and they emphasize the need for Cx32 mutation screening in famil ies previously diagnosed with CMT2.