Jan Senderek, Carsten Bergmann, Claudia Stendel, Jutta Kirfel, Nathalie Verpoorten, Peter De Jonghe, Vincent Timmerman, Roman Chrast, Mark H.G. Verheijen, Greg Lemke, Esra Battaloglu, Yesim Parman, Sevim Erdem, Ersin Tan, Haluk Topaloglu, Andreas Hahn, Wolfgang Müller-Felber, Nicolò Rizzuto, Gian Maria Fabrizi, Manfred Stuhrmann, Sabine Rudnik-Schöneborn, Stephan Züchner, J. Michael Schröder, Eckhard Buchheim, Volker Straub, Jörg Klepper, Kathrin Huehne, Bernd Rautenstrauss, Reinhard Büttner, Eva Nelis, Klaus Zerres

Charcot-Marie-Tooth disease type 4C (CMT4C) is a childhood-onset demyelinating form of hereditary motor and sensory neuropathy associated with an early-onset scoliosis and a distinct Schwann cell pathology. CMT4C is inherited as an autosomal recessive trait and has been mapped to a 13-cM linkage interval on chromosome 5q23-q33. By homozygosity mapping and allele-sharing analysis, we refined the CMT4C locus to a suggestive critical region of 1.7 Mb. We subsequently identified mutations in an uncharacterized transcript, KIAA1985, in 12 families with autosomal recessive neuropathy. We observed eight distinct protein-truncating mutations and three nonconservative missense mutations affecting amino acids conserved through evolution. In all families, we identified a mutation on each disease allele, either in the homozygous or in the compound heterozygous state. The CMT4C gene is strongly expressed in neural tissues, including peripheral nerve tissue. The translated protein defines a new protein family of unknown function with putative orthologues in vertebrates. Comparative sequence alignments indicate that members of this protein family contain multiple SH3 and TPR domains that are likely involved in the formation of protein complexes.