Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy (2003)

Author(s): Senderek J, Bergmann C, Stendel C, Kirfel J, Verpoorten N, De Jonghe P, Timmerman V, Chrast R, Verheijen MH, Lemke G, Battaloglu E, Parman Y, Erdem S, Tan E, Topaloglu H, Hahn A, Muller-Felber W, Rizzuto N, Fabrizi GM, Stuhrmann M, Rudnik-Schoneborn S, Zuchner S, Michael Schroder J, Buchheim E, Straub V, Klepper J, Huehne K, Rautenstrauss B, Buttner R, Nelis E, Zerres K

    Abstract: 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.

      • Date: 14-12-2007
      • Journal: American Journal of Human Genetics
      • Volume: 73
      • Issue: 5
      • Pages: 1106-1119
      • Publisher: Cell Press
      • Publication type: Article
      • Bibliographic status: Published

      Keywords: Adolescent Adult Alternative Splicing/genetics Amino Acid Sequence Animals Base Sequence Charcot-Marie-Tooth Disease/ genetics/physiopathology Child Child, Preschool Chromosomes, Human, Pair 5/genetics Consanguinity Female Gene Expression Profiling Genes, Recessive/ genetics Genome, Human Haplotypes/genetics Humans Infant Male Middle Aged Molecular Sequence Data Mutation/ genetics Pedigree Phenotype Proteins/ chemistry/ genetics RNA, Messenger/analysis/genetics src Homology Domains