Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy.
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.
Department of Human Genetics, Aachen University of Technology, Aachen, Germany. jsenderek@ukaachen.de
Jan
J
Senderek
Carsten
C
Bergmann
Claudia
C
Stendel
Jutta
J
Kirfel
Nathalie
N
Verpoorten
Peter
P
De Jonghe
Vincent
V
Timmerman
Roman
R
Chrast
Mark H G
MH
Verheijen
Greg
G
Lemke
Esra
E
Battaloglu
Yesim
Y
Parman
Sevim
S
Erdem
Ersin
E
Tan
Haluk
H
Topaloglu
Andreas
A
Hahn
Wolfgang
W
Müller-Felber
Nicolò
N
Rizzuto
Gian Maria
GM
Fabrizi
Manfred
M
Stuhrmann
Sabine
S
Rudnik-Schöneborn
Stephan
S
Züchner
J
J
Michael Schröder
Eckhard
E
Buchheim
Volker
V
Straub
Jörg
J
Klepper
Kathrin
K
Huehne
Bernd
B
Rautenstrauss
Reinhard
R
Büttner
Eva
E
Nelis
Klaus
K
Zerres
D000293:Adolescent; D000328:Adult; D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D003241:Consanguinity; D005260:Female; D020869:Gene Expression Profiling; D005808:Genes, Recessive / Q000235:genetics*; D015894:Genome, Human; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000737:chemistry* / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D018909:src Homology Domains
D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; C488620:SH3TC2 protein, human