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.
Senderek
Jan
J
Department of Human Genetics, Aachen University of Technology, Aachen, Germany. jsenderek@ukaachen.de
Bergmann
Carsten
C
Stendel
Claudia
C
Kirfel
Jutta
J
Verpoorten
Nathalie
N
De Jonghe
Peter
P
Timmerman
Vincent
V
Chrast
Roman
R
Verheijen
Mark H G
MH
Lemke
Greg
G
Battaloglu
Esra
E
Parman
Yesim
Y
Erdem
Sevim
S
Tan
Ersin
E
Topaloglu
Haluk
H
Hahn
Andreas
A
Müller-Felber
Wolfgang
W
Rizzuto
Nicolò
N
Fabrizi
Gian Maria
GM
Stuhrmann
Manfred
M
Rudnik-Schöneborn
Sabine
S
Züchner
Stephan
S
Michael Schröder
J
J
Buchheim
Eckhard
E
Straub
Volker
V
Klepper
Jörg
J
Huehne
Kathrin
K
Rautenstrauss
Bernd
B
Büttner
Reinhard
R
Nelis
Eva
E
Zerres
Klaus
K
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