title: Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot-Marie-Tooth neuropathy type 4B2/11p15.
abstract: Autosomal recessive hereditary motor and sensory neuropathy or Charcot-Marie-Tooth disease (CMT) is a severe childhood-onset neuromuscular disorder. Autosomal recessive CMT is genetically heterogeneous with one locus mapped to chromosome 11p15 (CMT4B2). The histopathological hallmarks of CMT4B2 are focal outfoldings of myelin in nerve biopsies. Homozygosity mapping, in a Turkish inbred family with four children affected by CMT characterized by focally folded myelin, provided linkage to the CMT4B2 locus. We identified a large, novel gene, named SET binding factor 2 (SBF2), that lies within this interval and is expressed in various tissues, including spinal cord and peripheral nerve. SBF2 is a member of the pseudo-phosphatase branch of myotubularins and was an obvious candidate for CMT4B2 by virtue of its striking homology to myotubularin-related protein 2 (MTMR2), causing another form of autosomal recessive CMT with outfoldings of the myelin sheaths. Molecular study of the SBF2 gene in the CMT4B family demonstrated the presence of a homozygous inframe deletion of SBF2 exons 11 and 12 in all four affected individuals. On the protein level, this mutation is predicted to disrupt an N-terminal domain that is conserved in SBF2 and its orthologues across species. Myotubularin-related proteins have been suggested to work in phosphoinositide-mediated signalling events that may also convey control of myelination. Localization of SBF2 within the candidate interval, cosegregation with the disease, expression in the peripheral nervous system, and resemblance of the histopathological phenotype to that related to mutations in its paralogue MTMR2 indicate that this gene is the CMT4B2 gene.
authors.affiliation: Department of Human Genetics, Aachen University of Technology, Aachen, Germany. jsenderek@ukaachen.de
authors.forename: Jan
authors.initials: J
authors.lastname: Senderek
authors.forename: Carsten
authors.initials: C
authors.lastname: Bergmann
authors.forename: Susanne
authors.initials: S
authors.lastname: Weber
authors.forename: Uwe-Peter
authors.initials: UP
authors.lastname: Ketelsen
authors.forename: Hubert
authors.initials: H
authors.lastname: Schorle
authors.forename: Sabine
authors.initials: S
authors.lastname: Rudnik-Schöneborn
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
authors.forename: Eckhard
authors.initials: E
authors.lastname: Buchheim
authors.forename: Klaus
authors.initials: K
authors.lastname: Zerres
mesh_terms: D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D009154:Mutation; D009186:Myelin Sheath / Q000378:metabolism; D010375:Pedigree; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D054558:Protein Tyrosine Phosphatases, Non-Receptor
chemical_list: D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C475072:SBF2 protein, human; C099588:myotubularin