title: The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy.
abstract: Hereditary inclusion body myopathy (HIBM; OMIM 600737) is a unique group of neuromuscular disorders characterized by adult onset, slowly progressive distal and proximal weakness and a typical muscle pathology including rimmed vacuoles and filamentous inclusions. The autosomal recessive form described in Jews of Persian descent is the HIBM prototype. This myopathy affects mainly leg muscles, but with an unusual distribution that spares the quadriceps. This particular pattern of weakness distribution, termed quadriceps-sparing myopathy (QSM), was later found in Jews originating from other Middle Eastern countries as well as in non-Jews. We previously localized the gene causing HIBM in Middle Eastern Jews on chromosome 9p12-13 (ref. 5) within a genomic interval of about 700 kb (ref. 6). Haplotype analysis around the HIBM gene region of 104 affected people from 47 Middle Eastern families indicates one unique ancestral founder chromosome in this community. By contrast, single non-Jewish families from India, Georgia (USA) and the Bahamas, with QSM and linkage to the same 9p12-13 region, show three distinct haplotypes. After excluding other potential candidate genes, we eventually identified mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) gene in the HIBM families: all patients from Middle Eastern descent shared a single homozygous missense mutation, whereas distinct compound heterozygotes were identified in affected individuals of families of other ethnic origins. Our findings indicate that GNE is the gene responsible for recessive HIBM.
authors.affiliation: Unit for Molecular Biology, Hadassah, Hospital, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Eisenberg
authors.forename: N
authors.initials: N
authors.lastname: Avidan
authors.forename: T
authors.initials: T
authors.lastname: Potikha
authors.forename: H
authors.initials: H
authors.lastname: Hochner
authors.forename: M
authors.initials: M
authors.lastname: Chen
authors.forename: T
authors.initials: T
authors.lastname: Olender
authors.forename: M
authors.initials: M
authors.lastname: Barash
authors.forename: M
authors.initials: M
authors.lastname: Shemesh
authors.forename: M
authors.initials: M
authors.lastname: Sadeh
authors.forename: G
authors.initials: G
authors.lastname: Grabov-Nardini
authors.forename: I
authors.initials: I
authors.lastname: Shmilevich
authors.forename: A
authors.initials: A
authors.lastname: Friedmann
authors.forename: G
authors.initials: G
authors.lastname: Karpati
authors.forename: W G
authors.initials: WG
authors.lastname: Bradley
authors.forename: L
authors.initials: L
authors.lastname: Baumbach
authors.forename: D
authors.initials: D
authors.lastname: Lancet
authors.forename: E B
authors.initials: EB
authors.lastname: Asher
authors.forename: J S
authors.initials: JS
authors.lastname: Beckmann
authors.forename: Z
authors.initials: Z
authors.lastname: Argov
authors.forename: S
authors.initials: S
authors.lastname: Mitrani-Rosenbaum
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002238:Carbohydrate Epimerases / Q000737:chemistry / Q000235:genetics*; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics*; D002874:Chromosome Mapping; D002899:Chromosomes, Human, Pair 9; D004247:DNA; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D018979:Myositis, Inclusion Body / Q000201:enzymology / Q000235:genetics*; D010375:Pedigree; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
chemical_list: D002352:Carrier Proteins; D004247:DNA; D017853:Phosphotransferases (Alcohol Group Acceptor); C018765:N-acylmannosamine kinase; D002238:Carbohydrate Epimerases; C024519:N-acyl-D-glucosamine 2-epimerase; C498259:RENBP protein, human