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1.
Nat Genet ; 29(1): 83-7, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11528398

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.


Subject(s)
Carbohydrate Epimerases/genetics , Carrier Proteins/genetics , Genes, Recessive , Mutation , Myositis, Inclusion Body/genetics , Phosphotransferases (Alcohol Group Acceptor)/genetics , Amino Acid Sequence , Base Sequence , Carbohydrate Epimerases/chemistry , Carrier Proteins/chemistry , Chromosome Mapping , Chromosomes, Human, Pair 9 , DNA , Female , Humans , Male , Molecular Sequence Data , Myositis, Inclusion Body/enzymology , Pedigree , Phosphotransferases (Alcohol Group Acceptor)/chemistry , Sequence Homology, Amino Acid
2.
Mol Gen Genet ; 215(3): 517-28, 1989 Feb.
Article in English | MEDLINE | ID: mdl-2651895

ABSTRACT

We have cloned three distinct nuclear genes, NAM1, NAM7, and NAM8, which alleviate mitochondrial intron mutations of the cytochrome b and COXI (subunit I of cytochrome oxidase) genes when present on multicopy plasmids. These nuclear genes show no sequence homology to each other and are localized on different chromosomes: NAM1 on chromosome IV, NAM7 on chromosome XIII and NAM8 on chromosome VIII. Sequence analysis of the NAM1 gene shows that it encodes a protein of 440 amino acids with a typical presequence that would target the protein to the mitochondrial matrix. Inactivation of the NAM1 gene by gene transplacement leads to a dramatic reduction of the overall synthesis of mitochondrial protein, and a complete absence of the COXI protein which is the result of a specific block in COXI pre-mRNA splicing. The possible mechanisms by which the NAM1 gene product may function are discussed.


Subject(s)
Genes, Fungal , Saccharomyces cerevisiae/genetics , Amino Acid Sequence , Base Sequence , Cell Nucleus/metabolism , DNA, Fungal/genetics , Fungal Proteins/biosynthesis , Fungal Proteins/genetics , Mitochondria/metabolism , Molecular Sequence Data , RNA Splicing , RNA, Fungal/metabolism , RNA, Messenger/metabolism , Restriction Mapping , Saccharomyces cerevisiae/metabolism , Sequence Homology, Nucleic Acid , Suppression, Genetic , Transcription, Genetic
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