title: Mutation profile of the GNE gene in Japanese patients with distal myopathy with rimmed vacuoles (GNE myopathy).
abstract: BACKGROUND
  GNE myopathy (also called distal myopathy with rimmed vacuoles or hereditary inclusion body myopathy) is an autosomal recessive myopathy characterised by skeletal muscle atrophy and weakness that preferentially involve the distal muscles. It is caused by mutations in the gene encoding a key enzyme in sialic acid biosynthesis, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE).
  
  
  METHODS
  We analysed the GNE gene in 212 Japanese GNE myopathy patients. A retrospective medical record review was carried out to explore genotype-phenotype correlation.
  
  
  RESULTS
  Sixty-three different mutations including 25 novel mutations were identified: 50 missense mutations, 2 nonsense mutations, 1 insertion, 4 deletions, 5 intronic mutations and 1 single exon deletion. The most frequent mutation in the Japanese population is c.1714G>C (p.Val572Leu), which accounts for 48.3% of total alleles. Homozygosity for this mutation results in more severe phenotypes with earlier onset and faster progression of the disease. In contrast, the second most common mutation, c.527A>T (p.Asp176Val), seems to be a mild mutation as the onset of the disease is much later in the compound heterozygotes with this mutation and c.1714G>C than the patients homozygous for c.1714G>C. Although the allele frequency is 22.4%, there are only three homozygotes for c.527A>T, raising a possibility that a significant number of c.527A>T homozygotes may not develop an apparent disease.
  
  
  CONCLUSIONS
  Here, we report the mutation profile of the GNE gene in 212 Japanese GNE myopathy patients, which is the largest single-ethnic cohort for this ultra-orphan disease. We confirmed the clinical difference between mutation groups. However, we should note that the statistical summary cannot predict clinical course of every patient.
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Anna
authors.initials: A
authors.lastname: Cho
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry, Tokyo, Japan Department of Neurophysiology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Yukiko K
authors.initials: YK
authors.lastname: Hayashi
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Monma
authors.affiliation: Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Oya
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Noguchi
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Ikuya
authors.initials: I
authors.lastname: Nonaka
authors.affiliation: Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan Department of Clinical Development, Translational Medical Center, National Center of Neurology and Psychiatry, Tokyo, Japan.
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
mesh_terms: D000328:Adult; D017668:Age of Onset; D000483:Alleles; D002238:Carbohydrate Epimerases / Q000235:genetics; D004247:DNA / Q000235:genetics; D016172:DNA Fingerprinting; D004252:DNA Mutational Analysis; D049310:Distal Myopathies / Q000235:genetics* / Q000473:pathology; D005260:Female; D005838:Genotype; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation; D010641:Phenotype; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D004247:DNA; D002238:Carbohydrate Epimerases; C100033:UDP acetylglucosamine-2-epimerase
keywords: Genetics; Muscle Disease; Myopathy