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.

日本語要旨:

212人の日本人GNEミオパチー患者の変異を同定した．患者の臨床症状を元に，表現型を遺伝子型の関連を調べた．63の異なる変異が見つかり，うち25が新たに見いだされた変異だった．c.1714G>C変異が最も多いであり，総変異アレルの48.3%を占めていた．この変異のホモ接合体が最も重い症状を示した．一方，二番目に多いc.527A>T変異は全体の22.4%を占めるが，患者の症状は軽度であり，特にホモ接合体は３名の患者のみしか見いだされていない．このことから，この変異のホモ接合体では症状を示さない例も存在する可能性を示唆していた．