論文

査読有り 国際誌
2020年2月

Biallelic mutation of HSD17B4 induces middle age-onset spinocerebellar ataxia.

Neurology. Genetics
  • Yukiko Matsuda
  • ,
  • Hiroyuki Morino
  • ,
  • Ryosuke Miyamoto
  • ,
  • Takashi Kurashige
  • ,
  • Kodai Kume
  • ,
  • Noriyoshi Mizuno
  • ,
  • Yuhei Kanaya
  • ,
  • Yui Tada
  • ,
  • Ryosuke Ohsawa
  • ,
  • Kazunori Yokota
  • ,
  • Nobuyuki Shimozawa
  • ,
  • Hirofumi Maruyama
  • ,
  • Hideshi Kawakami

6
1
開始ページ
e396
終了ページ
記述言語
英語
掲載種別
DOI
10.1212/NXG.0000000000000396

Objective: To determine the genetic underpinnings of slowly progressive spinocerebellar ataxia, autosomal recessive (SCAR), we performed exome analysis and examined the relationship between clinical severity and functional change induced by the mutation. Methods: Homozygosity fingerprinting and exome sequencing were performed to identify causative mutations in 2 consanguineous families. We assessed the expression of D-bifunctional protein (DBP) and the amount of dimerized DBP in fibroblasts by immunoblot and quantitative reverse transcription PCR. The pathogenicity of the mutation was evaluated using the Combined Annotation-Dependent Depletion (CADD) scores; these results were compared with the scores of previously reported mutations. Results: We identified a homozygous mutation as causative of middle age-onset SCAR: p.Ala175Thr, which is located in HSD17B4 that encodes peroxisomal DBP. The patients developed cerebellar ataxia, and the subsequent progression was slow. The symptoms presented were milder than those in previously reported cases. The messenger RNA expression levels were normal, but protein levels were diminished. Dimerization of DBP was also reduced. The CADD score of the identified mutation was lower than those of previously reported mutations. Conclusions: This is the report of middle age-onset DBP deficiency. Residual functional DBP caused relatively mild symptoms in the affected patients, i.e., slowly progressive ataxia and hearing loss. This study broadens the scope of DBP deficiency phenotypes and indicates that CADD scores may be used to estimate the severity of DBP deficiencies.

リンク情報
DOI
https://doi.org/10.1212/NXG.0000000000000396
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32042923
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6975179

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