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Human Genetics

, Volume 107, Issue 4, pp 320–326 | Cite as

Molecular and clinical analysis of Japanese patients with 3-hydroxy-3-methylglutaryl CoA lyase (HL) deficiency

  • Junko Muroi
  • Tohru Yorifuji
  • Ayumi Uematsu
  • Yosuke Shigematsu
  • Kazumichi Onigata
  • Hiroaki Maruyama
  • Tatsuro Nobutoki
  • Akiko Kitamura
  • Tatsutoshi Nakahata
Original investigation

Abstract.

Deficiency of mitochondrial 3-hydroxy-3-methylglutaryl CoA lyase (HL, EC4.1.3.4.) is an autosomal recessive genetic disorder characterized by acute episodes of vomiting, hypotonia, and lethargy in the neonatal period or in infancy. Except in Saudi Arabia, where HL deficiency is the most common organic acidemia, the disorder is quite rare with only 41 cases being reported in the English literature, and only five known cases among Japanese. In this study, we present the results of a molecular analysis of all five Japanese patients together with their clinical phenotypes. Five different mutations in the HL gene were identified: one large deletion, one nonsense mutation, one missense mutation, and two splice mutations. Except for G835A (E279K) with its relatively common occurrence among Japanese, these mutations were unique to each family. The results of expression studies with mutated HL cDNAs confirmed the pathogenicity of these mutations and supported the importance of previously identified functional domains of the HL molecule, i.e., the putative catalytic site or dimerization site. In addition, we identified an alternative splicing event that resulted in the skipping of exons 5 and 6. This alternatively spliced product did not show HL activity and was present in various tissues of normal subjects. Clinically, all patients presented with similar symptoms, except that the timing of the initial presentation varied considerably, from 1 day to 1 year 3 months. In general, patients with null-activity mutations presented earlier in life, whereas those with residual activities presented later.

Keywords

Alternative Splice Missense Mutation Japanese Patient Catalytic Site Nonsense Mutation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Springer-Verlag 2000

Authors and Affiliations

  • Junko Muroi
    • 1
  • Tohru Yorifuji
    • 1
  • Ayumi Uematsu
    • 1
  • Yosuke Shigematsu
    • 2
  • Kazumichi Onigata
    • 3
  • Hiroaki Maruyama
    • 4
  • Tatsuro Nobutoki
    • 5
  • Akiko Kitamura
    • 6
  • Tatsutoshi Nakahata
    • 1
  1. 1.Department of Pediatrics, Kyoto University Hospital, 54 Shogoin Sakyo, Kyoto 606-8507, Japan
  2. 2.Department of Pediatrics, Fukui Medical University, Fukui, Japan
  3. 3.Department of Pediatrics, Gunma University, Gunma, Japan
  4. 4.Department of Pediatrics, Kanazawa Red Cross Hospital, Kanazawa, Japan
  5. 5.Department of Pediatrics, Mie National Hospital, Mei, Japan
  6. 6.Department of Pediatrics, National Sanatorium Kagawa-Children's Hospital, Kagawa, Japan

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