Mutations in the X-linked pyruvate dehydrogenase (E1) α subunit gene (PDHA1) in patients with a pyruvate dehydrogenase complex deficiency
Corresponding Author
Willy Lissens
Center for Medical Genetics, University Hospital, Vrije Universiteit Brussel, Brussels, Belgium
Center for Medical Genetics, University Hospital VUB, Laarbeeklaan 101, 1090 Brussels, BelgiumSearch for more papers by this authorLinda De Meirleir
Center for Medical Genetics, University Hospital, Vrije Universiteit Brussel, Brussels, Belgium
Center for Neuropediatrics, University Hospital, Vrije Universiteit Brussel, Brussels, Belgium
Search for more papers by this authorSara Seneca
Center for Medical Genetics, University Hospital, Vrije Universiteit Brussel, Brussels, Belgium
Search for more papers by this authorInge Liebaers
Center for Medical Genetics, University Hospital, Vrije Universiteit Brussel, Brussels, Belgium
Search for more papers by this authorGarry K. Brown
Genetics Unit, Department of Biochemistry, University of Oxford, Oxford, United Kingdom
Search for more papers by this authorRuth M. Brown
Genetics Unit, Department of Biochemistry, University of Oxford, Oxford, United Kingdom
Search for more papers by this authorMichinori Ito
Department of Pediatrics, School of Medicine, University of Tokushima, Tokushima, Japan
Search for more papers by this authorEtsuo Naito
Department of Pediatrics, School of Medicine, University of Tokushima, Tokushima, Japan
Search for more papers by this authorYasuhiro Kuroda
Department of Pediatrics, School of Medicine, University of Tokushima, Tokushima, Japan
Search for more papers by this authorDouglas S. Kerr
Departments of Pediatrics and Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA
Search for more papers by this authorIsaiah D. Wexler
Departments of Pediatrics and Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA
Search for more papers by this authorMulchand S. Patel
Department of Biochemistry, State University of New York at Buffalo, Buffalo, New York, USA
Search for more papers by this authorBrian H. Robinson
Research Institute, The Hospital for Sick Children, Departments of Biochemistry and Pediatrics, University of Toronto, Toronto, Canada
Search for more papers by this authorAgnieszka Seyda
Research Institute, The Hospital for Sick Children, Departments of Biochemistry and Pediatrics, University of Toronto, Toronto, Canada
Search for more papers by this authorCorresponding Author
Willy Lissens
Center for Medical Genetics, University Hospital, Vrije Universiteit Brussel, Brussels, Belgium
Center for Medical Genetics, University Hospital VUB, Laarbeeklaan 101, 1090 Brussels, BelgiumSearch for more papers by this authorLinda De Meirleir
Center for Medical Genetics, University Hospital, Vrije Universiteit Brussel, Brussels, Belgium
Center for Neuropediatrics, University Hospital, Vrije Universiteit Brussel, Brussels, Belgium
Search for more papers by this authorSara Seneca
Center for Medical Genetics, University Hospital, Vrije Universiteit Brussel, Brussels, Belgium
Search for more papers by this authorInge Liebaers
Center for Medical Genetics, University Hospital, Vrije Universiteit Brussel, Brussels, Belgium
Search for more papers by this authorGarry K. Brown
Genetics Unit, Department of Biochemistry, University of Oxford, Oxford, United Kingdom
Search for more papers by this authorRuth M. Brown
Genetics Unit, Department of Biochemistry, University of Oxford, Oxford, United Kingdom
Search for more papers by this authorMichinori Ito
Department of Pediatrics, School of Medicine, University of Tokushima, Tokushima, Japan
Search for more papers by this authorEtsuo Naito
Department of Pediatrics, School of Medicine, University of Tokushima, Tokushima, Japan
Search for more papers by this authorYasuhiro Kuroda
Department of Pediatrics, School of Medicine, University of Tokushima, Tokushima, Japan
Search for more papers by this authorDouglas S. Kerr
Departments of Pediatrics and Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA
Search for more papers by this authorIsaiah D. Wexler
Departments of Pediatrics and Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA
Search for more papers by this authorMulchand S. Patel
Department of Biochemistry, State University of New York at Buffalo, Buffalo, New York, USA
Search for more papers by this authorBrian H. Robinson
Research Institute, The Hospital for Sick Children, Departments of Biochemistry and Pediatrics, University of Toronto, Toronto, Canada
Search for more papers by this authorAgnieszka Seyda
Research Institute, The Hospital for Sick Children, Departments of Biochemistry and Pediatrics, University of Toronto, Toronto, Canada
Search for more papers by this authorAbstract
Defects in the pyruvate dehydrogenase (PDH) complex are an important cause of primary lactic acidosis, a frequent manifestation of metabolic disease in children. Clinical symptoms can vary considerably in patients with PDH complex deficiencies, and almost equal numbers of affected males and females have been identified, suggesting an autosomal recessive mode of inheritance of the disease. However, the great majority of PDH complex deficiencies result from mutations in the X-linked pyruvate dehydrogenase (E1) α subunit gene (PDHA1). The major factors that contribute to the clinical variation in E1α deficiency and its resemblance to a recessive disease are developmental lethality in some males with severe mutations and the pattern of X-inactivation in females.
To date, 37 different missense/nonsense and 39 different insertion/deletion mutations have been identified in the E1α subunit gene of 130 patients (61 females and 69 males) from 123 unrelated families. Insertion/deletion mutations occur preferentially in exons 10 and 11, while missense/nonsense mutations are found in all exons. In males, the majority of missense/nonsense mutations are found in exons 3, 7, 8 and 11, and three recurrent mutations at codons R72, R263 and R378 account for half of these patients with missense/nonsense mutations (25 of 50). A significantly lower number of females is found with missense/nonsense mutations (25). However, 36 females out of 55 affected patients have insertion/deletion mutations. The total number of female and male patients is thus almost the same, although a difference in the distribution of the type of mutations is evident between both sexes. In many families, the parents of the affected patients were studied for the presence of the PDHA1 mutation. The mutation was never present in the somatic cells of the father; in 63 mothers studied, 16 were carriers (25%). In four families, the origin of the new mutation was determined to be twice paternal and twice maternal. Hum Mutat 15:209–219, 2000. © 2000 Wiley-Liss, Inc.
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