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Mutations in the X-linked E1 alpha subunit of pyruvate dehydrogenase leading to deficiency of the pyruvate
K Chun1, N MacKay, R Petrova-Benedict
1Department of Paediatrics, University of Toronto, Ontario, Canada.
Insights
Pyruvate dehydrogenase complex (PDH) deficiency presents heterogeneously. Genetic investigation of ten PDH E1 deficiency cases revealed mutations exclusively in the X-linked E1 alpha gene, not the E1 beta gene.
Area of Science:
- Biochemistry
- Genetics
- Human Disease
Background:
- Human pyruvate dehydrogenase complex (PDH) deficiency is a metabolic disorder with highly variable clinical presentations.
- The PDH complex (E1) is crucial for cellular energy metabolism, and its deficiency leads to neurological and developmental issues.
Purpose of the Study:
- To investigate the genetic basis of pyruvate dehydrogenase complex (E1) deficiency in ten patients.
- To identify specific mutations within the E1 alpha and E1 beta genes responsible for PDH deficiency.
Main Methods:
- Genetic analysis of the coding sequences of the E1 alpha and E1 beta genes in ten patients with PDH complex (E1) deficiency.
- Mutation screening, including missense mutations, deletions, and insertions, was performed on patient DNA.
- Parental DNA analysis was conducted in select cases to determine the inheritance pattern of identified mutations.
Main Results:
- All ten patients exhibited mutations solely within the X-linked E1 alpha gene; the E1 beta gene remained normal.
- Six patients (three males, three females) presented with missense mutations in the E1 alpha subunit at various amino acid positions (148, 170, 202, 234, 263).
- Four female patients had deletions or insertions in one E1 alpha allele, with the other allele being normal. Only two of the ten identified mutations were previously reported. Parental DNA analysis indicated de novo mutations in most cases.
Conclusions:
- The genetic basis of PDH complex (E1) deficiency in these cases is attributed to mutations in the X-linked E1 alpha gene.
- The identified mutations, including missense, deletion, and insertion types, contribute to the heterogeneity of PDH deficiency.
- Most mutations appear to arise de novo, highlighting the genetic complexity and variability in the inheritance of PDH deficiency.
Abstract:
Human PDH complex deficiency is an extremely heterogeneous disease in its presentation and clinical course. In an investigation at the level of the gene into ten cases of PDH complex (E1) deficiency, we found that all had mutations in the coding sequence of the X-linked E1 alpha gene while the E1 beta coding sequence was normal. Six of these patients (three males, three females) had missense mutations resulting in a changed amino acid residue in the E1 alpha subunit at positions amino acid 148 (in two siblings), 170, 202, 234 and 263 of the mature protein. Two of the females had one normal E1 alpha gene and one with a deletion at the sites of tandem repeats of AGTAAGA and TAT respectively. The two remaining females also had one normal E1 alpha gene and one with an insertion. Both insertions, one of 2 bp and one of 4 bp, occurred in DNA hotspots normally associated with deletions. Only two of these ten mutations have been reported in other patients previously. In the five cases (including the two siblings) where parent DNA was available, only in one case could the same mutation be found in the patient as well as the maternal genomic DNA.