PDHA1 encodes pyruvate dehydrogenase E1-α, a subcomponent of the pyruvate dehydrogenase complex (PDC), a large mitochondrial multi-enzyme complex. The PDC exhibits 3 main enzymatic functions (E1-3) and is required in the Krebs cycle for irreversibly converting pyruvate into acetyl-coA. E1, the structural core of the PDC, comprises a heterotetramer that consists of 2 PDHα and 2 PDHβ subunits. The PDHα subunit harbors the active oxidation site where pyruvate is decarboxylated; the released acetyl group is accepted by dihydrolipoamide acetyltransferase, which is the second main enzyme component (E2) in the PDC.
PDHA1 dysfunction causes pyruvate dehydrogenase E1-α deficiency, the most common disorder attributed to pyruvate dehydrogenase complex deficiency and X-linked Leigh syndrome. The disorders are biochemically characterized by lactic acidosis, the result of large quantities of unused pyruvate being converted into lactate.
PDHA1 is located on the p arm of the X chromosome and is 17,815 bases long ranging from 19,343,893 to 19,361,707 base pairs pter. It contains 11 exons and translates into a 390 aa long protein with a molecular weight of 43,296 Da. Two PDHA1 and two PDHB subunits form a heterotetramer responsible for decarboxylating pyruvate, an essential step in the mitochondrial matrix Krebs cycle. The protein is ubiquitously expressed in all cell types due its function in energy production. 3 alternatively spliced isoforms and 3 paralogs have been identified for PDHA1.
Mutations in PDHA1 result in pyruvate dehydrogenase E1-α deficiency (PDHAD), the major cause of pyruvate dehydrogenase complex deficiency (~80% of cases) and X-linked Leigh syndrome. PDHAD is thought to be inherited in an X-linked dominant fashion due to a significant proportion of affected females harboring heterozygous mutations; X-inactivation plays a major role in the severity of the phenotype. X-linked Leigh syndrome is thought to have a recessive inheritance pattern although many PDHAD cases fit the clinical description of Leigh syndrome. In PDHAD, mutations affect both genders equally; however insertion/deletion mutations were found to be more common in female cases and missense/nonsense variants were more common in males.
Al-Shamsi et al., 2016 performed Whole Exome Sequencing in 85 Emirati patients who were admitted to the metabolic unit with un-diagnosable inborn errors of metabolism (IEM) and other genetic disorders. Among the cohort with IEM in whom mutational pathogenicity was confirmed, 1 patient was diagnosed with pyruvate dehydrogenase E1-alpha deficiency. A heterozygous missense transversion in PDHA1 (c.787C>G; p.Arg263Gly) was identified as the cause. 2 other heterozygous novel missense transversions located on the same allele of SDHA (c.321C>G; p.Ile107Met and c.338A>T; p.Asn113Ile) were additionally identified in the patient and father.
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