PDHA1

Chr XXLD

pyruvate dehydrogenase E1 subunit alpha 1

Also known as: E1alpha, PDHA, PDHAD, PDHCE1A, PHE1A

NCBI Gene: 5160 ENSG00000131828 UniProt: P08559 OMIM: 300502

The protein encodes the E1 alpha subunit of the pyruvate dehydrogenase complex, which catalyzes the conversion of pyruvate to acetyl-CoA in mitochondria, providing the primary metabolic link between glycolysis and the citric acid cycle. Mutations cause pyruvate dehydrogenase E1-alpha deficiency through loss of function, resulting in lactic acidosis, developmental delay, and neurological dysfunction that can present as X-linked Leigh syndrome. The condition follows X-linked dominant inheritance with high penetrance.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle. The PDH complex is composed of multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and lipoamide dehydrogenase (E3). The E1 enzyme is a heterotetramer of two alpha and two beta subunits. This gene encodes the E1 alpha 1 subunit containing the E1 active site, and plays a key role in the function of the PDH complex. Mutations in this gene are associated with pyruvate dehydrogenase E1-alpha deficiency and X-linked Leigh syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Pyruvate dehydrogenase E1-alpha deficiencyMIM #312170

XLD

Clinical highlights

Gene-disease validity (ClinGen)

Leigh syndrome · XLDefinitivesufficient evidence for diagnostic panels2 gene-disease associations curated in total

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

119

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.27

LOEUF· LoF intol.

LOF

Mechanism· G2P

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