title: Biochemical and genetic studies of four patients with pyruvate dehydrogenase E1 alpha deficiency.
abstract: We report studies of four patients with pyruvate dehydrogenase complex (PDH) deficiency caused by mutations in the E1 alpha subunit. Two unrelated male patients presented with Leigh syndrome and a R263G missense mutation in exon 8. This mutation has previously been described in males with the same phenotype. The two other patients had different novel mutations: (1) an 8-bp deletion at the C-terminus (exon 11) was found in one allele of a young girl suffering from microcephaly and (2) a C88S missense mutation (exon 3) in a boy who only presented with motor neuropathy. These mutations were not found in the mothers of any of the four cases. Immunoblot analysis revealed decreased immunoreactivity for the E1 alpha and E1 beta subunits in three out of the four patients. These findings confirm that: (1) PDH deficiencies are genetically heterogeneous, (2) the R263G mutation is more frequent in male cases than are other mutations and this amino acid is a hot spot for gene mutations, (3) the last eight amino acids may be important for the conformation of the tetrameric E1-PDH enzyme, and (4) the amino acids at positions 88, 263 and 382-387 are essential for the linking of the alpha subunit with the beta subunit and for the activity of the holoenzyme.
authors.affiliation: INSERM U75, Faculté de médecine Necker, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Marsac
authors.forename: C
authors.initials: C
authors.lastname: Benelli
authors.forename: I
authors.initials: I
authors.lastname: Desguerre
authors.forename: M
authors.initials: M
authors.lastname: Diry
authors.forename: F
authors.initials: F
authors.lastname: Fouque
authors.forename: L
authors.initials: L
authors.lastname: De Meirleir
authors.forename: G
authors.initials: G
authors.lastname: Ponsot
authors.forename: S
authors.initials: S
authors.lastname: Seneca
authors.forename: F
authors.initials: F
authors.lastname: Poggi
authors.forename: J M
authors.initials: JM
authors.lastname: Saudubray
authors.forename: M T
authors.initials: MT
authors.lastname: Zabot
authors.forename: D
authors.initials: D
authors.lastname: Fontan
authors.forename: W
authors.initials: W
authors.lastname: Lissens
mesh_terms: D000293:Adolescent; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D018076:DNA, Complementary / Q000737:chemistry; D005260:Female; D006801:Humans; D007888:Leigh Disease / Q000201:enzymology / Q000235:genetics; D008297:Male; D010084:Oxidation-Reduction; D011048:Polarography; D018807:Polymorphism, Single-Stranded Conformational; D030481:Pyruvate Dehydrogenase (Lipoamide); D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics* / Q000378:metabolism; D015325:Pyruvate Dehydrogenase Complex Deficiency Disease / Q000201:enzymology / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D018076:DNA, Complementary; D011768:Pyruvate Dehydrogenase Complex; D030481:Pyruvate Dehydrogenase (Lipoamide); C065640:pyruvate dehydrogenase E1alpha subunit