Mutational study in the PDHA1 gene of 40 patients suspected of pyruvate dehydrogenase complex deficiency

• Published in: Clinical genetics 2010-05, Vol.77 (5), p.474-482
• Main Authors: Quintana, E, Gort, L, Busquets, C, Navarro-Sastre, A, Lissens, W, Moliner, S, Lluch, M, Vilaseca, MA, De Meirleir, L, Ribes, A, Briones, P
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Blotting, Western; Case-Control Studies; DNA Mutational Analysis; Female; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genetics of eukaryotes. Biological and molecular evolution; Haplotypes - genetics; Humans; Male; Medical genetics; Medical sciences; Medical screening; Molecular and cellular biology; mosaicism; Mutation; Mutation - genetics; mutation analysis; Patient Selection; Patients; PDH activity; PDHA1 gene; PDHc deficiency; Polymorphism, Single Nucleotide - genetics; Pyruvate Dehydrogenase (Lipoamide) - genetics; Pyruvate Dehydrogenase Complex Deficiency Disease - enzymology; Pyruvate Dehydrogenase Complex Deficiency Disease - genetics
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/j.1399-0004.2009.01313.x

Quintana E, Gort L, Busquets C, Navarro‐Sastre A, Lissens W, Moliner S, Lluch M, Vilaseca MA, De Meirleir L, Ribes A, Briones P, PDH Working Group. Mutational study in the PDHA1 gene of 40 patients suspected of pyruvate dehydrogenase complex deficiency. We screened for PDHA1 mutations in 40 patients with biochemically demonstrated PDHc deficiency or strong clinical suspicion, and found changes with probable pathological significance in 20. Five patients presented new mutations: p.A169V, c.932_938del, c.1143_1144 ins24, c.1146_1159dup and c.510‐30G> A, this latter is a new undescribed cause of exon 6 skipping. Another four mutations have been found, and previously reported, in our patients: p.H113D, p.P172L, p.Y243del and p.Y369Q. Eleven patients presented seven known mutations: p.R127Q, p.I166I, p.A198T, p.R263G, p.R302C, p.R378C and c.1142_1145dup. The latter three were found in more than one unrelated patient: p.R302C was detected in a heterozygous girl and a mosaic male, p.R378C in two males and finally, c.1142_1145dup in three females; only one in 20 mothers was found to be a carrier (p.R263G). Apart from those 20 patients, the only alteration detected in one girl with clear PDHc and PDH‐E1 deficiency was the silent change c.396A> C (p.R132R), and other eight PDHc deficient patients carry combinations of known infrequent polymorphisms that are overrepresented among our 20 unsolved patients. The importance of these changes on PDH activity is unclear. Investigations in the other PDHc genes are in course in order to elucidate the genetic defect in the unresolved patients.