Pyruvate Dehydrogenase Deficiency Due to a 20-bp Deletion in Exon II of the Pyruvate Dehydrogenase (PDH) E1 Alpha Gene

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 1991 Aug 1

PMID 1907799

Citations 6

Authors

K Chun

N Mackay

B H Robinson

Affiliations

Soon will be listed here.

Abstract

A 20-bp deletion in the last exon of the pyruvate dehydrogenase (PDH) E1 alpha gene was found in a severely affected female patient diagnosed with PDH deficiency. PDH-complex activity in the patient's fibroblasts was 22% of that in normal controls. The mutation was characterized using PCR techniques with both patient cDNA and genomic DNA, followed by sequencing of the products. E1 beta cDNA sequence was found to be the same as that in controls. The deletion causes a frameshift and the occurrence of a premature stop codon. Western blot analysis revealed an extra band migrating just above the PDH E1 beta band. Northern blot analysis showed normal levels of both E1 alpha and E1 beta message when probed with the respective cDNAs. However, a larger intermediate-size transcript was observed for this patient in the E1 beta blot. The 20-bp deletion was not found in either parent's genomic DNA, and hence we conclude that the mutation must have occurred de novo, either in the germ-line cells or immediately following fertilization.

Citing Articles

The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients.

Patel K, OBrien T, Subramony S, Shuster J, Stacpoole P Mol Genet Metab. 2012; 106(3):385-94.

PMID: 22896851 PMC: 4003492. DOI: 10.1016/j.ymgme.2012.03.017.

The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients.

Patel K, OBrien T, Subramony S, Shuster J, Stacpoole P Mol Genet Metab. 2011; 105(1):34-43.

PMID: 22079328 PMC: 3754811. DOI: 10.1016/j.ymgme.2011.09.032.

Mutations in the X-linked E1 alpha subunit of pyruvate dehydrogenase: exon skipping, insertion of duplicate sequence, and missense mutations leading to the deficiency of the pyruvate dehydrogenase complex.

Chun K, Mackay N, Federico A, Fois A, Cole D, Robertson E Am J Hum Genet. 1995; 56(3):558-69.

PMID: 7887409 PMC: 1801155.

Pyruvate dehydrogenase E1 alpha deficiency: males and females differ yet again.

Dahl H Am J Hum Genet. 1995; 56(3):553-7.

PMID: 7887408 PMC: 1801181.

Pyruvate dehydrogenase E1 alpha deficiency.

Brown G J Inherit Metab Dis. 1992; 15(4):625-33.

PMID: 1528021 DOI: 10.1007/BF01799619.

References

Chun K, Mackay N, Willard H, Robinson B . Isolation, characterization and chromosomal localization of cDNA clones for the E1 beta subunit of the pyruvate dehydrogenase complex. Eur J Biochem. 1990; 194(2):587-92. DOI: 10.1111/j.1432-1033.1990.tb15656.x. View

Linn T, Pettit F, Reed L . Alpha-keto acid dehydrogenase complexes. X. Regulation of the activity of the pyruvate dehydrogenase complex from beef kidney mitochondria by phosphorylation and dephosphorylation. Proc Natl Acad Sci U S A. 1969; 62(1):234-41. PMC: 285978. DOI: 10.1073/pnas.62.1.234. View

Saiki R, Gelfand D, Stoffel S, Scharf S, Higuchi R, Horn G . Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988; 239(4839):487-91. DOI: 10.1126/science.2448875. View

Brown R, Dahl H, Brown G . X-chromosome localization of the functional gene for the E1 alpha subunit of the human pyruvate dehydrogenase complex. Genomics. 1989; 4(2):174-81. DOI: 10.1016/0888-7543(89)90297-8. View

Robinson B, Macmillan H, Sherwood W . Variable clinical presentation in patients with defective E1 component of pyruvate dehydrogenase complex. J Pediatr. 1987; 111(4):525-33. DOI: 10.1016/s0022-3476(87)80112-9. View

McKay N, Thoene J, Bergen B, Wilson W, Robinson B . Lacticacidaemia due to pyruvate dehydrogenase deficiency, with evidence of protein polymorphism in the alpha-subunit of the enzyme. Eur J Pediatr. 1986; 144(5):445-50. DOI: 10.1007/BF00441736. View

Glerum M, Robinson B, Spratt C, Wilson J, Patrick D . Abnormal kinetic behavior of cytochrome oxidase in a case of Leigh disease. Am J Hum Genet. 1987; 41(4):584-93. PMC: 1684310. View

Dahl H, Hunt S, HUTCHISON W, Brown G . The human pyruvate dehydrogenase complex. Isolation of cDNA clones for the E1 alpha subunit, sequence analysis, and characterization of the mRNA. J Biol Chem. 1987; 262(15):7398-403. View

Endo H, Hasegawa K, Narisawa K, Tada K, Kagawa Y, Ohta S . Defective gene in lactic acidosis: abnormal pyruvate dehydrogenase E1 alpha-subunit caused by a frame shift. Am J Hum Genet. 1989; 44(3):358-64. PMC: 1715432. View

10.

HAWKINS C, Borges A, Perham R . A common structural motif in thiamin pyrophosphate-binding enzymes. FEBS Lett. 1989; 255(1):77-82. DOI: 10.1016/0014-5793(89)81064-6. View

11.

Maragos C, HUTCHISON W, Hayasaka K, Brown G, Dahl H . Structural organization of the gene for the E1 alpha subunit of the human pyruvate dehydrogenase complex. J Biol Chem. 1989; 264(21):12294-8. View

12.

Ho L, Wexler I, Liu T, Thekkumkara T, Patel M . Characterization of cDNAs encoding human pyruvate dehydrogenase alpha subunit. Proc Natl Acad Sci U S A. 1989; 86(14):5330-4. PMC: 297615. DOI: 10.1073/pnas.86.14.5330. View

13.

Lyon M . The William Allan memorial award address: X-chromosome inactivation and the location and expression of X-linked genes. Am J Hum Genet. 1988; 42(1):8-16. PMC: 1715299. View

14.

Miller S, Dykes D, Polesky H . A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988; 16(3):1215. PMC: 334765. DOI: 10.1093/nar/16.3.1215. View

15.

Dahl H, Maragos C, Brown R, Hansen L, Brown G . Pyruvate dehydrogenase deficiency caused by deletion of a 7-bp repeat sequence in the E1 alpha gene. Am J Hum Genet. 1990; 47(2):286-93. PMC: 1683706. View

16.

Robinson B, Taylor J, Sherwood W . The genetic heterogeneity of lactic acidosis: occurrence of recognizable inborn errors of metabolism in pediatric population with lactic acidosis. Pediatr Res. 1980; 14(8):956-62. DOI: 10.1203/00006450-198008000-00013. View

17.

Sheu K, Hu C, UTTER M . Pyruvate dehydrogenase complex activity in normal and deficient fibroblasts. J Clin Invest. 1981; 67(5):1463-71. PMC: 370714. DOI: 10.1172/jci110176. View

18.

Randle P, Sugden P, Kerbey A, Radcliffe P, Hutson N . Regulation of pyruvate oxidation and the conservation of glucose. Biochem Soc Symp. 1978; (43):47-67. View

19.

SANGER F, Nicklen S, Coulson A . DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977; 74(12):5463-7. PMC: 431765. DOI: 10.1073/pnas.74.12.5463. View

20.

Koike K, Ohta S, Urata Y, Kagawa Y, Koike M . Cloning and sequencing of cDNAs encoding alpha and beta subunits of human pyruvate dehydrogenase. Proc Natl Acad Sci U S A. 1988; 85(1):41-5. PMC: 279477. DOI: 10.1073/pnas.85.1.41. View