Identification of a novel pathogenic mutation in PDHA1 gene for pyruvate dehydrogenase complex deficiency
WU Mo-Ling1, LIU Li1, MAO Xiao-Jian1, PENG Min-Zhi1, LIU Hong-Sheng2, SHENG Hui-Ying1, CAI Yan-Na1, MEI Hui-Fen1, FAN Chun1, HUANG Yong-Lan1, LI Xiu-Zhen1, CHENG Jing1
Department of Genetics and Endocrinology, Guangzhou Children and Women's Medical Center, Guangzhou 510623, China
Abstract：Objective To study the molecular genetic mechanism and genetic diagnosis of pyruvate dehydrogenase complex deficiency (PHD), and to provide a basis for genetic counseling and prenatal genetic diagnosis of PHD. Methods Polymerase chain reaction (PCR) was performed to amplify the 11 exons and exon junction of the PDHA1 gene from a child who was diagnosed with PHD based on clinical characteristics and laboratory examination results. The PCR products were sequenced to determine the mutation. An analysis of amino acid conservation and prediction of protein secondary and tertiary structure were performed using bioinformatic approaches to identify the pathogenicity of the novel mutation. Results One novel duplication mutation, c.1111_1158dup48bp, was found in the exon 11 of the PDHA1 gene of the patient. No c.1111_1158dup48bp mutation was detected in the sequencing results from 50 normal controls. The results of protein secondary and tertiary structure prediction showed that the novel mutation c.1111 _1158dup48bp led to the duplication of 16 amino acids residues, serine371 to phenylalanine386, which induced a substantial change in protein secondary and tertiary structure. The conformational change was not detected in the normal controls. Conclusions The novel duplication mutation c.1111_1158dup48bp in the PDHA1 gene is not due to gene polymorphisms but a possible novel pathogenic mutation for PHD.
WU Mo-Ling,LIU Li,MAO Xiao-Jian et al. Identification of a novel pathogenic mutation in PDHA1 gene for pyruvate dehydrogenase complex deficiency[J]. CJCP, 2015, 17(8): 775-779.
Patel KP, O'Brien TW, Subramony SH, et al. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients[J]. Mol Genet Metab, 2012, 106(3): 385-394.
[2]
Linda JDM, Michele B, Angel GC. Disorders of pyruvate metabolism and the tricarboxylic acid cycle[M]//Jean MS, Georges VDB, John HW. Inborn Metabolic Diseases. Berlin: Springer Berlin Heidelberg, 2012: 187-200.
[3]
Steller J, Gargus JJ, Gibbs LH, et al. Mild phenotype in a male with pyruvate dehydrogenase complex deficiency associated with novel hemizygous in-frame duplication of the E1α subunit gene (PDHA1)[J]. Neuropediatrics, 2014, 45(1): 56-60.
[4]
Barnerias C, Saudubray J, Touati G, et al. Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis[J]. Dev Med Child Neurol, 2010, 52(2): e1-e9.
Lissens W, De Meirleir L, Seneca S, et al. Mutation analysis of the pyruvate dehydrogenase E1 alpha gene in eight patients with a pyruvate dehydrogenase complex deficiency[J]. Hum Mutat, 1996, 7(1): 46-51.
[9]
Ciszak EM, Korotchkina LG, Dominiak PM, et al. Structural basis for flip-flop action of thiamin pyrophosphate-dependent enzymes revealed by human pyruvate dehydrogenase[J]. J Biol Chem, 2003, 278(23): 21240-21246.
[10]
Imbard A, Boutron A, Vequaud C, et al. Molecular characterization of 82 patients with pyruvate dehydrogenase complex deficiency. Structural implications of novel amino acid substitutions in E1 protein[J]. Mol Genet Metab, 2011, 104(4): 507-516.
