Mutations in PDX1, the Human Lipoyl-Containing Component X of the Pyruvate Dehydrogenase–Complex Gene on Chromosome 11p1, in Congenital Lactic Acidosis

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Mutations in PDX1, the Human Lipoyl-Containing Component X of the Pyruvate Dehydrogenase–Complex Gene on Chromosome 11p1, in Congenital Lactic Acidosis Bernard Aral, Chantal Benelli, Ghania Ait-Ghezala, Mohamed Amessou, Françoise Fouque, Catherine Maunoury, Nicole Créau, Pierre Kamoun, Cécile Marsac The American Journal of Human Genetics Volume 61, Issue 6, Pages 1318-1326 (December 1997) DOI: 10.1086/301653 Copyright © 1997 The American Society of Human Genetics Terms and Conditions

Figure 1 Comparison of amino acid sequence (single-letter code) of HsPDX1 with that of PDC-E2 (A) and with that of ScPDX1 (B). The deduced sequences of HsPDX1, PDC-E2, and ScPDX1 are aligned for maximum similarities, by the sequence-alignment tool Clustal V. Identical amino acids are indicated by an asterisk (*); and similar amino acids are indicated by periods (.). The arrowhead indicates the putative cleavage site of the HsPDX1 leader peptide. Both the lipoyllysine residue in the lipoyl domain and the residues in the putative active site of PDC-E2 are denoted by black dots. The lipoyl domains (amino-terminal), E3-binding domains, and catalytic inner-core domains (carboxy-terminal) are denoted by unbroken lines. The American Journal of Human Genetics 1997 61, 1318-1326DOI: (10.1086/301653) Copyright © 1997 The American Society of Human Genetics Terms and Conditions

Figure 2 FISH to human metaphase chromosomes with the PAC clone F1172, containing the human gene for PDX1.The human gene encoding PDX1 is assigned to human chromosome 11p1.3. The American Journal of Human Genetics 1997 61, 1318-1326DOI: (10.1086/301653) Copyright © 1997 The American Society of Human Genetics Terms and Conditions

Figure 3 Western blotting of cultured skin fibroblast mitochondria with anti–PDH complex antibodies. Mitochondria (≈5 μg protein) from each cell line were solubilized in sample buffer and were resolved on a 10% SDS–polyacrylamide gel, under reducing conditions. The proteins were then electroblotted onto a nitrocellulose support matrix and were probed with antibodies that reacted with all subunits of the purified PDHc, except for the E3 subunit, which is poorly immunogenic. Immunoreactive proteins were visualized by electrogenerated chemiluminescence-detection reagents. Lane 1, Control cell lines. Lane 2, Patient S.D. Lane 3, Patient K.M. Lane 4, Patient R.D. The American Journal of Human Genetics 1997 61, 1318-1326DOI: (10.1086/301653) Copyright © 1997 The American Society of Human Genetics Terms and Conditions

Figure 4 Identification of mutations in the HsPDX1 mRNA transcripts in PDH-deficient patients. A, top, Northern blot of total RNA (20 mg total RNA/lane) from controls' and patients' fibroblasts probed with [32P]-HsPDX1 cDNA. A 2.5-kb PDX1 transcript is present in six of the seven lanes, which show results for control β-lymphoblastoid cell lines (lanes 1 and 2) and for fibroblast cell lines (lane 3, patient K.M.'s mother; lane 5, patient S.D.; and lanes 6 and 7, controls); the exception was patient K.M. (lane 4), whose PDX1 mRNA was undetectable. A, bottom, Same blot, probed with a PABP cDNA probe to control for the quality and quantity of the RNA. B, Detection of deleted RT-PCR–amplified cDNA fragments F2/DW2 by agarose gel electrophoresis. RT-PCR (using primers F2 and DW2; for the primer sequences, see the text) was used to amplify a 793-nt-long cDNA fragment (between bp +37 and bp +828) from two unaffected individuals (lanes 2 and 5), a 708-nt-long cDNA fragment from patient S.D. (lane 4), and, in a heterozygous state, both a 793-nt-long fragment and a 708-nt-long cDNA fragment from patient S.D.'s mother (lane 3). Standards of known size also were run (lanes 1 and 6). C, Detection of abnormal RT-PCR–amplified cDNA fragments UP2/XR by agarose gel electrophoresis. RT-PCR (using primers UP2 and XR; for the primer sequences, see the text) was used to amplify a 554-nt-long cDNA fragment (between bp +808 and bp +1362) from two unaffected individuals (lanes 2 and 4) and a 495-nt-long cDNA fragment from patient R.D. (lane 3). Standards of known size also were run (lanes 1 and 5). D, Schematic representation of HsPDX1 cDNA, along with the primers' positions for RT-PCR amplifications. The American Journal of Human Genetics 1997 61, 1318-1326DOI: (10.1086/301653) Copyright © 1997 The American Society of Human Genetics Terms and Conditions