Alternative titles; symbols
HGNC Approved Gene Symbol: PDHA2
Cytogenetic location: 4q22.3 Genomic coordinates (GRCh38): 4:95,840,093-95,841,464 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q22.3 | Spermatogenic failure 70 | 619828 | Autosomal recessive | 3 |
The pyruvate dehydrogenase (PDH) complex converts pyruvate to acetyl CoA, an essential step in aerobic glucose metabolism. Dahl et al. (1990) extended their previous work on the X-linked gene for the E1-alpha subunit of this complex, PDHA1 (300502), which is expressed in somatic tissues, and identified an autosomal gene, PDHA2. PDHA2 has 84% nucleotide sequence similarity with the PDHA1 cDNA. Dahl et al. (1990) found that PDHA2 was testis-specific and was expressed in postmeiotic spermatogenic cells. They suggested that to circumvent the problems of X-chromosome inactivation or the absence of an X chromosome in haploid spermatogenic cells for which PDH is essential for carbohydrate oxidation, an autosomal 'backup' gene, PDHA2, exists.
Dahl et al. (1990) found that the PDHA2 gene lacks introns and has characteristics of a functional processed gene. Protamine genes (e.g., 182880), which are also expressed only in germ cells, are likewise intronless. DNA sequencing of the gene showed that the transcribed region spans only approximately 1.4 kb. In contrast, the PDHA1 gene contains 10 introns and spans approximately 17 kb.
Pinheiro et al. (2010) identified 61 CpG sites along the human PDHA2 gene. Nineteen CpG sites were grouped in a CpG island that covered the core promoter and extended 73 nucleotides into the coding region, and 14 CpG sites formed an additional CpG island downstream within the PDHA2 coding region. Pinheiro et al. (2010) found that all CpG sites were heavily methylated in somatic tissues (gastric cells and lymphocytes) and that only the second CpG island was fully demethylated in diploid and haploid testicular germ cells. Pinheiro et al. (2010) concluded that demethylation of the PDHA2 core promoter is not a prerequisite for transcription initiation in germ cells.
Using a probe for PDHA1, Dahl et al. (1990) found significant in situ hybridization with an autosomal locus, PDHA2, located on chromosome 4q22-q23. Mapping of the gene to chromosome 4 was also done by isolation of the gene from a chromosome 4-specific genomic library.
Brown et al. (1990) showed by in situ hybridization that a PDH gene maps to the mouse X chromosome, homologous to human PDHA1, whereas the testis-specific form, Pdha2, is encoded by a gene on mouse chromosome 19.
Stumpf (2022) mapped the PDHA2 gene to chromosome 4q22.3 based on an alignment of the PDHA2 sequence (GenBank BC127638) with the genomic sequence (GRCh38).
In a consanguineous Algerian family with complex digital malformations and male infertility (SPGF70; 619828), Yildirim et al. (2018) performed exome sequencing and identified homozygosity for missense mutations in 2 different genes, both located within a linked region of homozygosity at 4q22, that segregated with disease. One was an M227V variant in the PDHA2 gene (179061.0001), believed to be responsible for the male infertility phenotype, whereas the other was an R214C variant in the brachydactyly-associated BMPR1B gene (603248). Segregation of the mutations was confirmed by Sanger sequencing.
By whole-exome sequencing in a cohort of 96 unrelated infertile men of North African origin with nonobstructive azoospermia, Kherraf et al. (2022) identified homozygosity for the previously reported M227V variant in the PDHA2 gene (179061.0001) in 2 men of Tunisian origin.
In 3 infertile brothers from a consanguineous Algerian family with azoospermia (patients 406 and 412) or severe oligoasthenospermia (patient 401) (SPGF70; 619828), Yildirim et al. (2018) identified homozygosity for a c.679A-G transition (c.679A-G, NM_005390.1) in the PDHA2 gene, resulting in a met227-to-val (M227V) substitution at a highly conserved residue. Sanger sequencing confirmed the mutation and segregation with disease in the family; a heterozygous brother (409) showed mild necrozoospermia on semen analysis but was fertile. Female fertility appeared to be unaffected: a homozygous unmarried sister (408) had normal gonadotropic hormone levels. The mutation was present in the ExAC database at a low minor allele frequency (0.00009 in the Latino population and .00006 in the non-Finnish European population). Seven of 10 sibs in the family, including the 3 infertile brothers, also exhibited digital anomalies that were attributed to a linked mutation in the BMPR1B gene (see 603248).
In 2 unrelated infertile Tunisian men (P0253 and P0144) with azoospermia, Kherraf et al. (2022) identified homozygosity for the previously reported M227V substitution in the PDHA2 gene. Familial segregation was not reported; the variant was present in the gnomAD database at low minor allele frequency (.00006). The authors noted that although both men were homozygous for the same mutation, they exhibited different histologic subphenotypes and different outcomes on testicular sperm extraction (TESE), with one (P0253) showing hypospermatogenesis and a positive TESE, and the other (P0144) showing meiotic arrest and a negative TESE.
Brown, R. M., Dahl, H.-H. M., Brown, G. K. Pyruvate dehydrogenase E1-alpha subunit genes in the mouse: mapping and comparison with human homologs. Somat. Cell Molec. Genet. 16: 487-492, 1990. [PubMed: 2122529] [Full Text: https://doi.org/10.1007/BF01233198]
Dahl, H.-H. M., Brown, R. M., Hutchison, W. M., Maragos, C., Brown, G. K. A testis-specific form of the human pyruvate dehydrogenase E1-alpha subunit is coded for by an intronless gene on chromosome 4. Genomics 8: 225-232, 1990. [PubMed: 2249846] [Full Text: https://doi.org/10.1016/0888-7543(90)90275-y]
Kherraf, Z.-E., Cazin, C., Bouker, A., Fourati Ben Mustapha, S., Hennebicq, S., Septier, A., Coutton, C., Raymond, L., Nouchy, M., Thierry-Mieg, N., Zouari, R., Arnoult, C., Ray, P. F. Whole-exome sequencing improves the diagnosis and care of men with non-obstructive azoospermia. Am. J. Hum. Genet. 109: 508-517, 2022. [PubMed: 35172124] [Full Text: https://doi.org/10.1016/j.ajhg.2022.01.011]
Pinheiro, A., Faustino, I., Silva, M. J., Silva, J., Sa, R., Sousa, M., Barros, A., Tavares de Almeida, I., Rivera, I. Human testis-specific PDHA2 gene: methylation status of a CpG island in the open reading frame correlates with transcriptional activity. Molec. Genet. Metab. 99: 425-430, 2010. [PubMed: 20005141] [Full Text: https://doi.org/10.1016/j.ymgme.2009.11.002]
Stumpf, A. M. Personal Communication. Baltimore, Md. 04/06/2022.
Yildirim, Y., Ouriachi, T., Woehlbier, U., Ouahioune, W., Balkan, M., Malik, S., Tolun, A. Linked homozygous BMPR1B and PDHA2 variants in a consanguineous family with complex digit malformation and male infertility. Europ. J. Hum. Genet. 26: 876-885, 2018. [PubMed: 29581481] [Full Text: https://doi.org/10.1038/s41431-018-0121-7]