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Mutations of the E1beta subunit gene (PDHB) in four families with pyruvate dehydrogenase deficiency
K Okajima1, L G Korotchkina, C Prasad
1Center for Inherited Disorders of Energy Metabolism, Rainbow Babies and Childrens Hospital, University Hospitals Case Medical Center, Department of Pediatrics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106 6004, USA.
Insights
Mutations in the PDHB gene, causing pyruvate dehydrogenase complex (PDC) deficiency, lead to lactic acidosis and developmental delays. These PDHB mutations are less common than PDHA1 mutations but share similar clinical features.
Area of Science:
- Biochemistry
- Genetics
- Neurology
Background:
- Pyruvate dehydrogenase complex (PDC) deficiency is a primary cause of lactic acidosis.
- Mutations in PDHA1 are the most common cause, while mutations in PDHB are less frequent.
Observation:
- Four cases of PDHB mutations were identified among 83 PDC deficiency cases.
- These mutations accounted for approximately 10% of PDC deficiencies, compared to PDHA1 mutations.
- Clinical presentations included lactic acidosis, developmental delay, agenesis of the corpus callosum, seizures, and hypotonia.
Findings:
- Specific PDHB mutations (R36C, C306R/D319V, I142M/W165S, Y132C) were identified in diverse ethnic groups.
- Consanguinity was noted in families with PDHB mutations.
- Computer analysis predicted that these mutations cause conformational changes affecting protein interactions and stability.
Implications:
- PDHB mutations represent a significant, though less common, cause of PDC deficiency.
- Understanding these mutations aids in diagnosing and managing primary lactic acidosis.
- The conserved nature of affected residues highlights their critical role in enzyme function.
Abstract:
Pyruvate dehydrogenase complex (PDC) deficiencies are a major cause of primary lactic acidosis. Most cases result from mutations of the gene for the pyruvate dehydrogenase E1alpha subunit (PDHA1), with fewer cases resulting from mutations in genes for E3, E3-binding protein, E2, and the E1beta subunit (PDHB). We have found four cases of PDHB mutations among 83 analyzed cases of PDC deficiency. In this series, PDHB mutations were found to be about 10% as frequent as PDHA1 mutations. All cases were diagnosed by low PDC activity, with normal E2 and E3 activities. These included a 6.5-year-old male (consanguineous, homozygous R36C); a neonatal female who died soon after birth, (compound heterozygous C306R/D319V), a 26-year-old female (heterozygous I142M/W165S), and a 13month old female (consanguineous, homozygous Y132C) who is a sibling of a previously published case. Their ethnic background is diverse (Caucasian, Arab, and African American descent). All cases had lactic acidosis and developmental delay. Three cases had agenesis of the corpus callosum, seizures, and hypotonia; one died within the first year of life. These clinical findings are similar to those of PDHA1 deficiency, except that ataxia was more frequent in PDHA1 cases and consanguinity was found only in PDHB families. PDC activity in lymphocytes from six parents is normal, who all are heterozygous carriers for the respective mutations. Immunoreactivity of E1beta was markedly reduced in one case and showed a slightly larger form of E1beta in one case. Computer analysis predicts that: R36C affects the interaction of several amino acids resulting in conformational change, C306R affects interaction of the two beta subunits, D319 is in the interface of E1 and E2, I142M affects conformation around a K ion affecting stability of the beta subunit, W165S affects hydrophobic interaction between the beta subunits, and Y132C affects interaction between the beta subunits. All of these residues are conserved in E1beta across species, and Y132 is also conserved in other TPP-requiring enzymes. These observations support the conclusion that these are pathogenic mutations.
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