Molecular Characterization of Pyruvate Carboxylase Deficiency in Two Consanguineous Families

丙酮酸羧化酶 缬氨酸 生物化学 生物 先天性代谢错误 遗传学 丙氨酸 氨基酸
作者
Isaiah D. Wexler,Douglas S. Kerr,Yuefen Du,Marie Kaung,William Stephenson,Marilyn M Lusk,Rebecca S. Wappner,Joseph Higgins
出处
期刊:Pediatric Research [Springer Nature]
卷期号:43 (5): 579-584 被引量:37
标识
DOI:10.1203/00006450-199805000-00004
摘要

Pyruvate carboxylase (PC) is a biotinylated mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate. Children with inborn errors of PC metabolism have lactic acidosis, hypoglycemia, and mental retardation. The variable severity of the clinical phenotype is dependent on both genetic and environmental factors. Two consanguineous families with moderate forms of PC deficiency were characterized at the biochemical and molecular levels. In both families, the probands were found to have low PC activity (range, 2-25% of control) in blood lymphocytes and skin fibroblasts associated with either diminished or normal protein levels. In the first case, sequencing of patient-specific PC cDNA demonstrated a T to C substitution at nucleotide 434, which causes a valine to alanine change at amino acid residue 145. Direct sequencing of the parents showed that they are heterozygous for this mutation. In the second family, a brother and sister had mental retardation and episodes of severe lactic/ketoacidosis in early childhood. In these cases, a C to T substitution at nucleotide 1351 results in a cysteine for arginine substitution at amino acid residue 451; the parents were also found to be heterozygous for this mutation. In both families, no other mutations were found, and both substitutions occurred in relatively conserved amino acid residues. These mutations, located in the biotin carboxylase domain, provide a unique opportunity to analyze how natural occurring mutations affect PC function.

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