Molecular genetic study on Chinese patients with propionic acidemia
| Autor: | 劉又寧 |
|---|---|
| Rok vydání: | 2002 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 90 Propionic acidemia (PA, MIM 232000, 232050) is a rare autosomal recessive metabolic error of propionic acid, the catabolism product of methionine, isoleucine, threonine and valine, odd-numbered chain length fatty acids and cholesterol. The disease is clinically very heterogeneous and characterized by recurrent metabolic ketoacidosis, vomiting, lethargy and hypotonia. It is caused by the deficiency of propionyl CoA carboxylase (PCC, EC 6.4.1.3), a biotin-dependent mitochondrial enzyme that catalyzes the carboxylation of propionyl-CoA to D-methylmalonyl-CoA. The PCC is composed of two types of subunits, an α subunit (74 kDa), containing the covalently attached biotin cofactor, and a β subunit (55 kDa), likely in an α6β6 structure. The PCCA and PCCB gene, which encode the α and β subunits, have been mapped to chromosomes 13 and 3, respectively. Defect either in α or β subunit will cause PCC deficiency. In this study, 24 exons of the PCCA gene and 15 exons of the PCCB gene, were PCR amplified and sequenced to analyze the mutations in Chinese PA families. One PA patient was identified to have c.1193C>T transition resulting in the replacement of Pro for Leu at codon 398 (P398L) in the PCCA gene. This c.1193C>T mutation had been reported in a Japanese PA patient. Five novel mutations, designated c.491C>T (A164V), c.560_561delinsA (S187X), c.580T>C (S194P), c.601G>A (A201T) and c.1301C>T (A434V) alteration, were identified in the PCCB gene of four PA patients. Two of these patients were homozygote of c.491C>T mutation and c.1301C>T mutation, respectively. All patients were born in a non-consanguineous family. No other mutation was detected in the coding region and exon/intron boundary of PCCA and PCCB gene for these 5 patients. All of these 6 variations identified in PCCA and PCCB gene were not detected in 100 Chinese normal alleles. These data indicated the c.1193C>T in the PCCA gene and the c.491C>T, c.560_561delinsA, c.580T>C, c.601G>A and c.1301C>T in the PCCB gene might be the disease causing mutations of PA. Two STR markers, D3S3528 and D3S2453, were analyzed to study whether the transmission of c.491C>T and c.1301C>T transition of the PCCB gene identified in the Chinese PA families were linked disequilibrium. The heterozygosity of D3S3528 and D3S2453 were found to be 38% and 64% in Chinese population. The homozygous c.491C>T mutation found in one PA family was linked to the same 272bp allele of D3S3528. Three c.1301C>T alleles identified in two PA families were linked to the same 270bp allele of D3S3528. The 270bp and 272bp allele of D3S3528 were found to be less frequent in normal Chinese population (11.0% and 6.1%, respectively). These data suggested that the c.491C>T and c.1301C>T mutation in Chinese PA patients might have founder effects. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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