Molecular analysis of PCCB gene in Korean patients with propionic acidemia.
Propionic acidemia (PA) is an autosomal recessive inborn error in the catabolism of methionine, isoleucine, threonine, and valine, odd-numbered chain length fatty acids and cholesterol. Clinical symptoms are very heterogeneous and present as a severe neonatal-onset or a late-onset form. It is caused by a deficiency of propionyl-CoA carboxylase (PCC, EC 6.4.1.3), a biotin-dependent enzyme that catalyzes the carboxylation of propionyl-CoA to D-methylmalonyl-CoA. PCC is a heteropolymeric enzyme composed of alpha- and beta-subunits. A greater heterogeneity is observed in the PCCA gene, while for the PCCB gene, a limited number of mutations is responsible for the majority of the alleles characterized in both Caucasian and Oriental populations. We identified eight Korean patients with PA by organic acid analysis confirmed in five patients by the PCC enzyme assay in the lymphoblasts. Two neonatal-onset patients showed undetectable PCC activities while three cases with residual enzyme activities had relatively late manifestations. In the molecular analysis, we identified five novel mutations, Y439C, 1527del3, 1357insT, IVS12-8T-->A, and 31del10, and one known mutation, T428I in PCCB gene. Alleleic frequency of T428I in Korean patients with PA was 56.3% in this study. Two neonatal-onset patients with null enzyme activities were homozygotes with 1527del3 and T428I, respectively. This finding implies that T428I and 1527del3 mutation could be responsible for their severe clinical courses and null enzyme activities. The mRNA of PCCB gene in T428I and 1527del3 homozygotes were normal but in Western blot analysis, the betaPCC-subunit was only absent in 1527del3 homozygote patient suggesting different molecular pathology.
T10 T11 T12 T13 T14 T15 T16 T17 T18 T19 T1 T20 T21 T22 T23 T24 T25 T26 T27 T28 T29 T2 T30 T3 T4 T5 T6 T7 T8 T9
CHEMICAL CHEMICAL GENE-N GENE-N GENE-N GENE-Y GENE-N GENE-N GENE-N GENE-Y CHEMICAL GENE-N GENE-Y GENE-N GENE-N GENE-Y GENE-N GENE-Y GENE-Y GENE-N GENE-N CHEMICAL GENE-Y CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
isoleucine propionic Y439C IVS12-8T-->A T428I PCCB T428I T428I T428I PCCB threonine T428I betaPCC propionyl-CoA carboxylase PCC EC 6.4.1.3 PCC PCCA PCCB PCC PCC valine PCCB odd-numbered chain length fatty acids cholesterol propionyl-CoA biotin propionyl-CoA D-methylmalonyl-CoA methionine