Genetic heterogeneity in propionic acidemia patients with alpha-subunit defects. Identification of five novel mutations, one of them causing instability of the protein
E. Richard et al., Genetic heterogeneity in propionic acidemia patients with alpha-subunit defects. Identification of five novel mutations, one of them causing instability of the protein, BBA-MOL BAS, 1453(3), 1999, pp. 351-358
Citations number
25
Categorie Soggetti
Medical Research General Topics
Journal title
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
The inherited metabolic disease propionic acidemia (PA) can result from mut
ations in either of the genes PCCA or PCCB, which encode the alpha and beta
subunits, respectively, of the mitochondrial enzyme propionyl CoA-carboxyl
ase. In this work we have analyzed the molecular basis of PCCA gene defects
, studying mRNA levels and identifying putative disease causing mutations.
A total of 10 different mutations, none predominant, are present in a sampl
e of 24 mutant alleles studied. Five novel mutations are reported here for
the first time. A neutral polymorphism and a variant allele present in the
general population were also detected. To examine the effect of a point mut
ation (M348K) involving a highly conserved residue, we have carried out in
vitro expression of normal and mutant PCCA cDNA and analyzed the mitochondr
ial import and stability of the resulting proteins. Both wild-type and muta
nt proteins were imported into mitochondria and processed into the mature f
orm with similar efficiency, but the mature mutant M348K protein decayed mo
re rapidly than did the wild-type, indicating a reduced stability, which is
probably the disease-causing mechanism. (C) 1999 Elsevier Science B.V. All
rights reserved.