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Pyruvate carboxylase deficiency type A and type C: Characterization of five novel pathogenic variants in PC and analysis of the genotype–phenotype correlation
Author(s) -
Coci Emanuele G.,
Gapsys Vytautas,
Shur Natasha,
ShinPodskarbi Yoon,
Groot Bert L.,
Miller Kathryn,
Vockley Jerry,
Sondheimer Neal,
Ganetzky Rebecca,
Freisinger Peter
Publication year - 2019
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23742
Subject(s) - biology , genotype , phenotype , wild type , genetics , in silico , gene , genotype phenotype distinction , compound heterozygosity , mutation , microbiology and biotechnology , mutant
Pyruvate carboxylase deficiency (PCD) is caused by biallelic mutations of the PC gene. The reported clinical spectrum includes a neonatal form with early death (type B), an infantile fatal form (type A), and a late‐onset form with isolated mild intellectual delay (type C). Apart from homozygous stop‐codon mutations leading to type B PCD, a genotype–phenotype correlation has not otherwise been discernible. Indeed, patients harboring biallelic heterozygous variants leading to PC activity near zero can present either with a fatal infantile type A or with a benign late onset type C form. In this study, we analyzed six novel patients with type A (three) and type C (three) PCD, and compared them with previously reported cases. First, we observed that type C PCD is not associated to homozygous variants in PC . In silico modeling was used to map former and novel variants associated to type A and C PCD, and to predict their potential effects on the enzyme structure and function. We found that variants lead to type A or type C phenotype based on the destabilization between the two major enzyme conformers. In general, our study on novel and previously reported patients improves the overall understanding on type A and C PCD.