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Genetic and cellular studies of oxidative stress in methylmalonic aciduria (MMA) cobalamin deficiency type C ( cblC ) with homocystinuria (MMACHC)
Author(s) -
Richard Eva,
JorgeFinnigan Ana,
GarciaVilloria Judit,
Merinero Begoña,
Desviat Lourdes R.,
Gort Laura,
Briones Paz,
Leal Fátima,
PérezCerdá Celia,
Ribes Antonia,
Ugarte Magdalena,
Pérez Belén
Publication year - 2009
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.21107
Subject(s) - cobalamin , methylmalonic aciduria , methylmalonic acidemia , biology , oxidative stress , homocystinuria , microbiology and biotechnology , biochemistry , genetics , vitamin b12 , endocrinology , methionine , amino acid
Abstract Methylmalonic aciduria (MMA) cobalamin deficiency type C ( cblC ) with homocystinuria (MMACHC) is the most frequent genetic disorder of vitamin B 12 metabolism. The aim of this work was to identify the mutational spectrum in a cohort of cblC ‐affected patients and the analysis of the cellular oxidative stress and apoptosis processes, in the presence or absence of vitamin B 12 . The mutational spectrum includes nine previously described mutations: c.3G>A (p.M1L), c.217C>T (p.R73X), c.271dupA (p.R91KfsX14), c.331C>T (p.R111X), c.394C>T (p.R132X), c.457C>T (p.R153X), c.481C>T (p.R161X), c.565C>A (p.R189S), and c.615C>G (p.Y205X), and two novel changes, c.90G>A (p.W30X) and c.81+2T>G (IVS1+2T>G). The most frequent change was the known c.271dupA mutation, which accounts for 85% of the mutant alleles characterized in this cohort of patients. Owing to its high frequency, a real‐time PCR and subsequent high‐resolution melting (HRM) analysis for this mutation has been established for diagnostic purposes. All cell lines studied presented a significant increase of intracellular reactive oxygen species (ROS) content, and also a high rate of apoptosis, suggesting that elevated ROS levels might induce apoptosis in cblC patients. In addition, ROS levels decreased in hydroxocobalamin‐incubated cells, indicating that cobalamin might either directly or indirectly act as a scavenger of ROS. ROS production might be considered as a phenotypic modifier in cblC patients, and cobalamin supplementation or additional antioxidant drugs might suppress apoptosis and prevent cellular damage in these patients. Hum Mutat 30:1–9, 2009. © 2009 Wiley‐Liss, Inc.