Premium
Molecular basis of methylmalonyl‐CoA mutase apoenzyme defect in 40 European patients affected by mut ° and mut – forms of methylmalonic acidemia: Identification of 29 novel mutations in the MUT gene
Author(s) -
Acquaviva Cécile,
Benoist JeanFrançois,
Pereira Sabrina,
Callebaut Isabelle,
Koskas Thu,
Porquet Dominique,
Elion Jacques
Publication year - 2005
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.20128
Subject(s) - methylmalonic acidemia , mutase , biology , genetics , biochemistry , enzyme , identification (biology) , computational biology , botany , endocrinology
Abstract Methylmalonyl‐CoA mutase (MCM) apoenzyme deficiency is a rare metabolic disease that may result in distinct biochemical phenotypes of methylmalonic acidemia (MMA), namely mut ° and mut –. We analyzed a cohort of 40 MCM‐deficient patients with MMA affected by either the mut ° or the mut – form of the disease. By direct sequencing of cDNA and gDNA of the MUT gene, we detected 42 mutations, 29 of which were novel mutations. These included five frameshift mutations (insertion, deletion, or duplication of a single nucleotide), five sequence modifications in consensus splice sites, six nonsense and 12 missense mutations, and a large genomic deletion including exon 12. We explored how the 12 novel missense mutations might cause the observed phenotype by mapping them onto a three‐dimensional model of the human MCM generated by homology with the P. shermanii enzyme. In this work we update the spectrum of MCM mutations (n=84), and then discuss their prevalence and distribution throughout the coding sequence in relation to the enzyme structure. Hum Mutat 25:167–176, 2005. © 2005 Wiley‐Liss, Inc.