A novel familial case of diffuse leukodystrophy related to NDUFV1 compound heterozygous mutations

Highlights

• NDUFV1 mutations are related to mitochondrial energy metabolism disturbances.

• We identified a novel pathogenic NDUFV1 mutation associated with diffuse leukodystrophy.

• The results add information on the molecular basis and the phenotypic features of mitochondrial disease.

Abstract

NDUFV1 mutations have been related to encephalopathic phenotypes due to mitochondrial energy metabolism disturbances. In this study, we report two siblings affected by a diffuse leukodystrophy, who carry the NDUFV1 c.1156C>T (p.Arg386Cys) missense mutation and a novel 42-bp deletion. Bioinformatic and molecular analysis indicated that this deletion lead to the synthesis of mRNA molecules carrying a premature stop codon, which might be degraded by the nonsense-mediated decay system. Our results add information on the molecular basis and the phenotypic features of mitochondrial disease caused by NDUFV1 mutations.

Introduction

Mitochondrial respiratory chain disorders (MD) are a group of phenotypically heterogeneous pathologies characterized by energy metabolism disturbances. Clinical manifestations include hepatopathy, cardiomyopathy, lactic acidosis, leukoencephalopathy and Leigh syndrome. MD are among the most frequent inherited neurological disorders (Skladal et al., 2003, Thorburn, 2004). They are caused by both nuclear and mitochondrial DNA mutations, especially in genes encoding Complex I (CI) proteins (Pagniez-Mammeri et al., 2012). CI, also named nicotinamide adenine dinucleotide (NADH): ubiquinone oxidoreductase, is a multi-protein complex assembled from more than 40 subunits, encoded by nuclear and mitochondrial DNA (Brandt, 2006). The CI central catalytic core is composed by 14 functional subunits forming three major modules (named N, P and Q) (Brandt, 2006, Pagniez-Mammeri et al., 2012). Briefly, the N module (input module) oxidizes NADH, the P module translocates protons across the membrane and the Q module (output module) reduces ubiquinone. The NADH dehydrogenase (ubiquinone) flavoprotein 1 (NDUFV1) subunit is a part of the N module and binds to the flavin mononucleotide, a structure that transfers electrons from NADH to iron-sulfur clusters. Up to now, sixteen pathogenic NDUFV1 mutations have been reported in patients displaying encephalopathic phenotypes (Benit et al., 2001, Breningstall et al., 2008, Bugiani et al., 2004, Calvo et al., 2010, Koene et al., 2012, Laugel et al., 2007, Moran et al., 2010, Schuelke et al., 1999, Vilain et al., 2012, Zafeiriou et al., 2008). However, no genotype–phenotype correlations have been clearly identified. This might be due to the structural and functional complexity of CI and to the difficulty to perform functional tests.

In this study, we report two siblings affected by a diffuse leukodystrophy, who carry a previously reported point mutation (p.Arg386Cys) and a novel 42 bp deletion encompassing the intron 6/exon 7 junction of NDUFV1. Bioinformatic and molecular analysis indicated that this mutation lead to the synthesis of mRNA molecules carrying a premature stop codon, which might be degraded by the nonsense-mediated decay (NMD) system. Our results add information on the molecular basis and the phenotypic features of mitochondrial disease caused by NDUFV1 mutations.