title: Genotyping microsatellite DNA markers at putative disease loci in inbred/multiplex families with respiratory chain complex I deficiency allows rapid identification of a novel nonsense mutation (IVS1nt -1) in the NDUFS4 gene in Leigh syndrome.
abstract: Complex I deficiency, the most common cause of mitochondrial disorders, accounts for a variety of clinical symptoms and its genetic heterogeneity makes identification of the disease genes particularly tedious. Indeed, most of the 43 complex I subunits are encoded by nuclear genes, only seven of them being mitochondrially encoded. In order to offer urgent prenatal diagnosis, we have studied an inbred/multiplex family with complex I deficiency by using microsatellite DNA markers flanking the putative disease loci. Microsatellite DNA markers have allowed us to exclude the NDUFS7, NDUFS8, NDUFV1 and NDUFS1 genes and to find homozygosity at the NDUFS4 locus. Direct sequencing has led to identification of a homozygous splice acceptor site mutation in intron 1 of the NDUFS4 gene (IVS1nt -1, G-->A); this was not found in chorion villi of the ongoing pregnancy. We suggest that genotyping microsatellite DNA markers at putative disease loci in inbred/multiplex families helps to identify the disease-causing mutation. More generally, we suggest giving consideration to a more systematic microsatellite analysis of putative disease loci for identification of disease genes in inbred/multiplex families affected with genetically heterogeneous conditions.
authors.affiliation: Département de Génétique, Maternité and INSERM U393, Hôpital Necker-Enfants Malades, 149 Rue de Sèvres, 75015, Paris, France.
authors.forename: Paule
authors.initials: P
authors.lastname: Bénit
authors.forename: Julie
authors.initials: J
authors.lastname: Steffann
authors.forename: Sophie
authors.initials: S
authors.lastname: Lebon
authors.forename: Dominique
authors.initials: D
authors.lastname: Chretien
authors.forename: Noman
authors.initials: N
authors.lastname: Kadhom
authors.forename: Pascale
authors.initials: P
authors.lastname: de Lonlay
authors.forename: Alice
authors.initials: A
authors.lastname: Goldenberg
authors.forename: Yves
authors.initials: Y
authors.lastname: Dumez
authors.forename: Marc
authors.initials: M
authors.lastname: Dommergues
authors.forename: Pierre
authors.initials: P
authors.lastname: Rustin
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Agnès
authors.initials: A
authors.lastname: Rötig
mesh_terms: D018389:Codon, Nonsense; D042967:Electron Transport Complex I; D005260:Female; D006801:Humans; D007888:Leigh Disease / Q000235:genetics*; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D018895:Microsatellite Repeats; D028361:Mitochondrial Diseases / Q000235:genetics*; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism; D009245:NADH Dehydrogenase; D009247:NADH, NADPH Oxidoreductases / Q000172:deficiency / Q000235:genetics*; D010375:Pedigree
chemical_list: D018389:Codon, Nonsense; D009247:NADH, NADPH Oxidoreductases; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C427643:NDUFS4 protein, human