title: Pathological mutations of the human NDUFS4 gene of the 18-kDa (AQDQ) subunit of complex I affect the expression of the protein and the assembly and function of the complex.
abstract: Presented is a study of the impact on the structure and function of human complex I of three different homozygous mutations in the NDUFS4 gene coding for the 18-kDa subunit of respiratory complex I, inherited by autosomal recessive mode in three children affected by a fatal neurological Leigh-like syndrome. The mutations consisted, respectively, of a AAGTC duplication at position 466-470 of the coding sequence, a single base deletion at position 289/290, and a G44A nonsense mutation in the first exon of the gene. All three mutations were found to be associated with a defect of the assembly of a functional complex in the inner mitochondrial membrane. In all the mutations, in addition to destruction of the carboxyl-terminal segment of the 18-kDa subunit, the amino-terminal segment of the protein was also missing. In the mutation that was expected to produce a truncated subunit, the disappearance of the protein was associated with an almost complete disappearance of the NDUFS4 transcript. These observations show the essential role of the NDUFS4 gene in the structure and function of complex I and give insight into the pathogenic mechanism of NDUFS4 gene mutations in a severe defect of complex I.
authors.affiliation: Department of Medical Biochemistry and Medical Biology, University of Bari, 70124 Bari, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Scacco
authors.forename: Vittoria
authors.initials: V
authors.lastname: Petruzzella
authors.forename: Sandy
authors.initials: S
authors.lastname: Budde
authors.forename: Rosaria
authors.initials: R
authors.lastname: Vergari
authors.forename: Rosanna
authors.initials: R
authors.lastname: Tamborra
authors.forename: Damiano
authors.initials: D
authors.lastname: Panelli
authors.forename: Lambert P
authors.initials: LP
authors.lastname: van den Heuvel
authors.forename: Jan A
authors.initials: JA
authors.lastname: Smeitink
authors.forename: Sergio
authors.initials: S
authors.lastname: Papa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002417:Cattle; D002478:Cells, Cultured; D018389:Codon, Nonsense; D018076:DNA, Complementary / Q000737:chemistry; D042967:Electron Transport Complex I; D004591:Electrophoresis, Polyacrylamide Gel; D005347:Fibroblasts / Q000737:chemistry; D017353:Gene Deletion; D020440:Gene Duplication; D006801:Humans; D007888:Leigh Disease / Q000235:genetics*; D008929:Mitochondria, Heart / Q000737:chemistry; D008969:Molecular Sequence Data; D009154:Mutation; D009245:NADH Dehydrogenase; D009247:NADH, NADPH Oxidoreductases / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D012867:Skin; D013329:Structure-Activity Relationship
chemical_list: D018389:Codon, Nonsense; D018076:DNA, Complementary; D012333:RNA, Messenger; D009247:NADH, NADPH Oxidoreductases; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C427643:NDUFS4 protein, human