Demonstration of a New Pathogenic Mutation in Human Complex I Deficiency: A 5-bp Duplication in the Nuclear Gene Encoding the 18-kD (AQDQ) Subunit

Abstract

We report the cDNA cloning, chromosomal localization, and a mutation in the human nuclear gene encoding the 18-kD (AQDQ) subunit of the mitochondrial respiratory chain complex I. The cDNA has an open reading frame of 175 amino acids and codes for a protein with a molecular mass of 23.2 kD. Its gene was mapped to chromosome 5. A homozygous 5-bp duplication, destroying a consensus phosphorylation site, in the 18-kD cDNA was found in a complex I-deficient patient. The patient showed normal muscle morphology and a remarkably nonspecific fatal progressive phenotype without increased lactate concentrations in body fluids. The child's parents were heterozygous for the mutation. In 19 other complex I-deficient patients, no mutations were found in the 18-kD gene.

Effects of disrupting the 21 kDa subunit of complex I from Neurospora crassa

“…This is not surprising because many (if not all) subunits of the fungal complex I can be disrupted [5,14]. The first (and yet unique) mutation in nuclear-coded subunits of complex I involved in mitochondrial diseases was found in the AQDQ human homologue of the 21 kDa protein [10]. The patient presented with a multisystemic disorder with a fatal progressive phenotype, owing to a pathological duplication of five base pairs in the gene that altered the C-terminal region and abolished the putative phosphorylation site of the protein [10,11].…”

“…The first (and yet unique) mutation in nuclear-coded subunits of complex I involved in mitochondrial diseases was found in the AQDQ human homologue of the 21 kDa protein [10]. The patient presented with a multisystemic disorder with a fatal progressive phenotype, owing to a pathological duplication of five base pairs in the gene that altered the C-terminal region and abolished the putative phosphorylation site of the protein [10,11]. The fact that the patient was homozygous for the mutation and originated from two heterozygous parents [10] suggests that a ' loss-of-function ' phenotype is involved.…”

“…The patient presented with a multisystemic disorder with a fatal progressive phenotype, owing to a pathological duplication of five base pairs in the gene that altered the C-terminal region and abolished the putative phosphorylation site of the protein [10,11]. The fact that the patient was homozygous for the mutation and originated from two heterozygous parents [10] suggests that a ' loss-of-function ' phenotype is involved. Thus the nuo21 mutant of N. crassa, in which expression of the protein was abrogated, should mimic the human situation.…”

“…In addition, there is no homologue of the 21 kDa polypeptide among the 14 protein constituents of prokaryotic complex I, which are considered to be the ' minimal structure ' required for the coupling of electron transfer with proton translocation [1][2][3][4]. It should be noticed that an increased lactate concentration in body fluids, found in other complex I-deficient patients [40,41], was not seen in the AQDQ-defective patient [10]. Another strong possibility, however, is that a mutation in, or a lack of, the 21 kDa protein interferes with the efficiency of energy transduction by complex I.…”

“…However, most of the nuclear-coded subunits of complex I are missing from bacterial genomes and it is expected that mutations in these proteins will be found as more human diseases are studied in detail. In fact, the first description of a human mutation affecting a nuclearcoded subunit of complex I has appeared recently [10]. The protein, called AQDQ, is phosphorylated by a mitochondrial cAMP-dependent kinase, although the role of this modification is unknown [11].…”