R. Smeets

Leigh syndrome associated with a mutation in the NDUFS7 (PSST) nuclear encoded subunit of complex I

Leigh syndrome is the phenotypical expression of a genetically heterogeneous cluster of disorders, with pyruvate dehydrogenase complex deficiency and respiratory chain disorders as the main biochemical causes. We report the first missense mutation within the nuclear encoded complex I subunit, NDUFS7, in 2 siblings with neuropathologically proven complex I–deficient Leigh syndrome. Ann Neurol 1999;45:787–790

Clinical heterogeneity in patients with mutations in the NDUFS4 gene of mitochondrial complex I

Summary: A comparison of the clinical presentation, disease course and results of laboratory and imaging studies of all patients so far published with a NDUFS4 mutation are presented. This reveals marked clinical heterogeneity, even in patients with the same genotype.

The human nuclear-encoded acyl carrier subunit (NDUFAB1) of the mitochondrial complex I in human pathology.

We present the cDNA sequence of the human mitochondrial acyl carrier protein NDUFAB1, a nuclear-encoded subunit of complex I of the mitochondrial respiratory chain. We obtained the NDUFAB1 cDNA using the cDNA sequence of the bovine mitochondrial acyl carrier protein. The human cDNA contains two putative translation initiation codons. The human NDUFAB1 protein contains a phosphopantetheine attachment site (DLGLDSLDQVEIIMAM), unique for acyl carrier proteins, and an EF-hand calcium binding domain (DIDAEKLMCPQEI). Transcripts of this gene are found in a wide range of human tissues. The highest expression levels were observed, in descending order, in adult heart, skeletal muscle and fetal heart. We subjected NDUFAB1 fibroblast cDNA of 20 patients with an isolated enzymatic complex I deficiency to mutational detection. No mutations in the NDUFAB1 open reading frame were observed. Future studies will answer whether mutations in the NDUFAB1 promoter or transcription elements are responsible for the observed complex I deficiency.

Fumarase deficiency presenting with periventricular cysts.

SummaryA fumarase-deficient patient expressed a novel phenotype of congenital cerebral ventricular dilatation and periventricular cysts. The patient was a compound heterozygote for two mutations that are the only ones among the 12 published mutations that have been found in multiple, unrelated, fumarase-deficient patients.

The X-chromosomal NDUFA1 gene of complex I in mitochondrial encephalomyopathies: Tissue expression and mutation detection

electron transport chain consists of four protein enzyme complexes, of which The the NADH:ubiquinone oxidoreductase (complex I) is the largest. Complex I contains at least 41 subunits, 7 of which are encoded by the mitochondrial DNA (ND16 and ND4L) ; nuclear genes encode the remainder (HateÐ 1985 ; Walker 1992 ; Complex I catalyses the transfer of electrons from NADH to ubiRobinson 1993). quinone, which is coupled to the translocation of protons across the inner mitochondrial membrane. Patients described with a (partial) complex I deÐciency can generally be categorized into two major clinical phenotypes : an isolated myopathy and a multisystem disorder with predominantly encephalopathy. Respiratory chain defects may be inherited as autosomal, or X-linked Mendelian traits et al et al or in the case of certain muta(Orstavik 1993 ; Zhuchenko 1996), tions in mitochondrial DNA as maternal traits. To date, no mutations in a nuclearencoded subunit of complex I have been described. In our biochemically proven complex I-deÐcient patients as well as among the a†ected siblings, (the latter currently not all biochemically evaluated), we observed a strong male preponderance, suggestive of an X-linked inheritance. Recently, the NDUFA1 gene, one of the nuclear-encoded complex I genes, was isolated and mapped to chromosome Xq24 et al The NDUFA1 (Zhuchenko 1996). gene is composed of three exons, and spans about 5.0 kb of genomic DNA. It shows 80% homology with the bovine MWFE subunit of complex I. The knowledge of function of the human NDUFA1, and the bovine MWFE subunit is very limited. The bovine MWFE subunit is thought to be situated in the extrinsic membrane domain of complex I (Walker 1992).

The nuclear-encoded human NADH:ubiquinone oxidoreductase NDUFA8 subunit: CDNA cloning, chromosomal localization, tissue distribution, and mutation detection in complex-I-deficient patients

We report the cloning of the cDNA sequence of the nuclear-encoded NDUFA8 subunit of NADH: ubiquinone oxidoreductase, the first mitochondrial respiratory chain complex. The NDUFA8 open reading frame (ORF) includes 519 bp and encodes 172 amino acids (Mr=20.1 kDa). The human cDNA sequence shows 86.2% identity with the bovine sequence, whereas the human NDUFA8 amino acid sequence is 87.8% similar to its bovine PGIV protein counterpart. Both human and bovine NDUFA8 contain a conserved cysteine motif. Polymerase chain reaction analysis of rodent/human somatic cell hybrids maps the human NDUFA8 gene to chromosome 9. A multiple tissue blot has revealed the highest NDUFA8 mRNA expression in human heart, skeletal muscle, and fetal heart. Mutation analysis of the NDUFA8 fibroblast cDNA in 20 patients with an isolated enzymatic complex I deficiency in cultured skin fibroblasts has revealed two polymorphisms, one within the ORF and the other in the 3’ untranslated region of the NDUFA8 cDNA sequence. The allelic frequency of both polymorphisms was similar in controls and complex-I-deficient patients.

Molecular characterization and mutational analysis of the human B17 subunit of the mitochondrial respiratory chain complex I

Abstract Bovine NADH:ubiquinone oxidoreductase (complex I) of the mitochondrial respiratory chain consists of about 36 nuclear-encoded subunits. We review the current knowledge of the 15 human complex I subunits cloned so far, and report the 598-bp cDNA sequence, the chromosomal localization and the tissue expression of an additional subunit, the B17 subunit. The cDNA open reading frame of B17 comprises 387 bp and encodes a protein of 128 amino acids (calculated Mr 15.5 kDa). There is 82.7% and 78.1% homology, respectively, at the cDNA and amino acid level with the bovine counterpart. The gene of the B17 subunit has been mapped to chromosome 2. Multiple-tissue dot-blots showed ubiquitous expression of the mRNA with relatively higher expression in tissues known for their high energy demand. Of these, kidney showed the highest expression. Mutational analysis of the subunit revealed no mutations or polymorphisms in 20 patients with isolated enzymatic complex I deficiency in cultured skin fibroblasts.

The human NADH:ubiquinone oxidoreductase NDUFS5 (15kDa) subunit: cDNA cloning, chromosomal localization, tissue distribution and the absence of mutations in isolated complex I-deficient patients

We have cloned the cDNA of the NDUFS5 subunit (15 kDa) of the human mitochondrial respiratory chain complex NADH:ubiquinone oxidoreductase (complex I). The open reading frame consists of 321 base-pairs, coding for 106 amino acids, with a calculated molecular mass of 12.5 kDa. There is an 81.0% identity with the bovine equivalent on cDNA level and 74.5% identity on amino acid basis. PCR analysis of rodent–human somatic cell hybrids revealed that the human NDUFS5 gene maps to chromosome 1. The NDUFS5 mRNA is expressed ubiquitously in human tissues, with a relative higher expression in human heart, skeletal muscle, liver, kidney and fetal heart. A mutation detection study of twenty isolated enzymatic complex I-deficient patients revealed no mutations, nor polymorphisms.