The human skeletal muscle adenine nucleotide translocator gene maps to chromosome 4q35 in the region of the facioscapulohumeral muscular dystrophy locus

Wijmenga, Cisca; Winokur, S. T.; Padberg, G.W.A.M.; Skraastad, M. I.; Altherr, Michael R.; Wasmuth, John J.; Murray, Jeffrey C.; Hofker, Marten H.; Frants, Rune R.

doi:10.1007/bf00219692

Cited by 21 publications

(11 citation statements)

References 14 publications

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“…Nonetheless, evidence consistent with the loss-of-PEV hypothesis for FSHD was recently reported by Gabellini et al (26) from RT-PCR analysis of levels of ANT1, FRG1, and FRG2 RNA from several 4q35 genes. Of these genes, ANT1 (26,58,59) is the best candidate because it encodes an adenine nucleotide translocator that has been implicated in a myopathy (progressive external ophthalmoplegia), has been reported to be predominantly expressed in heart and skeletal muscle (26), and is specific for 4q35. However, it is very distant from the D4Z4 array (Fig.…”

Section: Discussionmentioning

confidence: 99%

Testing the position-effect variegation hypothesis for facioscapulohumeral muscular dystrophy by analysis of histone modification and gene expression in subtelomeric 4q

Jiang¹

2003

Human Molecular Genetics

138

125

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Facioscapulohumeral muscular dystrophy (FSHD) is a unique dominant disorder involving shortening of an array of tandem 3.3 kb repeats. This copy-number polymorphic repeat, D4Z4, is present in arrays at both 4q35 and 10q26, but only 4q35 arrays with one to 10 copies of the repeat are linked to FSHD. The most popular model for how the 4q35 array-shortening causes FSHD is that it results in a loss of postulated D4Z4 heterochromatinization, which spreads proximally, leading to overexpression of FSHD genes in cis. This would be similar to a loss of position-effect variegation (PEV) in Drosophila. To test for the putative heterochromatinization, we quantitated chromatin immunoprecipitation with an antibody for acetylated histone H4 that discriminates between constitutive heterochromatin and unexpressed euchromatin. Contrary to the above model, H4 acetylation levels of a non-repeated region adjacent to the 4q35 and 10q26 D4Z4 arrays in normal and FSHD lymphoid cells were like those in unexpressed euchromatin and not constitutive heterochromatin. Also, these control and FSHD cells displayed similar H4 hyperacetylation (like that of expressed genes) at the 5' regions of 4q35 candidate genes FRG1 and ANT1. Contrary to the loss-of-PEV model and a recent report, there was no position-dependent increase in transcript levels from these genes in FSHD skeletal muscle samples compared with controls. Our results favor a new model for the molecular genetic etiology of FSHD, such as, differential long-distance cis looping that depends upon the presence of a 4q35 D4Z4 array with less than a threshold number of copies of the 3.3 kb repeat.

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Section: Discussionmentioning

confidence: 99%

Testing the position-effect variegation hypothesis for facioscapulohumeral muscular dystrophy by analysis of histone modification and gene expression in subtelomeric 4q

Jiang¹

2003

Human Molecular Genetics

138

125

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“…There are multiple ANT isoforms derived from different genes. In humans there are three tissue‐specific isoforms [Stepien et al, 1992]: a heart‐muscle specific isoform (ANT1) located at the chromosome 4q35 locus [Neckelmann et al, 1987; Houldsworth and Attardi, 1988; Cozens et al, 1989; Li et al, 1989; Wijmenga et al, 1992, 1993; Haraguchi et al, 1993; Giraud et al, 1998], an inducible isoform (ANT2) located at Xq24 [Battini et al, 1987; Houldsworth and Attardi, 1988; Chen et al, 1990; Ku et al, 1990; Schiebel et al, 1994], and a systemic isoform (ANT3) located in the pseudoautosomal region at Xp22.3 [Houldsworth and Attardi, 1988; Schiebel et al, 1993; Slim et al, 1993; Giraud et al, 1998]. In mice there are only two ANT genes ( Ant1 and Ant2 ), homologues of the human ANT1 and ANT2 proteins [Levy et al, 2000].…”

Section: Mitochondrial Biology and Geneticsmentioning

confidence: 99%

Mouse models for mitochondrial disease

Wallace

2001

Am. J. Med. Genet.

164

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Mutations in mitochondrial genes encoded by both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) genes have been implicated in a wide range of neuromuscular diseases. MtDNA base substitution and rearrangement mutations generally inactivate one or more tRNA or rRNA genes and can cause myopathy, cardiomyopathy, cataracts, growth retardation, diabetes, etc. nDNA mutations can cause Leigh syndrome, cardiomyopathy, and nephropathy, due to defects in oxidative phosphorylation (OXPHOS) enzyme complexes; cartilage-hair hypoplasia (CHH) and mtDNA depletion syndrome, through defects in mitochondrial nucleic acid metabolism; and ophthalmoplegia with multiple mtDNA deletions, caused by adenine nucleotide translocator-1 (ANT1) mutations. Mouse models have been prepared that recapitulate a number of these diseases. The mtDNA 16S rRNA chloramphenicol (CAP) resistance mutation was introduced into the mouse female germline and caused cataracts and rod and cone abnormalities in chimeras and neonatal lethal myopathy and cardiomyopathy in mutant animals. A mtDNA deletion was introduced into the mouse germline and caused myopathy, cardiomyopathy, and nephropathy. Conditional inactivation of the nDNA mitochondrial transcription factor (Tfam) gene in the heart resulted in neonatal lethal cardiomyopathy, while its inactivation in the pancreatic beta-cells caused diabetes. The ATP/ADP ratio was implicated in mitochondrial diabetes through transgenic modification of the beta-cell ATP-sensitive K(+) channel (K(ATP)). Mutational inactivation of the mouse Ant1 gene resulted in myopathy, cardiomyopathy, and multiple mtDNA deletions in association with elevated reactive oxygen species (ROS) production. Inactivation of uncoupler proteins (Ucp) 1-3 revealed that mitochondrial Delta Psi regulated ROS production. The role of mitochondrial ROS toxicity in disease and aging was confirmed by inactivating glutathione peroxidase (GPx1), resulting in growth retardation, and by total and partial inactivation of Mn superoxide dismutase (MnSOD; Sod2), resulting in neonatal lethal dilated cardiomyopathy and accelerated apoptosis in aging, respectively. The importance of mitochondrial ROS in degenerative diseases and aging was confirmed by treating Sod2 -/- mice and C. elegans with catalytic antioxidant drugs.

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“…We also examined a facio-scapulo-humeral muscular dystrophy (FSHMD) muscle sample, because this mutation maps close to ANT1 on the long arm of chromosome 4 (42,43). A summary of the patients and their percentages of heteroplasmy are provided in Table I.…”

Section: Energy Gene Induction In Skeletal Muscle From Patients With mentioning

confidence: 99%

Coordinate Induction of Energy Gene Expression in Tissues of Mitochondrial Disease Patients

Heddi¹,

Stepien²,

Benke³

et al. 1999

Journal of Biological Chemistry

159

100

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We have examined the transcript levels of a variety of oxidative phosphorylation (OXPHOS) and associated bioenergetic genes in tissues of a patient carrying the myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) A3243G mitochondrial DNA (mtDNA) mutation and the skeletal muscles of 14 patients harboring other pathogenic mtDNA mutations. The patients' tissues, which harbored 88% or more mutant mtDNA, had increased levels of mtDNA transcripts, increased nuclear OXPHOS gene transcripts including the ATP synthase ␤ subunit and the heart-muscle isoform of the adenine nucleotide translocator, and increased ancillary gene transcripts including muscle mitochondrial creatine phosphokinase, muscle glycogen phosphorylase, hexokinase I, muscle phosphofructokinase, the E1␣ subunit of pyruvate dehydrogenase, and the ubiquinone oxidoreductase. A similar coordinate induction of bioenergetic genes was observed in the muscle biopsies of severe pathologic mtDNA mutations. The more significant coordinated expression was found in muscle from patients with the MELAS, myoclonic epilepsy with ragged red fibers, and chronic progressive external ophthalmoplegia deletion syndromes, with ragged red muscle fibers and mitochondrial paracrystalline inclusions. High levels of mutant mtDNAs were linked to a high induction of the mtDNA and nuclear OXPHOS genes and of several associated bioenergetic genes. These observations suggest that human tissues attempt to compensate for OXPHOS defects associated with mtDNA mutations by stimulating mitochondrial biogenesis, possibly mediated through redox-sensitive transcription factors.

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The human skeletal muscle adenine nucleotide translocator gene maps to chromosome 4q35 in the region of the facioscapulohumeral muscular dystrophy locus

Cited by 21 publications

References 14 publications

Testing the position-effect variegation hypothesis for facioscapulohumeral muscular dystrophy by analysis of histone modification and gene expression in subtelomeric 4q

Testing the position-effect variegation hypothesis for facioscapulohumeral muscular dystrophy by analysis of histone modification and gene expression in subtelomeric 4q

Mouse models for mitochondrial disease

Coordinate Induction of Energy Gene Expression in Tissues of Mitochondrial Disease Patients

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