Multiple origins of the mtDNA 7472insC mutation associated with hearing loss and neurological dysfunction

Hutchin, Tim; Navarro-Coy, Nuria; Camp, Guy Van; Tiranti, Valeria; Zeviani, Massimo; Schuelke, Markus; Jaksch, Michaela; Newton, Valerie; Mueller, Robert F.

doi:10.1038/sj.ejhg.5200640

Cited by 19 publications

(7 citation statements)

References 11 publications

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“…For instance, sensorineural deafness has been shown to be caused by mutations in the mitochondrial gene encoding tRNA Ser UCN . 20 However, the consequences of MT mutations are hardly predictable. Indeed, mutations in the mitochondrial gene encoding tRNA Ser AGY , which theoretically prevent its ability to be acylated by serine, similar to the effect of the p.Asp390Gly mutation in SARS2, were reported to result in a completely different phenotype consisting primarily of a neurological disease affecting the central nervous system (basal ganglia and cerebral atrophy) and the proximal muscles.…”

Section: Patient F1:iii-6mentioning

confidence: 99%

Mutations in the Mitochondrial Seryl-tRNA Synthetase Cause Hyperuricemia, Pulmonary Hypertension, Renal Failure in Infancy and Alkalosis, HUPRA Syndrome

Belostotsky

Ben-Shalom

Rinat

et al. 2011

The American Journal of Human Genetics

162

128

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An uncharacterized multisystemic mitochondrial cytopathy was diagnosed in two infants from consanguineous Palestinian kindred living in a single village. The most significant clinical findings were tubulopathy (hyperuricemia, metabolic alkalosis), pulmonary hypertension, and progressive renal failure in infancy (HUPRA syndrome). Analysis of the consanguineous pedigree suggested that the causative mutation is in the nuclear DNA. By using genome-wide SNP homozygosity analysis, we identified a homozygous identity-by-descent region on chromosome 19 and detected the pathogenic mutation c.1169A>G (p.Asp390Gly) in SARS2, encoding the mitochondrial seryl-tRNA synthetase. The same homozygous mutation was later identified in a third infant with HUPRA syndrome. The carrier rate of this mutation among inhabitants of this Palestinian isolate was found to be 1:15. The mature enzyme catalyzes the ligation of serine to two mitochondrial tRNA isoacceptors: tRNA(Ser)(AGY) and tRNA(Ser)(UCN). Analysis of amino acylation of the two target tRNAs, extracted from immortalized peripheral lymphocytes derived from two patients, revealed that the p.Asp390Gly mutation significantly impacts on the acylation of tRNA(Ser)(AGY) but probably not that of tRNA(Ser)(UCN). Marked decrease in the expression of the nonacylated transcript and the complete absence of the acylated tRNA(Ser)(AGY) suggest that this mutation leads to significant loss of function and that the uncharged transcripts undergo degradation.

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Section: Patient F1:iii-6mentioning

confidence: 99%

Mutations in the Mitochondrial Seryl-tRNA Synthetase Cause Hyperuricemia, Pulmonary Hypertension, Renal Failure in Infancy and Alkalosis, HUPRA Syndrome

Belostotsky

Ben-Shalom

Rinat

et al. 2011

The American Journal of Human Genetics

162

128

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“…The most commonly reported non-syndromic deafnesscausing mtDNA mutations are: A1555G [1,3,4,16,18], C1494T [19], a C insertion or deletion at position 961 [20][21][22] in the 12S rRNA gene, and A7445G [9,23,24], 7472insC [25,26], T7510C [10] and T7511C [27][28][29] in the tRNA Ser(UCN) gene. Several other variants in the 12S rRNA gene have been identified [30].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial non-syndromic sensorineural hearing loss: a clinical, audiological and pathological study from Italy, and revision of the literature

et al. 2008

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Over the last decade, a number of distinct mutations in the mtDNA (mitochondrial DNA) have been found to be associated with both syndromic and non-syndromic forms of hearing impairment. Their real incidence as a cause of deafness is poorly understood and generally underestimated. Among the known mtDNA mutations, the A1555G mutation in the 12S gene has been identified to be one of the most common genetic cause of deafness, and it has been described to be both associated to non-syndromic progressive SNHL (sensorineural hearing loss) and to aminoglycoside-induced SNHL. In the present study, we have investigated the presence of mtDNA alterations in patients affected by idiopathic non-syndromic SNHL, both familiar and sporadic, in order to evaluate the frequency of mtDNA alterations as a cause of deafness and to describe the audiological manifestations of mitochondrial non-syndromic SNHL. In agreement with previous studies, we found the A1555G mutation to be responsible for a relevant percentage (5.4%) of cases affected with isolated idiopathic sensorineural hearing impairment.

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“…We did not expect to find this mutation as it had only been reported in syndromic cases (hearing loss associated with neurological troubles). 16,17 The proband's deafness was diagnosed at the age of 7. The patient is now 30-year-old and has a mild hearing loss with a U-curve audiogram.…”

Section: Screening For A1555g Trnaser(ucn) and Trnaleu(uur) Gene Mutmentioning

confidence: 99%

Whole mitochondrial genome screening in maternally inherited non-syndromic hearing impairment using a microarray resequencing mitochondrial DNA chip

et al. 2007

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Multiple origins of the mtDNA 7472insC mutation associated with hearing loss and neurological dysfunction

Cited by 19 publications

References 11 publications

Mutations in the Mitochondrial Seryl-tRNA Synthetase Cause Hyperuricemia, Pulmonary Hypertension, Renal Failure in Infancy and Alkalosis, HUPRA Syndrome

Mutations in the Mitochondrial Seryl-tRNA Synthetase Cause Hyperuricemia, Pulmonary Hypertension, Renal Failure in Infancy and Alkalosis, HUPRA Syndrome

Mitochondrial non-syndromic sensorineural hearing loss: a clinical, audiological and pathological study from Italy, and revision of the literature

Whole mitochondrial genome screening in maternally inherited non-syndromic hearing impairment using a microarray resequencing mitochondrial DNA chip

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