Dataset Information

Bilateral Nonsyndromic Sensorineural Hearing Loss Caused by a NARS2 Mutation.

ABSTRACT: Mitochondrial diseases disrupt the process of energy generation by the mitochondria, leading to manifestations that can affect almost any organ in the body. Although various possible clinical phenotypes can result, neurological and neuromuscular affection is most frequently encountered. NARS2 encodes an enzyme responsible for the conjugation of asparagine to its cognate mitochondrial transfer ribonucleic acid (tRNA) molecule, representing an essential step necessary for effective mitochondrial protein synthesis. As such, mutations in this gene can lead to poor mitochondrial gene expression and, consequently, poor energy output resulting in disease. Pathogenic variants in NARS2 have been known to cause neurodegenerative and myopathic syndromes in combined oxidative phosphorylation deficiency 24 (COXPD24). However, nonsyndromic autosomal recessive deafness 94 (DFNB94), with which only one family is known to be affected, has also been reported concerning NARS2. Our report demonstrates the association of a new pathogenic variant in mitochondrial asparaginyl-tRNA synthetase (NARS2) with nonsyndromic sensorineural hearing loss, thus confirming biallelic mutations in NARS2 as a cause of nonsyndromic deafness.

SUBMITTER: Al-Sharif F

PROVIDER: S-EPMC9748626 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Bilateral Nonsyndromic Sensorineural Hearing Loss Caused by a NARS2 Mutation.

Al-Sharif Fawzia F Alsadeq Hussain H Rozan Aahid A Halabi Molham B MB Badwilan Hamzah H Mohammed Adel A AA Rahman Moshiur M Balgith Turki T

Cureus 20221114 11

Mitochondrial diseases disrupt the process of energy generation by the mitochondria, leading to manifestations that can affect almost any organ in the body. Although various possible clinical phenotypes can result, neurological and neuromuscular affection is most frequently encountered. NARS2 encodes an enzyme responsible for the conjugation of asparagine to its cognate mitochondrial transfer ribonucleic acid (tRNA) molecule, representing an essential step necessary for effective mitochondrial p ...[more]

PMID: 36523694

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Project description:ImportanceSensorineural hearing loss (SNHL) is commonly caused by conditions that affect cochlear structures or the auditory nerve, and the genes identified as causing SNHL to date only explain a fraction of the overall genetic risk for this debilitating disorder. It is likely that other genes and mutations also cause SNHL.ObjectiveTo identify a candidate gene that causes bilateral, symmetric, progressive SNHL in a large multigeneration family of Northern European descent.Design, setting, and participantsIn this prospective genotype and phenotype study performed from January 1, 2006, through April 1, 2016, a 6-generation family of Northern European descent with 19 individuals having reported early-onset hearing loss suggestive of an autosomal dominant inheritance were studied at a tertiary academic medical center. In addition, 179 unrelated adult individuals with SNHL and 186 adult individuals reporting nondeafness were examined.Main outcomes and measuresSensorineural hearing loss.ResultsNine family members (5 women [55.6%]) provided clinical audiometric and medical records that documented hearing loss. The hearing loss is characterized as bilateral, symmetric, progressive SNHL that reached severe to profound loss in childhood. Audiometric configurations demonstrated a characteristic dip at 1000 to 2000 Hz. All affected family members wear hearing aids or have undergone cochlear implantation. Exome sequencing and linkage and association analyses identified a fully penetrant sequence variant (rs35725509) on chromosome 12q21 (logarithm of odds, 3.3) in the TMTC2 gene region that segregates with SNHL in this family. This gene explains the SNHL occurrence in this family. The variant is also associated with SNHL in a cohort of 363 unrelated individuals (179 patients with confirmed SNHL and 184 controls, P = 7 × 10-4).Conclusions and relevanceA previously uncharacterized gene, TMTC2, has been identified as a candidate for causing progressive SNHL in humans. This finding identifies a novel locus that causes autosomal dominant SNHL and therefore a more detailed understanding of the genetic basis of SNHL. Because TMTC2 has not been previously reported to regulate auditory function, the discovery reveals a potentially new, uncharacterized mechanism of hearing loss.

Dataset Information

Bilateral Nonsyndromic Sensorineural Hearing Loss Caused by a NARS2 Mutation.

Publications

Bilateral Nonsyndromic Sensorineural Hearing Loss Caused by a NARS2 Mutation.

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