A novel mutation of TMPRSS3 related to milder auditory phenotype in Korean postlingual deafness: a possible future implication for a personalized auditory rehabilitation.

Abstract

Appropriate customized auditory rehabilitation for hearing impaired subjects

requires prediction of residual hearing and progression of hearing loss.

Mutations in TMPRSS3 encoding a transmembrane serine protease were reported to be

associated with two different autosomal recessive nonsyndromic hearing loss

(arNSHL) phenotypes, DFNB8 and DFNB10, in terms of residual hearing that may

mandate different rehabilitation. We aimed to reveal the genetic contribution of

TMPRSS3 mutations among Korean populations and to correlate the clinical

phenotype with TMPRSS3 genotypes. Fifty families that segregated arNSHL and have

visited our clinic recently for 2 years were recruited for TMPRSS3 screening.

Novel TMPRSS3 variants detected in our cohort were modeled using a predicted

three-dimensional (3D) structure of the serine protease domain. The prevalence

reached up to 11.2 % (3/27) among subjects with either prelingual hearing loss

but retaining some degree of language development or with postlingual ski-slope

hearing loss. We also found that a p.A306T allele is a founder allele in this

population. Based upon the 3D modeling, we were able to correlate significant

retention of residual low-frequency hearing and slower progression of its loss to

this novel variant p.T248M that was predicted to have milder pathogenicity. A

yeast-based protease assay confirmed a mild pathogenic potential of the p.T248M

variant and a tight correlation between the protease activity and the residual

hearing. Preservation of this low-frequency hearing should be of utmost

importance when considering auditory rehabilitation. Our results significantly

narrow down the candidate population for TMPRSS3 sequencing for more efficient

genetic diagnosis. More importantly, genotype-phenotype correlation of this gene

observed in our cohort suggests that TMPRSS3 can be an appropriate candidate for

personalized and customized auditory rehabilitation. KEY MESSAGE: The prevalence

of TMPRSS3 mutations among Korean postlingual hearing loss is 8.3 %. The p.A306T

variant of TMPRSS3 is the common founder allele in Koreans. A novel variant,

p.T248M of TMPRSS3, was predicted to have milder pathogenicity. There was a

genotype-phenotype correlation of this gene in Koreans. Our data support

implication of this gene for personalized rehabilitation.