BGN Mutations in X-Linked Spondyloepimetaphyseal Dysplasia.

Spondyloepimetaphyseal dysplasias (SEMDs) comprise a heterogeneous group of autosomal-dominant and autosomal-recessive disorders. An apparent X-linked recessive (XLR) form of SEMD in a single Italian family was previously reported. We have been able to restudy this family together with a second family from Korea by segregating a severe SEMD in an X-linked pattern. Exome sequencing showed missense mutations in BGN c.439A>G (p.Lys147Glu) in the Korean family and c.776G>T (p.Gly259Val) in the Italian family; the c.439A>G (p.Lys147Glu) mutation was also identified in a further simplex SEMD case from India. Biglycan is an extracellular matrix proteoglycan that can bind transforming growth factor beta (TGF-ß) and thus regulate its free concentration. In 3-dimensional simulation, both altered residues localized to the concave arc of leucine-rich repeat domains of biglycan that interact with TGF-ß. The observation of recurrent BGN mutations in XLR SEMD individuals from different ethnic backgrounds allows us to define "XLR SEMD, BGN type" as a nosologic entity.

Identification and Clinical Implications of Novel MYO15A Mutations in a Non-consanguineous Korean Family by Targeted Exome Sequencing.

Mutations of MYO15A are generally known to cause severe to profound hearing loss throughout all frequencies. Here, we found two novel MYO15A mutations, c.3871C>T (p.L1291F) and c.5835T>G (p.Y1945X) in an affected individual carrying congenital profound sensorineural hearing loss (SNHL) through targeted resequencing of 134 known deafness genes. The variant, p.L1291F and p.Y1945X, resided in the myosin motor and IQ2 domains, respectively. The p.L1291F variant was predicted to affect the structure of the actin-binding site from three-dimensional protein modeling, thereby interfering with the correct interaction between actin and myosin. From the literature analysis, mutations in the N-terminal domain were more frequently associated with residual hearing at low frequencies than mutations in the other regions of this gene. Therefore we suggest a hypothetical genotype-phenotype correlation whereby MYO15A mutations that affect domains other than the N-terminal domain, lead to profound SNHL throughout all frequencies and mutations that affect the N-terminal domain, result in residual hearing at low frequencies. This genotype-phenotype correlation suggests that preservation of residual hearing during auditory rehabilitation like cochlear implantation should be intended for those who carry mutations in the N-terminal domain and that individuals with mutations elsewhere in MYO15A require early cochlear implantation to timely initiate speech development.

Downsloping high-frequency hearing loss due to inner ear tricellular tight junction disruption by a novel ILDR1 mutation in the Ig-like domain.

The immunoglobulin (Ig)-like domain containing receptor 1 (ILDR1) gene encodes angulin-2/ILDR1, a recently discovered tight junction protein, which forms tricellular tight junction (tTJ) structures with tricellulin and lipolysis-stimulated lipoprotein receptor (LSR) at tricellular contacts (TCs) in the inner ear. Previously reported recessive mutations within ILDR1 have been shown to cause severe to profound nonsyndromic sensorineural hearing loss (SNHL), DFNB42. Whole-exome sequencing of a Korean multiplex family segregating partial deafness identified a novel homozygous ILDR1 variant (p.P69H) within the Ig-like domain. To address the pathogenicity of p.P69H, the angulin-2/ILDR1 p.P69H variant protein, along with the previously reported pathogenic ILDR1 mutations, was expressed in angulin-1/LSR knockdown epithelial cells. Interestingly, partial mislocalization of the p.P69H variant protein and tricellulin at TCs was observed, in contrast to a severe mislocalization and complete failure of tricellulin recruitment of the other reported ILDR1 mutations. Additionally, three-dimensional protein modeling revealed that angulin-2/ILDR1 contributed to tTJ by forming a homo-trimer structure through its Ig-like domain, and the p.P69H variant was predicted to disturb homo-trimer formation. In this study, we propose a possible role of angulin-2/ILDR1 in tTJ formation in the inner ear and a wider audiologic phenotypic spectrum of DFNB42 caused by mutations within ILDR1.

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

UNLABELLED: 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.