Molecular genetics of MARVELD2 and clinical phenotype in Pakistani and Slovak families segregating DFNB49 hearing loss

Nayak, Gowri; Varga, Lukáš; Trincot, Claire E.; Shahzad, Mohsin; Friedman, Penelope L.; Klimeš, I; Greinwald, John H.; Riazuddin, Sheikh; Masindova, Ivica; Profant, Milan; Khan, Shaheen N.; Friedman, Thomas B.; Ahmed, Zubair M.; Gašperíková, Daniela; Riazuddin, Saima

doi:10.1007/s00439-015-1532-y

Cited by 18 publications

(18 citation statements)

References 29 publications

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“…In addition, the morphology of the Tric −/− mouse ES remained normal (Figure 3), with no indication of endolymphatic hydrops. These findings were compatible with the observation that Tric −/− mice show no disturbance in the sense of equilibrium, [10] and the fact that TRIC gene (DFNB49) mutations lead to hearing loss with no obvious vestibular phenotype in humans [9,16,17] .…”

Section: Discussionsupporting

confidence: 79%

Tricellulin Expression and its Deletion Effects in the Endolymphatic Sac

et al. 2018

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OBJECTIVES:Tricellulin is a tight junction (TJ)-forming protein that participates in the sealing function of tricellular TJs. Tricellulin-knockout (Tric−/−) mice show progressive hearing loss with degeneration of hair cells in the cochlea without physiological or physical disorders. In the present study, we investigated the tricellulin expression and its deletion effects in the endolymphatic sac (ES) using Tric−/− mice. MATERIALS and METHODS:The ES epithelia from wild-type (WT) mice were laser-microdissected, and RT-PCR was performed. The ES sections from Tric−/− and WT mice were immunostained with an anti-tricellulin antibody. Hematoxylin and eosin staining was performed for morphological examination. The inner ear of Tric−/− mice was perfused with biotinylation reagents, and the ES sections were observed for tracer permeability assay after applying streptavidin-Alexa Fluor 488 conjugate. RESULTS:The tricellulin expression was confirmed by RT-PCR and by immunohistochemistry in the WT ES. The ES in Tric−/− mice showed normal morphology and revealed no biotin leakage from the lumen. CONCLUSION:The ES in Tric−/− mice showed no changes in morphology or disruption in macromolecular barrier function. The effects of solute leakages in the ES of Tric−/− mice may be very limited and compensatable, or that the ES epithelia may have other sealing system covering the lack of tricellulin.

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Section: Discussionsupporting

confidence: 79%

Tricellulin Expression and its Deletion Effects in the Endolymphatic Sac

et al. 2018

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“…Linkage analysis of NSRHL segregating in family PKDF041 with STR markers across the genome, previously revealed linkage to DFNB49 locus on chromosome 5, with a maximum two-point lod score (Zmax) of 4.44 (θ = 0) for marker D5S2055 [ 13 ]. Subsequently, mutations in TRIC were identified as the cause of DFNB49 -linked HL [ 14 , 15 ]. Full sequencing of TRIC in the genomic DNA from two affected individuals from the PKDF041 family along with a normal hearing sibling did not reveal any pathogenic variants, suggesting there is an additional gene in the PKDF041 linkage interval in which a pathogenic variant is associated with deafness.…”

Section: Resultsmentioning

confidence: 99%

Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse

Yousaf

Ahmed

et al. 2018

PLoS Genet

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Autosomal recessive nonsyndromic hearing loss is a genetically heterogeneous disorder. Here, we report a severe-to-profound sensorineural hearing loss locus, DFNB100 on chromosome 5q13.2-q23.2. Exome enrichment followed by massive parallel sequencing revealed a c.2510G>A transition variant in PPIP5K2 that segregated with DFNB100-associated hearing loss in two large apparently unrelated Pakistani families. PPIP5Ks enzymes interconvert 5-IP7 and IP8, two key members of the inositol pyrophosphate (PP-IP) cell-signaling family. Their actions at the interface of cell signaling and bioenergetic homeostasis can impact many biological processes. The c.2510G>A transition variant is predicted to substitute a highly invariant arginine residue with histidine (p.Arg837His) in the phosphatase domain of PPIP5K2. Biochemical studies revealed that the p.Arg837His variant reduces the phosphatase activity of PPIP5K2 and elevates its kinase activity. We found that in mouse inner ear, PPIP5K2 is expressed in the cochlear and vestibular sensory hair cells, supporting cells and spiral ganglion neurons. Mice homozygous for a targeted deletion of the Ppip5k2 phosphatase domain exhibit degeneration of cochlear outer hair cells and elevated hearing thresholds. Our demonstration that PPIP5K2 has a role in hearing in humans indicates that PP-IP signaling is important to hair cell maintenance and function within inner ear.

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“…Mutations in MARVELD2 , which encodes tricellulin, and located at the DFNB49 locus, cause ARNSHL [ 31 ]. Seven different pathogenic variants of human MARVELD2 have been identified in patients with moderate to profound hearing loss [ 31 , 32 ]. Nayak et al reported that MARVELD2 mutations were responsible for about 1.5% of NSHL in their cohort of 800 Pakistani families[ 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…Seven different pathogenic variants of human MARVELD2 have been identified in patients with moderate to profound hearing loss [ 31 , 32 ]. Nayak et al reported that MARVELD2 mutations were responsible for about 1.5% of NSHL in their cohort of 800 Pakistani families[ 32 ]. The splice junction mutation (c.1331+2T>C (IVS4ds+2T-C)) detected in our study has been recurrently reported in Pakistani population [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of Deafness Genes in Families with Autosomal Recessive Nonsyndromic Hearing Loss

et al. 2015

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Comprehensive genetic testing has the potential to become the standard of care for individuals with hearing loss. In this study, we investigated the genetic etiology of autosomal recessive nonsyndromic hearing loss (ARNSHL) in a Turkish cohort including individuals with cochlear implant, who had a pedigree suggestive of an autosomal recessive inheritance. A workflow including prescreening of GJB2 and a targeted next generation sequencing panel (Illumına TruSightTM Exome) covering 2761 genes that we briefly called as mendelian exome sequencing was used. This panel includes 102 deafness genes and a number of genes causing Mendelian disorders. Using this approach, we identified causative variants in 21 of 29 families. Three different GJB2 variants were present in seven families. Remaining 14 families had 15 different variants in other known NSHL genes (MYO7A, MYO15A, MARVELD2, TMIE, DFNB31, LOXHD1, GPSM2, TMC1, USH1G, CDH23). Of these variants, eight are novel. Mutation detection rate of our workflow is 72.4%, confirming the usefulness of targeted sequencing approach in NSHL.

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Molecular genetics of MARVELD2 and clinical phenotype in Pakistani and Slovak families segregating DFNB49 hearing loss

Cited by 18 publications

References 29 publications

Tricellulin Expression and its Deletion Effects in the Endolymphatic Sac

Tricellulin Expression and its Deletion Effects in the Endolymphatic Sac

Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse

Comprehensive Analysis of Deafness Genes in Families with Autosomal Recessive Nonsyndromic Hearing Loss

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