A Rare Genomic Duplication in 2p14 Underlies Autosomal Dominant Hearing Loss DFNA58

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2020 Apr 28

PMID 32337552

Citations 10

Authors

Karina Lezirovitz

Gleiciele A Vieira-Silva

Ana C Batissoco

Debora Levy

Joao P Kitajima

Alix Trouillet

Ellen Ouyang

Navid Zebarjadi

Juliana Sampaio-Silva

Vinicius Pedroso-Campos

Larissa R Nascimento

Cindy Y Sonoda

Vinicius M Borges

Laura G Vasconcelos

Roberto M O Beck

Signe S Grasel

Daniel J Jagger

Nicolas Grillet

Ricardo F Bento

Regina C Mingroni-Netto

Jeanne Oiticica

Affiliations

Soon will be listed here.

Abstract

Here we define a ~200 Kb genomic duplication in 2p14 as the genetic signature that segregates with postlingual progressive sensorineural autosomal dominant hearing loss (HL) in 20 affected individuals from the DFNA58 family, first reported in 2009. The duplication includes two entire genes, PLEK and CNRIP1, and the first exon of PPP3R1 (protein coding), in addition to four uncharacterized long non-coding (lnc) RNA genes and part of a novel protein-coding gene. Quantitative analysis of mRNA expression in blood samples revealed selective overexpression of CNRIP1 and of two lncRNA genes (LOC107985892 and LOC102724389) in all affected members tested, but not in unaffected ones. Qualitative analysis of mRNA expression identified also fusion transcripts involving parts of PPP3R1, CNRIP1 and an intergenic region between PLEK and CNRIP1, in the blood of all carriers of the duplication, but were heterogeneous in nature. By in situ hybridization and immunofluorescence, we showed that Cnrip1, Plek and Ppp3r1 genes are all expressed in the adult mouse cochlea including the spiral ganglion neurons, suggesting changes in expression levels of these genes in the hearing organ could underlie the DFNA58 form of deafness. Our study highlights the value of studying rare genomic events leading to HL, such as copy number variations. Further studies will be required to determine which of these genes, either coding proteins or non-coding RNAs, is or are responsible for DFNA58 HL.

Citing Articles

The known structural variations in hearing loss and their diagnostic approaches: a comprehensive review.

Naghinejad M, Parvizpour S, Shekari Khaniani M, Mehri M, Mansoori Derakhshan S, Amirfiroozy A Mol Biol Rep. 2025; 52(1):131.

PMID: 39821465 DOI: 10.1007/s11033-025-10231-w.

Rare germline disorders implicate long non-coding RNAs disrupted by chromosomal structural rearrangements.

Andersen R, Alkuraya I, Ajeesh A, Sakamoto T, Mena E, Amr S medRxiv. 2024; .

PMID: 38946951 PMC: 11213069. DOI: 10.1101/2024.06.16.24307499.

Autosomal Dominant Non-Syndromic Hearing Loss (DFNA): A Comprehensive Narrative Review.

Alde M, Cantarella G, Zanetti D, Pignataro L, La Mantia I, Maiolino L Biomedicines. 2023; 11(6).

PMID: 37371710 PMC: 10296186. DOI: 10.3390/biomedicines11061616.

The long and short: Non-coding RNAs in the mammalian inner ear.

Koffler-Brill T, Noy Y, Avraham K Hear Res. 2022; 428:108666.

PMID: 36566643 PMC: 9883734. DOI: 10.1016/j.heares.2022.108666.

New Insights into the Identity of the DFNA58 Gene.

Nascimento L, Vieira-Silva G, Kitajima J, Batissoco A, Lezirovitz K Genes (Basel). 2022; 13(12).

PMID: 36553541 PMC: 9777997. DOI: 10.3390/genes13122274.

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