A rare genomic duplication in 2p14 underlies autosomal dominant hearing loss DFNA58

Author(s):Show less -

Lezirovitz, Karina ^{[1, 2]} ; Vieira-Silva, Gleiciele A. ^{[1, 2]} ; Batissoco, Ana C. ^{[1, 2]} ; Levy, Debora ^[3] ; Kitajima, Joao P. ^[4] ; Trouillet, Alix ^[5] ; Ouyang, Ellen ^[5] ; Zebarjadi, Navid ^[5] ; Sampaio-Silva, Juliana ^[1] ; Pedroso-Campos, Vinicius ^[1] ; Nascimento, Larissa R. ^{[1, 2]} ; Sonoda, Cindy Y. ^[1] ; Borges, Vinicius M. ^[6] ; Vasconcelos, Laura G. ^[2] ; Beck, Roberto M. O. ^[2] ; Grasel, Signe S. ^[2] ; Jagger, Daniel J. ^[7] ; Grillet, Nicolas ^[5] ; Bento, Ricardo F. ^{[1, 2]} ; Mingroni-Netto, Regina C. ^[6] ; Oiticica, Jeanne ^{[1, 2]}

Affiliation

^[1] Univ Sao Paulo, Hosp Clin HCFMUSP, Fac Med, Otorhinolaryngol, LIM32, BR-01246000 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Med FMUSP, Dept Otorrinolaringol, BR-05403000 Sao Paulo - Brazil

^[3] Univ Sao Paulo, Hosp Clin HCFMUSP, Lipids Oxidat & Cell Biol Grp, Lab Immunol LIM19, Heart Inst InCor, Fac Med, BR-05403900 Sao Paulo - Brazil

^[4] Mendel Genom Anal, BR-04013000 Sao Paulo - Brazil

^[5] Stanford Univ, Dept Otolaryngol Head & Neck Surg, Stanford, CA 94305 - USA

^[6] Univ Sao Paulo, Ctr Pesquisas Genoma Humano & Celulas Tronco, Inst Biociencias, Dept Genet & Biol Evolut, BR-05508900 Sao Paulo - Brazil

^[7] UCL, UCL Ear Inst, London WC1E 6BT - England

• Document type: Journal article
• Source: Human Molecular Genetics; v. 29, n. 9, p. 1520-1536, MAY 1 2020.
• Web of Science Citations: 1

Abstract

Here we define a similar to 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. (AU)

• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 14/13071-6 - Identification of novel genes and functional studies in nonsyndromic deafness
• Grantee: Karina Lezirovitz Mandelbaum
• Support type: Regular Research Grants
• FAPESP's process: 18/03433-9 - 145/5000 Use of IPS cells and animal models to elucidate the pathophysiology of post-lingual sensorineural hearing loss of genetic etiology
• Grantee: Karina Lezirovitz Mandelbaum
• Support type: Regular Research Grants