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Hum Genet. 2018 Jul;137(6-7):437-446. doi: 10.1007/s00439-018-1895-y. Epub 2018 Jun 2.

A dominant variant in the PDE1C gene is associated with nonsyndromic hearing loss.

Author information

1
Institute of Medical Genetics, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China.
2
Department of Otolaryngology (D-48), Miller School of Medicine, University of Miami, 1666 NW 12th Avenue, Miami, FL, 33136, USA.
3
Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, China.
4
Laboratory of Cell Structure and Dynamics, NIDCD, NIH, Bethesda, MD, 20892, USA.
5
Department of Physics, Florida International University, Miami, FL, USA.
6
Biomolecular Sciences Institute, Florida International University, Miami, FL, USA.
7
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
8
Department of Otolaryngology (D-48), Miller School of Medicine, University of Miami, 1666 NW 12th Avenue, Miami, FL, 33136, USA. xliu@med.miami.edu.
9
Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, China. xliu@med.miami.edu.
10
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, 33136, USA. xliu@med.miami.edu.

Abstract

Identification of genes with variants causing non-syndromic hearing loss (NSHL) is challenging due to genetic heterogeneity. The difficulty is compounded by technical limitations that in the past prevented comprehensive gene identification. Recent advances in technology, using targeted capture and next-generation sequencing (NGS), is changing the face of gene identification and making it possible to rapidly and cost-effectively sequence the whole human exome. Here, we characterize a five-generation Chinese family with progressive, postlingual autosomal dominant nonsyndromic hearing loss (ADNSHL). By combining population-specific mutation arrays, targeted deafness genes panel, whole exome sequencing (WES), we identified PDE1C (Phosphodiesterase 1C) c.958G>T (p.A320S) as the disease-associated variant. Structural modeling insights into p.A320S strongly suggest that the sequence alteration will likely affect the substrate-binding pocket of PDE1C. By whole-mount immunofluorescence on postnatal day 3 mouse cochlea, we show its expression in outer (OHC) and inner (IHC) hair cells cytosol co-localizing with Lamp-1 in lysosomes. Furthermore, we provide evidence that the variant alters the PDE1C hydrolytic activity for both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Collectively, our findings indicate that the c.958G>T variant in PDE1C may disrupt the cross talk between cGMP-signaling and cAMP pathways in Ca2+ homeostasis.

PMID:
29860631
DOI:
10.1007/s00439-018-1895-y

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