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

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.

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Acknowledgements

Immunofluorescence confocal imaging was performed in Dr. Bechara Kachar’s lab (NIDCD-NIH; Bethesda, MD). This study was supported by the National Natural Science Foundation Nos. 81771024, 81771023, and medical science and technology project of Henan Province No. 87 from China; R01 DC005575, R01 DC01246, and R01 DC012115 from the National Institutes of Health/National Institute on Deafness and Other Communication Disorders, and Action on hearing loss grant.

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LW, FY, DY, LQ, MG, RM, TL, ASK, YL, PC, SHB, SL, and XL planned and performed the study and participated in writing the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to Xuezhong Liu.

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Wang, L., Feng, Y., Yan, D. et al. A dominant variant in the PDE1C gene is associated with nonsyndromic hearing loss. Hum Genet 137, 437–446 (2018). https://doi.org/10.1007/s00439-018-1895-y

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