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

Li Wang, Yong Feng, Denise Yan, Litao Qin, M’hamed Grati, Rahul Mittal, Tao Li, Abhiraami Kannan Sundhari, Yalan Liu, Prem Chapagain, Susan H Blanton, Shixiu Liao, Xue Z Liu

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalHuman Genetics
DOIs
StateAccepted/In press - Jun 2 2018

Fingerprint

Phosphoric Diester Hydrolases
Exome
Inner Auditory Hair Cells
Genes
Genetic Heterogeneity
Cochlea
Deafness
Lysosomes
Hearing Loss
Cytosol
Fluorescent Antibody Technique
Homeostasis
Technology
Costs and Cost Analysis
Mutation
Nonsyndromic Deafness
Population
cyclic guanosine monophosphate-adenosine monophosphate

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

A dominant variant in the PDE1C gene is associated with nonsyndromic hearing loss. / Wang, Li; Feng, Yong; Yan, Denise; Qin, Litao; Grati, M’hamed; Mittal, Rahul; Li, Tao; Sundhari, Abhiraami Kannan; Liu, Yalan; Chapagain, Prem; Blanton, Susan H; Liao, Shixiu; Liu, Xue Z.

In: Human Genetics, 02.06.2018, p. 1-10.

Research output: Contribution to journalArticle

Wang, L, Feng, Y, Yan, D, Qin, L, Grati, M, Mittal, R, Li, T, Sundhari, AK, Liu, Y, Chapagain, P, Blanton, SH, Liao, S & Liu, XZ 2018, 'A dominant variant in the PDE1C gene is associated with nonsyndromic hearing loss', Human Genetics, pp. 1-10. https://doi.org/10.1007/s00439-018-1895-y
Wang, Li ; Feng, Yong ; Yan, Denise ; Qin, Litao ; Grati, M’hamed ; Mittal, Rahul ; Li, Tao ; Sundhari, Abhiraami Kannan ; Liu, Yalan ; Chapagain, Prem ; Blanton, Susan H ; Liao, Shixiu ; Liu, Xue Z. / A dominant variant in the PDE1C gene is associated with nonsyndromic hearing loss. In: Human Genetics. 2018 ; pp. 1-10.
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AU - Mittal, Rahul

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AU - Sundhari, Abhiraami Kannan

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AU - Chapagain, Prem

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AU - Liao, Shixiu

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