A dominant variant in the PDE1C gene is associated with nonsyndromic hearing loss
| Autor: | Denise Yan, Prem P. Chapagain, Li Wang, Rahul Mittal, Susan H. Blanton, Litao Qin, Shixiu Liao, Abhiraami Kannan Sundhari, Yong Feng, Tao Li, Yalan Liu, M'hamed Grati, Xuezhong Liu |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Genotype Hearing loss Biology Deafness medicine.disease_cause Article 03 medical and health sciences chemistry.chemical_compound Mice Asian People Exome Sequencing Genetics medicine Cyclic AMP Animals Homeostasis Humans Cyclic adenosine monophosphate Exome Gene Genetics (clinical) Exome sequencing Genes Dominant Regulation of gene expression Mutation Genetic heterogeneity Gene Expression Regulation Developmental Lysosome-Associated Membrane Glycoproteins Cyclic Nucleotide Phosphodiesterases Type 1 Cochlea Pedigree Disease Models Animal 030104 developmental biology chemistry Female medicine.symptom Lysosomes |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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