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PLoS Genet. 2018 Mar 28;14(3):e1007297. doi: 10.1371/journal.pgen.1007297. eCollection 2018 Mar.

Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse.

Author information

1
Laboratory of Molecular Genetics, Department of Otorhinolaryngology-Head & Neck Surgery, School of Medicine University of Maryland, Baltimore, MD, United States of America.
2
Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, United States of America.
3
Laboratory of Neurogenetics and Regenerative Medicine, Department of Otorhinolaryngology-Head & Neck Surgery, School of Medicine University of Maryland, Baltimore, MD, United States of America.
4
National Center for Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
5
Section on Human Genetics, Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, United States of America.
6
Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad, Pakistan.

Abstract

Autosomal recessive nonsyndromic hearing loss is a genetically heterogeneous disorder. Here, we report a severe-to-profound sensorineural hearing loss locus, DFNB100 on chromosome 5q13.2-q23.2. Exome enrichment followed by massive parallel sequencing revealed a c.2510G>A transition variant in PPIP5K2 that segregated with DFNB100-associated hearing loss in two large apparently unrelated Pakistani families. PPIP5Ks enzymes interconvert 5-IP7 and IP8, two key members of the inositol pyrophosphate (PP-IP) cell-signaling family. Their actions at the interface of cell signaling and bioenergetic homeostasis can impact many biological processes. The c.2510G>A transition variant is predicted to substitute a highly invariant arginine residue with histidine (p.Arg837His) in the phosphatase domain of PPIP5K2. Biochemical studies revealed that the p.Arg837His variant reduces the phosphatase activity of PPIP5K2 and elevates its kinase activity. We found that in mouse inner ear, PPIP5K2 is expressed in the cochlear and vestibular sensory hair cells, supporting cells and spiral ganglion neurons. Mice homozygous for a targeted deletion of the Ppip5k2 phosphatase domain exhibit degeneration of cochlear outer hair cells and elevated hearing thresholds. Our demonstration that PPIP5K2 has a role in hearing in humans indicates that PP-IP signaling is important to hair cell maintenance and function within inner ear.

PMID:
29590114
PMCID:
PMC5891075
DOI:
10.1371/journal.pgen.1007297
[Indexed for MEDLINE]
Free PMC Article

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