Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse
PublisherPublic Library of Science
MetadataShow full item record
AbstractAutosomal 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. Copyright 2018 Public Library of Science. All Rights Reserved.
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85044822762&doi=10.1371%2fjournal.pgen.1007297&partnerID=40&md5=5af998c41a0eb8e454efddc7e33dddda; http://hdl.handle.net/10713/9314
- MPZL2 is a novel gene associated with autosomal recessive nonsyndromic moderate hearing loss.
- Authors: Bademci G, Abad C, Incesulu A, Rad A, Alper O, Kolb SM, Cengiz FB, Diaz-Horta O, Silan F, Mihci E, Ocak E, Najafi M, Maroofian R, Yilmaz E, Nur BG, Duman D, Guo S, Sant DW, Wang G, Monje PV, Haaf T, Blanton SH, Vona B, Walz K, Tekin M
- Issue date: 2018 Jul
- A variant in LMX1A causes autosomal recessive severe-to-profound hearing impairment.
- Authors: Schrauwen I, Chakchouk I, Liaqat K, Jan A, Nasir A, Hussain S, Nickerson DA, Bamshad MJ, Ullah A, Ahmad W, Leal SM
- Issue date: 2018 Jul
- A biallelic variant in CLRN2 causes non-syndromic hearing loss in humans.
- Authors: Vona B, Mazaheri N, Lin SJ, Dunbar LA, Maroofian R, Azaiez H, Booth KT, Vitry S, Rad A, Rüschendorf F, Varshney P, Fowler B, Beetz C, Alagramam KN, Murphy D, Shariati G, Sedaghat A, Houlden H, Petree C, VijayKumar S, Smith RJH, Haaf T, El-Amraoui A, Bowl MR, Varshney GK, Galehdari H
- Issue date: 2021 Jun
- The Significance of the Bifunctional Kinase/Phosphatase Activities of Diphosphoinositol Pentakisphosphate Kinases (PPIP5Ks) for Coupling Inositol Pyrophosphate Cell Signaling to Cellular Phosphate Homeostasis.
- Authors: Gu C, Nguyen HN, Hofer A, Jessen HJ, Dai X, Wang H, Shears SB
- Issue date: 2017 Mar 17
- The kinetic properties of a human PPIP5K reveal that its kinase activities are protected against the consequences of a deteriorating cellular bioenergetic environment.
- Authors: Weaver JD, Wang H, Shears SB
- Issue date: 2013 Feb 5