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

• DOI: 10.1371/journal.pgen.1007297
• Publication Date: 2018-03-28T13:34:18Z
• Authors: Rizwan Yousaf; Chunfang Gu; Zubair M. Ahmed; Shaheen N. Khan; Thomas B. Friedman; Sheikh Riazuddin; Stephen B. Shears; Saima Riazuddin
• Keywords: Spiral ganglion

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