#618422
Table of Contents
A number sign (#) is used with this entry because of evidence that autosomal recessive deafness-100 (DFNB100) is caused by homozygous mutation in the PPIP5K2 gene (611648) on chromosome 5q21.
DFNB100 is characterized by prelingual onset of profound sensorineural deafness without vestibular involvement (Yousaf et al., 2018).
Yousaf et al. (2018) reported 12 patients from 2 apparently unrelated consanguineous Pakistani families (PKDF041 and PKDF751) with prelingual onset of profound sensorineural deafness. No hearing was noted since birth in all affected individuals. Three affected individuals from family PKDF751 failed a transient evoked otoacoustic emission test, indicating defective function of outer hair cells. There was no evidence of vestibular dysfunction or retinopathy. Family PKDF041 had previously been reported by Ramzan et al. (2005).
The transmission pattern of DFNB100 in the families reported by Yousaf et al. (2018) was consistent with autosomal recessive inheritance.
In affected members of 2 apparently unrelated consanguineous Pakistani families (PKDF041 and PKDF751) with DFNB100, Yousaf et al. (2018) identified a homozygous missense mutation in the PPIP5K2 gene (R837H; 611648.0001). The mutation, which was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Haplotype analysis indicated a founder effect between the 2 families. In vitro functional expression studies in HEK293 cells showed that the IP8 phosphatase activity of the mutant protein was reduced by 21% compared to controls. This was accompanied by accumulation of 60% higher levels of IP8 compared to controls, likely due to an increase in kinase activity. The findings indicated that PP-IP signaling is important to hair cell maintenance and function in the inner ear.
Yousaf et al. (2018) found that mice with targeted deletion of the Ppip5k2 phosphatase domain exhibited degeneration of the cochlear outer hair cells. These changes were associated with progressive hearing loss and increased hearing thresholds, as well as increased levels of intracellular IP8.
Ramzan, K., Shaikh, R. S., Ahmad, J., Khan, S. N., Riazuddin, S., Ahmed, Z. M., Friedman, T. B., Wilcox, E. R., Riazuddin, S. A new locus for nonsyndromic deafness DFNB49 maps to chromosome 5q12.3-q14.1. Hum. Genet. 116: 17-22, 2005. [PubMed: 15538632, related citations] [Full Text]
Yousaf, R., Gu, C., Ahmed, Z. M., Khan, S. N., Friedman, T. B., Riazuddin, S., Shears, S. B., Riazuddin, S. Mutations in diphosphoinositol-pentakisphosphate kinase PPIP5K2 are associated with hearing loss in human and mouse. PLoS Genet. 14: e1007297, 2018. Note: Electronic Article. [PubMed: 29590114, related citations] [Full Text]
ORPHA: 90636; DO: 0111638;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
5q21.1 | Deafness, autosomal recessive 100 | 618422 | Autosomal recessive | 3 | PPIP5K2 | 611648 |
A number sign (#) is used with this entry because of evidence that autosomal recessive deafness-100 (DFNB100) is caused by homozygous mutation in the PPIP5K2 gene (611648) on chromosome 5q21.
DFNB100 is characterized by prelingual onset of profound sensorineural deafness without vestibular involvement (Yousaf et al., 2018).
Yousaf et al. (2018) reported 12 patients from 2 apparently unrelated consanguineous Pakistani families (PKDF041 and PKDF751) with prelingual onset of profound sensorineural deafness. No hearing was noted since birth in all affected individuals. Three affected individuals from family PKDF751 failed a transient evoked otoacoustic emission test, indicating defective function of outer hair cells. There was no evidence of vestibular dysfunction or retinopathy. Family PKDF041 had previously been reported by Ramzan et al. (2005).
The transmission pattern of DFNB100 in the families reported by Yousaf et al. (2018) was consistent with autosomal recessive inheritance.
In affected members of 2 apparently unrelated consanguineous Pakistani families (PKDF041 and PKDF751) with DFNB100, Yousaf et al. (2018) identified a homozygous missense mutation in the PPIP5K2 gene (R837H; 611648.0001). The mutation, which was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Haplotype analysis indicated a founder effect between the 2 families. In vitro functional expression studies in HEK293 cells showed that the IP8 phosphatase activity of the mutant protein was reduced by 21% compared to controls. This was accompanied by accumulation of 60% higher levels of IP8 compared to controls, likely due to an increase in kinase activity. The findings indicated that PP-IP signaling is important to hair cell maintenance and function in the inner ear.
Yousaf et al. (2018) found that mice with targeted deletion of the Ppip5k2 phosphatase domain exhibited degeneration of the cochlear outer hair cells. These changes were associated with progressive hearing loss and increased hearing thresholds, as well as increased levels of intracellular IP8.
Ramzan, K., Shaikh, R. S., Ahmad, J., Khan, S. N., Riazuddin, S., Ahmed, Z. M., Friedman, T. B., Wilcox, E. R., Riazuddin, S. A new locus for nonsyndromic deafness DFNB49 maps to chromosome 5q12.3-q14.1. Hum. Genet. 116: 17-22, 2005. [PubMed: 15538632] [Full Text: https://doi.org/10.1007/s00439-004-1205-8]
Yousaf, R., Gu, C., Ahmed, Z. M., Khan, S. N., Friedman, T. B., Riazuddin, S., Shears, S. B., Riazuddin, S. Mutations in diphosphoinositol-pentakisphosphate kinase PPIP5K2 are associated with hearing loss in human and mouse. PLoS Genet. 14: e1007297, 2018. Note: Electronic Article. [PubMed: 29590114] [Full Text: https://doi.org/10.1371/journal.pgen.1007297]
Dear OMIM User,
To ensure long-term funding for the OMIM project, we have diversified our revenue stream. We are determined to keep this website freely accessible. Unfortunately, it is not free to produce. Expert curators review the literature and organize it to facilitate your work. Over 90% of the OMIM's operating expenses go to salary support for MD and PhD science writers and biocurators. Please join your colleagues by making a donation now and again in the future. Donations are an important component of our efforts to ensure long-term funding to provide you the information that you need at your fingertips.
Thank you in advance for your generous support,
Ada Hamosh, MD, MPH
Scientific Director, OMIM