The autosomal recessive nonsyndromic deafness locus DFNB72 is located on chromosome 19p13.3

Ain, Quratul; Nazli, Sabiha; Riazuddin, Saima; Jaleel, Ateeq Ul; Riazuddin, A.; Zafar, Ahmad Usman; Khan, Shaheen N.; Husnain, Tayyab; Griffith, Andrew J.; Ahmed, Zubair M.; Friedman, Thomas B.

doi:10.1007/s00439-007-0418-z

Cited by 22 publications

(17 citation statements)

References 34 publications

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“…2A). Nixin was previously described as being involved in murine spermatogenesis (29) and is connected to the autosomal recessive nonsyndromic deafness locus DFNB72 (30). The ER localization of Nixin was confirmed by staining Nixin-YFP-transfected cells for calretinin as marker for the ER (Fig.…”

Section: Resultsmentioning

confidence: 99%

A Systematic Search for Endoplasmic Reticulum (ER) Membrane-associated RING Finger Proteins Identifies Nixin/ZNRF4 as a Regulator of Calnexin Stability and ER Homeostasis

Neutzner

Benischke

et al. 2011

Journal of Biological Chemistry

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To identify novel regulators of endoplasmic reticulum (ER)-linked protein degradation and ER function, we determined the entire inventory of membrane-spanning RING finger E3 ubiquitin ligases localized to the ER. We identified 24 ER membraneanchored ubiquitin ligases and found Nixin/ZNRF4 to be central for the regulation of calnexin turnover. Ectopic expression of wild type Nixin induced a dramatic down-regulation of the ER-localized chaperone calnexin that was prevented by inactivation of the Nixin RING domain. Importantly, Nixin physically interacts with calnexin in a glycosylation-independent manner, induces calnexin ubiquitination, and p97-dependent degradation, indicating an ER-associated degradation-like mechanism of calnexin turnover.The endoplasmic reticulum (ER) 3 is a major cellular site for production, folding, quality control, and distribution of proteins. Many regulatory mechanisms are in place to keep these processes in balance and therefore to ensure cellular fitness and survival, with ubiquitin-dependent protein degradation playing an important part (1). One major challenge the ER faces is an overload with unfolded or folding proteins. An excess of folding proteins in the ER triggers a cellular response called the unfolded protein response (UPR) (2, 3). UPR entails lowering of the protein load by the attenuation of protein translation and the up-regulation of chaperones thereby increasing the protein folding capacity of the cells. If the capacity of UPR is exceeded, the cell utilizes ER-associated degradation (ERAD), a system for the recognition of terminally misfolded proteins and their disposal (4). Misfolded proteins destined for ERAD are ubiquitinated by the RING domain containing ubiquitin ligases (5), Hrd1 (6), and Doa1 (7, 8), retrotranslocated across the ER membrane into the cytosol by the AAA-ATPase p97 (9), and then degraded by the 26 S proteasome.Upon entry into the ER, most nascent polypeptides are recognized by glycosidases and modified on specific asparagine residues (Asn-Xaa-(Thr/Ser)) with the N-glycan GlcNAc 2 Man 9 Gluc 3 (10). Core glycosylation of nascent polypeptides decreases their overall hydrophobicity. Trimming of the terminal two glucose residues by glucosidase I allows for binding of the lectins/chaperones calreticulin and calnexin thereby facilitating the proper folding of the newly synthesized protein (10,11).Although the importance of regulated degradation of ER resident proteins is firmly established, only a small number of RING finger-containing ubiquitin ligases are known to be involved in such processes to date, namely SYVN1/hHrd1 (6, 12), AMFR/gp78 (13), TEB4/MARCH6 (14), RNF5/Rma1 (15), RNF77/TRIM13 (16), and RNF13 (17). Given the importance of protein metabolism and degradation in the ER and the vast number of ubiquitin ligases encoded in the human genome, we asked whether other ubiquitin ligases are involved in the regulation of ER-related degradation processes.Based on the assumption that the ER lumen is devoid of E1 and E2 ubiquitination activity and on the...

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Section: Resultsmentioning

confidence: 99%

A Systematic Search for Endoplasmic Reticulum (ER) Membrane-associated RING Finger Proteins Identifies Nixin/ZNRF4 as a Regulator of Calnexin Stability and ER Homeostasis

Neutzner

Benischke

et al. 2011

Journal of Biological Chemistry

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“…Ascertainment and linkage analysis of families PKDF335, PKDF793, and PKDF291 was described previously (Ain et al 2007). Families DEM4322, PKDF1048, DEM4197, and PKSR22A were ascertained through special education schools from Pakistan while family PKDF1258 contacted us on the recommendation of an audiologist.…”

Section: Methodsmentioning

confidence: 99%

“…We previously mapped a nonsyndromic recessive hearing loss locus DFNB72 to chromosome 19p13.3 based on analyses of three large consanguineous Pakistani families, PKDF335, PKDF793, and PKDF291, each independently yielding a LOD score of greater than 3.0 (Ain et al 2007). Assuming locus homogeneity as the least complex explanation of our data, the smallest interval of shared homozygosity within these families spanned 1.16 megabases (Mb) between markers D19S216 and D19S1034 , which excluded GIPC3 .…”

Section: Introductionmentioning

confidence: 99%

Mutations of GIPC3 cause nonsyndromic hearing loss DFNB72 but not DFNB81 that also maps to chromosome 19p

et al. 2011

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A missense mutation of Gipc3 was previously reported to cause age-related hearing loss in mice. Point mutations of human GIPC3 were found in two small families, but association with hearing loss was not statistically significant. Here, we describe one frameshift and six missense mutations in GIPC3 cosegregating with DFNB72 hearing loss in six large families that support statistically significant evidence for genetic linkage. However, GIPC3 is not the only nonsyndromic hearing impairment gene in this region; no GIPC3 mutations were found in a family cosegregating hearing loss with markers of chromosome 19p. Haplotype analysis excluded GIPC3 from the obligate linkage interval in this family and defined a novel locus spanning 4.08 Mb and 104 genes. This closely linked but distinct nonsyndromic hearing loss locus was designated DFNB81.

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“…LOXHD1 and GIPC3 are not components of the stereocilia; however, mutations in these genes in mice were shown to lead to degeneration of the stereocilia. [43][44][45] All of these genes are only expressed in the IHCs and OHCs.…”

Section: Table 3 (Continued)mentioning

confidence: 99%

Gene Expression Profiles of the Cochlea and Vestibular Endorgans

Nishio

Hattori

Moteki

et al. 2015

Ann Otol Rhinol Laryngol

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Objectives: We sought to elucidate the gene expression profiles of the causative genes as well as the localization of the encoded proteins involved in hereditary hearing loss. Methods: Relevant articles (as of September 2014) were searched in PubMed databases, and the gene symbols of the genes reported to be associated with deafness were located on the Hereditary Hearing Loss Homepage using localization, expression, and distribution as keywords. Results: Our review of the literature allowed us to systematize the gene expression profiles for genetic deafness in the inner ear, clarifying the unique functions and specific expression patterns of these genes in the cochlea and vestibular endorgans. Conclusions:The coordinated actions of various encoded molecules are essential for the normal development and maintenance of auditory and vestibular function.

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The autosomal recessive nonsyndromic deafness locus DFNB72 is located on chromosome 19p13.3

Cited by 22 publications

References 34 publications

A Systematic Search for Endoplasmic Reticulum (ER) Membrane-associated RING Finger Proteins Identifies Nixin/ZNRF4 as a Regulator of Calnexin Stability and ER Homeostasis

A Systematic Search for Endoplasmic Reticulum (ER) Membrane-associated RING Finger Proteins Identifies Nixin/ZNRF4 as a Regulator of Calnexin Stability and ER Homeostasis

Mutations of GIPC3 cause nonsyndromic hearing loss DFNB72 but not DFNB81 that also maps to chromosome 19p

Gene Expression Profiles of the Cochlea and Vestibular Endorgans

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