Disease relevance of DFNA5

• Localization of a gene for non-syndromic hearing loss (DFNA5) to chromosome 7p15 [1].
• As DFNA5 was considered an excellent candidate ARHI susceptibility gene, we performed linkage analysis to a quantitive measure of high frequency hearing loss [2].
• Characterization of a gene that is inversely correlated with estrogen receptor expression (ICERE-1) in breast carcinomas [3].
• Northern blot analysis of a panel of breast cancer cell lines demonstrated that an ICERE-1 mRNA of approximately 2.2 kb was abundantly expressed in the ER-negative breast carcinoma cell lines, MDA-MB-231 and HBL-100, and the ER-negative cell lines [3].
• DFNA5 (ICERE-1) contributes to acquired etoposide resistance in melanoma cells [4].

High impact information on DFNA5

• However, no significant linkage between ARHI and microsatellite markers from the DFNA5 region could be detected [2].
• Subsequently, the DFNA5 coding region was analysed for single nucleotide polymorphisms (SNPs) [2].
• To evaluate the hypothesis that a decrease in DFNA5 mRNA expression level contributes to the acquired etoposide resistance phenotype exhibited by MeWo ETO 1 cells, this drug-resistant line was stably transfected with the DFNA5-encoding cDNA [4].
• By that approach it could be demonstrated that the expression level of a mRNA encoded by a gene found to be mutated in non-syndromic hearing impairment, DFNA5 (ICERE-1), was distinctly decreased in the 33-fold etoposide-resistant melanoma cell line MeWo ETO 1 [4].
• However, the refinement of the candidate region of DFNA5 excludes the HOXA1 gene as a candidate for DFNA5 [5].

Biological context of DFNA5

• A gene for an autosomal dominant form of progressive sensorineural hearing loss (DFNA5) was previously assigned by us to a 15-cM region on chromosome 7p15 [5].
• Yeast cells tolerated expression of wild-type DFNA5, while expression of the mutant DFNA5 allele, which is responsible for nonsyndromic autosomal dominant hearing impairment, led to cell cycle arrest [6].
• We identified new rat and horse DFNA5 homologues and we describe a domain of homology shared between DFNA5 and the Mcm10 family of DNA replication proteins [6].
• Here, we report a novel role of the DFNA5 gene in p53-mediated etoposide-induced cell death [7].
• The potential role of DFNA5, a hearing impairment gene, in p53-mediated cellular response to DNA damage [7].

Anatomical context of DFNA5

• We cloned a novel candidate gene (CG1, candidate gene 1), which is expressed in human fetal cochlea, from the DFNA5 candidate region [5].
• The HOXA1 gene located in 7p15 was considered to be a good candidate gene for DFNA5 as it harbours mutations leading to developmental defects of the inner ear in mice [5].
• METHODS: We performed transfection experiments in mammalian cell lines (HEK293T and COS-1) with green fluorescent protein (GFP) tagged wildtype and mutant DFNA5 and analysed cell death with flow cytometry and fluorescence microscopy [8].

Other interactions of DFNA5

• Mutation analysis of the CG1 gene in DFNA5 patients, however, could not reveal a disease-causing mutation [5].
• 5. Two loci for nonsyndromic forms of deafness, DFNA5 and DFNA11, have previously been mapped to these two chromosomal regions [9].
• Speech recognition scores were compared with those of DFNA2, DFNA5, DFNA9, and presbyacusis subjects [10].
• Compared with subjects having DFNA2 and DFNA5, speech recognition in those with DFNA20/26 scored better at threshold levels below 85 dB hearing level, but worse at levels above 90 dB [10].

Analytical, diagnostic and therapeutic context of DFNA5

• The chromatin immunoprecipitation assay indicated that a potential p53-binding sequence is located in intron 1 of the DFNA5 gene [7].
• A longer clone of ICERE-1 was isolated from a MDA-MB-231 cDNA library and sequence analysis indicated that this 2168-bp cDNA contained an ORF encoding a protein of 234 amino acids that bears little similarity with any previously described protein sequence [3].
• Reverse transcription/PCR was used to examine ICERE-1 expression in 29 primary breast carcinomas, 15 of which had been designated as ER positive and 14 as ER negative by immunohistochemistry [3].

References