DIABLO Research Paper

Background:

Hearing loss and deafness are currently major health issues globally. The World Health Organization (2014) estimates 360 million people worldwide suffer from disabling hearing loss. Despite this relatively high prevalence, causes of hearing loss have been difficult to diagnose with traditional genetic testing methods available. This is due to high genetic heterogeneity and lacking phenotypic variance combined with expensive or low throughput genetic tests (Shearer and Smith 2012). However, massively parallel sequencing technology has allowed more comprehensive and affordable genetic testing for deafness in the last few years (Shearer and Smith 2012). These recent advances in the ability to diagnose genetic causes of deafness make …show more content…
This suggests DIABLO is likely to have a role in the development and homeostasis of the inner ear hair cells. Understanding DIABLO’s role is vital as the number of post mitotic hair cells are limited and can’t simply replace themselves in higher vertebrates through mitosis like other cells in the body (Liu et al. 2014).

Since the DIABLO protein is involved in the apoptotic pathway it was hypothesized that it directly acted through a gain of function mutation within this pathway, therefore affecting hearing loss. However, multiple mechanisms supporting this hypothesis were thoroughly disproven by the Cheng et al. 2011 study. Overexpression of wild type or mutant DIABLO did not increase apoptosis in the cell viability assays. Additionally, immunoblot analysis did not detect an increase of aberrant DIABLO protein when the p.Ser71Leu DIABLO was overexpressed, which would be expected if a buildup of mutated DIABLO caused DFNA64. Since the DIABLO p.Ser71Leu mutant is not located near the IAP or dimer binding sites (Figure 2), it doesn’t appear to significantly affect the apoptotic function of …show more content…
It was determined that the degradation was due to dimerization between wild type and mutant DIABLO leading to a significant decrease in overall DIABLO levels. Through gel electrophoresis which compared the wild type and mutant profiles, it was determined that the p.Ser71Leu DIABLO mutant could form a dimer (Figure 3). A binding activity assay was used to measure the activation and cleavage of caspase 3. This indicated whether the DIABLO-IAP binding site is functional since DIABLO interacts with XIAP to release caspase 3. This confirmed that the DIABLO-IAP binding site is unaffected by the mutant p.Ser71Leu DIABLO. This was again established when cell viability of cells overexpressing either wild type or mutated DIABLO was not affected when treated with apoptotic

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