DFNA5, a Gene Involved in Hearing Loss and Cancer: A Review

Beeck, Ken Op de; Laer, Lut Van; Camp, Guy Van

doi:10.1177/000348941212100310

Cited by 64 publications

(55 citation statements)

References 54 publications

(65 reference statements)

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“…All DFNA5 mutations leading to hearing loss in humans have been attributed to exon 8 skipping at the pre-mRNA level leading to the translation of a C-terminally truncated DFNA5 protein2151. Because ectopic expression of this mutant protein cause cell death, it has been proposed that the DFNA5 mutations represent gain of function mutations that increase the apoptotic activity of DFNA5 (ref.…”

Section: Discussionmentioning

confidence: 99%

“…Because ectopic expression of this mutant protein cause cell death, it has been proposed that the DFNA5 mutations represent gain of function mutations that increase the apoptotic activity of DFNA5 (ref. 51). Indeed, this conclusion is supported by our results which show that truncation of the C-terminus of DFNA5 by caspase-3 activates the necrotic activity of DFNA5.…”

Section: Discussionmentioning

confidence: 99%

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Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death

et al. 2017

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Apoptosis is a genetically regulated cell suicide programme mediated by activation of the effector caspases 3, 6 and 7. If apoptotic cells are not scavenged, they progress to a lytic and inflammatory phase called secondary necrosis. The mechanism by which this occurs is unknown. Here we show that caspase-3 cleaves the GSDMD-related protein DFNA5 after Asp270 to generate a necrotic DFNA5-N fragment that targets the plasma membrane to induce secondary necrosis/pyroptosis. Cells that express DFNA5 progress to secondary necrosis, when stimulated with apoptotic triggers such as etoposide or vesicular stomatitis virus infection, but disassemble into small apoptotic bodies when DFNA5 is deleted. Our findings identify DFNA5 as a central molecule that regulates apoptotic cell disassembly and progression to secondary necrosis, and provide a molecular mechanism for secondary necrosis. Because DFNA5-induced secondary necrosis and GSDMD-induced pyroptosis are dependent on caspase activation, we propose that they are forms of programmed necrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death

et al. 2017

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“…GSDME is expressed in placenta, brain, heart, kidney, cochlea, intestines, and IgE-primed mast cells[9,37]. Deafness associated with GSDME is characterized by an autosomal dominant inheritance and gradual loss of hearing, typically starting at high frequency by age fifteen[67]. All known mutations in GSDME associated with deafness are characterized by skipping of exon 8, resulting in frameshifts and the formation of truncated gasdermin E protein[64–66].…”

Section: Gasdermin D Pores Are the Effectors Of Pyroptosismentioning

confidence: 99%

Gasdermins: Effectors of Pyroptosis

Kovacs

Miao

2017

Trends in Cell Biology

962

662

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Pyroptosis is a form of lytic programmed cell death initiated by inflammasomes, which detect cytosolic contamination or perturbation. This drives activation of caspase-1 or caspase-11/4/5, which cleave gasdermin D, separating its N-terminal pore-forming domain (PFD) from the C-terminal repressor domain (RD). The PFD oligomerizes to form large pores in the membrane that drive swelling and membrane rupture. Gasdermin D is one of six (in humans) gasdermin family members; several other gasdermins have also been shown to form pores that cause pyroptosis after cleavage to activate their PFDs. One of these, gasdermin E, is activated by caspase-3 cleavage. We review our current understanding of pyroptosis as well as current knowledge of the gasdermin family.

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“…DNFA5 is a tumor suppressor gene involved in apoptosis and response to DNA damage[80,81]. Its hypermethylation has been reported in colorectal and gastric cancer, where it is associated with EBV-positive status[82,83].…”

Section: Cimp and Promoter Hypermethylation Of Tumor Suppressor Genesmentioning

confidence: 99%

CpG island methylator phenotype in adenocarcinomas from the digestive tract: Methods, conclusions, and controversies

Sánchez-Vega¹,

Gotea²,

Chen³

et al. 2017

WJGO

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Over the last two decades, cancer-related alterations in DNA methylation that regulate transcription have been reported for a variety of tumors of the gastrointestinal tract. Due to its relevance for translational research, great emphasis has been placed on the analysis and molecular characterization of the CpG island methylator phenotype (CIMP), defined as widespread hypermethylation of CpG islands in clinically distinct subsets of cancer patients. Here, we present an overview of previous work in this field and also explore some open questions using cross-platform data for esophageal, gastric, and colorectal adenocarcinomas from The Cancer Genome Atlas. We provide a data-driven, pan-gastrointestinal stratification of individual samples based on CIMP status and we investigate correlations with oncogenic alterations, including somatic mutations and epigenetic silencing of tumor suppressor genes. Besides known events in CIMP such as BRAF V600E mutation, CDKN2A silencing or MLH1 inactivation, we discuss the potential role of emerging actors such as Wnt pathway deregulation through truncating mutations in RNF43 and epigenetic silencing of WIF1. Our results highlight the existence of molecular similarities that are superimposed over a larger backbone of tissue-specific features and can be exploited to reduce heterogeneity of response in clinical trials.

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DFNA5, a Gene Involved in Hearing Loss and Cancer: A Review

Abstract: DFNA5 is a tumor suppressor gene that is involved in apoptosis pathways and as such performs a basic role in cell survival. In view of the known role of apoptosis in several forms of hearing loss, DFNA5 may be a player in the underlying disease mechanisms.

Cited by 64 publications

References 54 publications

Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death

Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death

Gasdermins: Effectors of Pyroptosis

CpG island methylator phenotype in adenocarcinomas from the digestive tract: Methods, conclusions, and controversies

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