DFNA5

Official Full Name

gasdermin E

Organism

Homo sapiens

GeneID

1687

Background

Hearing impairment is a heterogeneous condition with over 40 loci described. The protein encoded by this gene is expressed in fetal cochlea, however, its function is not known. Nonsyndromic hearing impairment is associated with a mutation in this gene. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Synonyms

GSDME; DFNA5; ICERE-1;

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Detailed Information

Cleavage of gasdermin proteins produces pore-forming amino-terminal fragments that lead to inflammatory cell death (heat exhaustion). Gasdermin E (GSDME, also known as DFNA5), which is mutated in familial age-associated hearing loss, can be catabolised by caspase 3, which converts non-inflammatory apoptosis to pyoptosis in GSDME-expressing cells.

DFNA5 Gene Linked to Hearing Loss

Mutations in the DFNA5 gene cause autosomal dominant nonsyndromic hereditary hearing loss (NSHHL). To date, four different DFNA5 gene mutations causing hearing loss have been reported. DFNA5 was first identified as the gene responsible for autosomal dominant hearing loss (HL). The different mutations that have been identified have highly specific gain-of-function effects, with skipping of exon 8 leading to hearing loss. Subsequent reports have shown that the gene is associated with different types of cancer.

DFNA5 may act as a tumor suppressor

DFNA5 expression is suppressed in many cancers, and reduced levels of DFNA5 have been associated with reduced survival in breast cancer patients, suggesting that DFNA5 may be a tumor suppressor. There is evidence that GSDME acts as a tumor suppressor (including epigenetic inactivation of GSDME by promoter DNA methylation in many cancer lines and primary cancers; GSDME inhibits colony formation and cell proliferation in gastric, melanoma and colorectal cancers, and invasiveness in breast cancers; and breast cancers with hypo-expressed GSDME have a lower five-year survival and higher metastasis rates). GSDME-expressing breast cancers have lower five-year survival and higher metastatic rates). Inflammatory cell death is induced in GSDME-expressing cancers subjected to intrinsic stress (hypoxia or endoplasmic reticulum stress) or extrinsic challenge (chemotherapy, radiotherapy, or cytotoxic cell attack). or cytotoxic lymphocyte attack) activates caspase 3, with significant effects on the tumor microenvironment, immune cell recruitment and function, and tumor growth.

Mechanisms by which DFNA5 exerts tumor-suppressive effects

DFNA5 expression enhances phagocytosis of tumor cells by tumor-associated macrophages and increases the number and function of tumor-infiltrating natural killer lymphocytes and CD8+ T lymphocytes. Killer cell granzyme B also directly cleaves DFNA5 at the same site as caspase 3, thereby activating caspase-independent thermal apoptosis in target cells. Non-cleavable or pore-deficient DFNA5 proteins are not tumor inhibitory. Therefore, tumor DFNA5 acts as a tumor suppressor by activating pyoptosis and enhancing anti-tumor immunity.

References:

Zhang Z, Zhang Y, Xia S, et al. Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature. 2020;579(7799):415-420. doi:10.1038/s41586-020-2071-9
Op de Beeck K, Van Camp G, Thys S, Cools N, Callebaut I, Vrijens K, Van Nassauw L, Van Tendeloo VF, Timmermans JP, Van Laer L. The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein. Eur J Hum Genet. 2011 Sep;19(9):965-73. doi: 10.1038/ejhg.2011.63. Epub 2011 Apr 27. PMID: 21522185; PMCID: PMC3179363.

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