title: The DFNA5 gene, responsible for hearing loss and involved in cancer, encodes a novel apoptosis-inducing protein.
abstract: DFNA5 was first identified as a gene causing autosomal dominant hearing loss (HL). Different mutations have been found, all exerting a highly specific gain-of-function effect, in which skipping of exon 8 causes the HL. Later reports revealed the involvement of the gene in different types of cancer. Epigenetic silencing of DFNA5 in a large percentage of gastric, colorectal and breast tumors and p53-dependent transcriptional activity have been reported, concluding that DFNA5 acts as a tumor suppressor gene in different frequent types of cancer. Despite these data, the molecular function of DFNA5 has not been investigated properly. Previous transfection studies with mutant DFNA5 in yeast and in mammalian cells showed a toxic effect of the mutant protein, which was not seen after transfection of the wild-type protein. Here, we demonstrate that DFNA5 is composed of two domains, separated by a hinge region. The first region induces apoptosis when transfected in HEK293T cells, the second region masks and probably regulates this apoptosis inducing capability. Moreover, the involvement of DFNA5 in apoptosis-related pathways in a physiological setting was demonstrated through gene expression microarray analysis using Dfna5 knockout mice. In view of its important role in carcinogenesis, this finding is expected to lead to new insights on the role of apoptosis in many types of cancer. In addition, it provides a new line of evidence supporting an important role for apoptosis in monogenic and complex forms of HL.
authors.affiliation: Center of Medical Genetics, Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, Wilrijk, Belgium.
authors.forename: Ken
authors.initials: K
authors.lastname: Op de Beeck
authors.forename: Guy
authors.initials: G
authors.lastname: Van Camp
authors.forename: Sofie
authors.initials: S
authors.lastname: Thys
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cools
authors.forename: Isabelle
authors.initials: I
authors.lastname: Callebaut
authors.forename: Karen
authors.initials: K
authors.lastname: Vrijens
authors.forename: Luc
authors.initials: L
authors.lastname: Van Nassauw
authors.forename: Viggo F I
authors.initials: VF
authors.lastname: Van Tendeloo
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Timmermans
authors.forename: Lut
authors.initials: L
authors.lastname: Van Laer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D003638:Deafness / Q000235:genetics; D005091:Exons; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D057809:HEK293 Cells; D006367:HeLa Cells; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics*; D017434:Protein Structure, Tertiary; D011960:Receptors, Estrogen / Q000235:genetics*; D014162:Transfection; D000094524:Gasdermins
chemical_list: D051017:Apoptosis Regulatory Proteins; D011960:Receptors, Estrogen; C111432:GSDME protein, human; D000094524:Gasdermins