Further evidence for “gain-of-function” mechanism of DFNA5 related hearing loss

Abstract

To report two DFNA5 pathogenic splice-site variations and a novel benign frameshift variation to further support the gain-of-function mechanism of DFNA5 related hearing impairment, targeted genes capture and next generation sequencing were performed on selected members from Family 1007208, 1007081 and a sporadic case with sensorineural hearing loss. Reverse transcriptase polymerase chain reaction was conducted on the proband from Family 1007208 to test how the splice-site variation affects the transcription in RNA level. A novel heterozygous splice-site variation c.991-3 C > A in DFNA5 was found in Family 1007208; a known hotspot heterozygous splice-site variation c.991-15_991_13delTTC was identified in Family 1007081. Both the splice-site variations were segregated with the late onset hearing loss phenotype, leading to the skipping of exon 8 at RNA level. In addition, a novel DFNA5 frameshift variation c.116_119delAAAA was found in the sporadic case, but was not segregated with the hearing impairment phenotype. In conclusion, we identified one novel and one known pathogenic DFNA5 splice-site variation in two Chinese Families, as well as a novel DFNA5 frameshift variation c.116_119delAAAA in a sporadic case, which does not the cause for the hearing loss case. Both the two pathogenic splice-site variations and the nonpathogenic frameshift variation provide further support for the specific gain-of-function mechanism of DFNA5 related hearing loss.

DFNA5 (GSDME) c.991-15_991-13delTTC: Founder Mutation or Mutational Hotspot?

“…DFNA5 (GDSME) is part of the gasdermin family of proteins that produce pore-forming complexes which lead to pyroptosis (inflammatory cell death). Although DFNA5 is widely expressed throughout the body (https://www.proteinatlas.org/ENSG00000105928-GSDME/tissue), the toxic gain-of-function protein that is produced as a result of skipping exon 8 results only in deafness [6][7][8][9]15,16]. The cause for this limited cochlear phenotype is not known, but may reflect regulatory mechanisms in other tissues, or simply cell turnover.…”

“…To date, DFNA5 mutations have been reported in families of European, Iranian, Chinese, Korean, and Japanese descent [6][7][8][9][10][11][12]. One mutation (c.991-15_991-13delTTC), has been identified in six families of East Asian descent [7][8][9]15,16]. Analysis of flanking single nucleotide polymorphisms in families from Korea, China, and Japan has identified a common haplotype, suggesting that the c.991-15_991-13delTTC mutation is a founder mutation in the East Asian population [8,9].…”

Case Report: Novel Heterozygous DFNA5 Splicing Variant Responsible for Autosomal Dominant Non-syndromic Hearing Loss in a Chinese Family

“…All DFNA5 mutations reported to date are splice-site variants leading to the skipping of exon 8 (Table 1; Van Laer et al, 1998;Yu et al, 2003;Bischoff et al, 2004;Cheng et al, 2007;Park et al, 2010;Chai et al, 2014;Nishio et al, 2014;Li-Yang et al, 2015;Nadol et al, 2015;Booth et al, 2018;Wang et al, 2018;Booth et al, 2020). The common phenotype in families with a DFNA5 mutation is bilateral, symmetrical, late-onset hearing loss, starting at high frequencies and ultimately progressing to involve all frequencies, with the severity ranging from moderate to profound.…”

GSDME and its role in cancer: From behind the scenes to the front of the stage

“…protein. [2][3][4][5][6][7][8][9][10][11][12] GSDME belongs to the gasdermin (GSDM) family, which owes its nomenclature to its high expression pattern along the gastrointestinal tract and skin (dermis). 13,14 In addition, expression of GSDME is reported in all vital organs.…”

“…16 Recently, the N-terminal (N-GSDM) domain of GSDMA, -D and -E was shown to execute cell death by pore formation, 17 and this function is apparently inhibited by the C-terminal domain (C-GSDM) in the full-length protein. In case of hearing loss, it is hypothesized that truncation of C-GSDME by skipping of exon 8 represents a gain-offunction mutation that unleashes the intrinsic pore-forming activity and might result in increased death of terminally differentiated cochlear hair cells or other cells important for hearing 3,4,16,18,19 (Figure 1).…”