ClinVar

In a South African Xhosa mother and son with progressive prelingual sensorineural hearing loss (DFNA27; 612431), Manyisa et al. (2021) identified heterozygosity for a c.1244G-C transversion (c.1244G-C, NM_005612.5) in exon 4 of the REST gene, resulting in a cys415-to-ser (C415S) substitution at a highly conserved residue. The mutation was not found in the proband's unaffected half-brother or unaffected maternal grandmother, in 103 black South African controls or 52 sporadic South African probands of black or mixed ancestry with nonsyndromic hearing impairment, or in the gnomAD, UK10K, Greater Middle East Variome (GME), or dbSNP databases. Experiments using GFP tagging in HEK293 cells showed that the wildtype REST protein is located exclusively within the nucleus, whereas the mutant showed localization throughout the cell, indicating loss of exclusive nuclear shuttling/localization. In addition, wildtype REST competently repressed transcription of the known REST target AF1Q (604684) in transiently transfected HEK293 cells, whereas transcriptional repression was lost in cells expressing the mutant REST protein.