Fig. 4: Loss-of-function variants in GPR156 give rise to recessive congenital hearing loss.
From: Genetic association analysis of 77,539 genomes reveals rare disease etiologies
a, Schematic of the three pedigrees with cases homozygous or compound heterozygous for loss-of-function variants in the canonical transcript of GPR156, ENST00000464295.6. Blank symbols indicate individuals with an unknown genotype. b, Histograms of expression log fold changes for different sets of genes in mouse hair cells compared with surrounding cells: all mouse genes (left) and mouse genes homologous to their human counterparts in the ‘Hearing loss’ PanelApp panel, stratified by whether they had a stereocilia-related Gene Ontology (GO) term (that is, a term whose name contained ‘stereocilia’ or ‘stereocilium’ or the descendant of such a term) (right). The log fold change for Gpr156 is shown as a horizontal line. c, Maximum intensity projections of confocal Z stacks in the organ of Corti and vestibular system of a P10 wild-type mouse immunostained with GPR156 antibody (green) and counterstained with phalloidin (red). Top row, overview of the organ of Corti and vestibular system. Middle and bottom rows, magnified images of outer hair cells and inner hair cells, respectively. No stereociliary bundle staining was observed. The punctate staining observed in the organ of Corti was absent or significantly decreased in the utricle of the vestibular system. Scale bars, 10 μm (each image is representative of three replicates). d, Schematic showing the effects of each variant at the cDNA and amino acid level and on the protein product. e, Exemplar western blot taken from three replicates of GPR156–GFP using anti-GPR156 antibody in untransfected Cos7 cells (Cos7); Cos7 cells transfected with the wild-type construct (WT); and Cos7 cells transfected with the constructs containing each of the mutant alleles p.S642Afs*162 (S642), p.P718Lfs*86 (P718) and p.S207Vfs*113 (S207).
