AUTHOR=Parzefall Thomas , Frohne Alexandra , Koenighofer Martin , Neesen Juergen , Laccone Franco , Eckl-Dorna Julia , Waters Jonathan J. , Schreiner Markus , Amr Sami Samir , Ashton Emma , Schoefer Christian , Gstœttner Wolfgang , Frei Klemens , Lucas Trevor 

TITLE=A Novel Variant in the TBC1D24 Lipid-Binding Pocket Causes Autosomal Dominant Hearing Loss: Evidence for a Genotype-Phenotype Correlation

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=Volume 14 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2020.585669

DOI=10.3389/fncel.2020.585669

ISSN=1662-5102

ABSTRACT=Background: Hereditary hearing loss is a disorder with high genetic and allelic heterogeneity. Diagnostic screening of candidate genes commonly yields novel variants of unknown clinical significance. TBC1D24 is a pleiotropic gene associated with recessive DOORS syndrome, epileptic encephalopathy, myoclonic epilepsy and both recessive and dominant hearing impairment. Genotype-phenotype correlations have not been established to date but could facilitate diagnostic variant assessment and elucidation of pathomechanisms.
Methods and Results: Whole-exome and gene panel screening identified a novel (c.919A>C; p.Asn307His) causative variant in TBC1D24 in two unrelated Caucasian families with autosomal dominant nonsyndromic late-onset hearing loss. Protein modelling on the Drosophila TBC1D24 ortholog Skywalker crystal structure showed close interhelix proximity (6.8Å) between the highly conserved residue p.Asn307 in alpha-18 and the position of the single known pathogenic dominant variation (p.Ser178Leu) in alpha-11 that causes a form of deafness with similar clinical characteristics.
Conclusion: Genetic variants affecting two polar hydrophilic residues in neighboring helices of TBC1D24 cause autosomal dominant nonsyndromic late-onset hearing loss. The spatial proximity of the affected residues suggests the first genotype-phenotype association in TBC1D24-related disorders. Three conserved residues in alpha-18 contribute to the formation of a functionally relevant cationic phosphoinositide binding pocket that regulates synaptic vesicle trafficking which may be involved in the molecular mechanism of disease.