We report a consanguineous Iranian family affected by congenital profound sensorineural
deafness segregating in an autosomal recessive mode. Auditory tests implicated at least a cochlear defect in these patients. We mapped the
deafness, autosomal recessive (DFNB) locus involved by linkage analysis to a 4.8 Mb region at chromosome 21q22.3-qter. Exclusion of the DFNB8/10 gene TMPRSS3, located in this chromosomal interval, led us to identify a new
deafness locus, DFNB98. Whole exome sequencing allowed us to identify a homozygous frame-shifting mutation (c.1726G>T+c.1728delC) in the gene TSPEAR (
thrombospondin-type
laminin G domain and EAR repeats). This truncating mutation (p.V576LfsX37) impeded the secretion of the encoded
protein by cells transfected with the mutated gene. Alternative splicing of TSPEAR transcripts predict two
protein isoforms, 522 and 669
amino acids in length, both of which would be affected by the mutation. These
isoforms are composed of a
thrombospondin-type
laminin G (TSP) domain followed by seven tandemly organized
epilepsy-associated repeats (EARs), probably forming a β-propeller domain. Tspear is expressed in a variety of murine tissues. Only the larger Tspear transcript was found in the cochlea, and the
protein was detected by immunofluorescence at the surface of the hair bundles of sensory cells. The mammalian EAR
protein family includes six known members. Defects in four of them, i.e. Lgi1, Lgi2, Vlgr1 and, we show here, TSPEAR, cause disorders with auditory features:
epilepsy, which can include auditory features in humans; audiogenic
seizures in animals; and/or hearing impairments in humans and mice. These observations demonstrate that EAR-containing
proteins are essential for the development and function of the auditory system.