Timely termination of the light response in retinal photoreceptors requires rapid inactivation of the G protein transducin. This is achieved through the stimulation of transducin GTPase activity by the complex of the ninth member of the regulator of G protein signaling protein family (RGS9) with type 5 G protein ␤ subunit (G␤5). RGS9⅐G␤5 is anchored to photoreceptor disc membranes by the transmembrane protein, R9AP. In this study, we analyzed visual signaling in the rods of R9AP knockout mice. We found that light responses from R9AP knockout rods were very slow to recover and were indistinguishable from those of RGS9 or G␤5 knockout rods. This effect was a consequence of the complete absence of any detectable RGS9 from the retinas of R9AP knockout mice. On the other hand, the level of RGS9 mRNA was not affected by the knockout. These data indicate that in photoreceptors R9AP determines the stability of the RGS9⅐G␤5 complex, and therefore all three proteins, RGS9, G␤5, and R9AP, are obligate members of the regulatory complex that speeds the rate at which transducin hydrolyzes GTP.Timely termination of the light response in retinal photoreceptors is essential for normal vision (reviewed in Refs. 1 and 2). On the molecular level, the normal time course of the light response requires rapid deactivation of the G protein transducin, which relays the visual signal to the effector, cyclic GMP phosphodiesterase. Deactivation of transducin occurs when the transducin ␣ subunit hydrolyzes its bound GTP. In normal rods, GTP hydrolysis is catalyzed by the complex of the regulator of G protein signaling protein (RGS9) 1 with type 5 G protein ␤ subunit (G␤5) (reviewed in Refs. 2 and 3). Recent studies have demonstrated that photoreceptors lacking RGS9 or G␤5 produce light responses that recover at an abnormally slow rate (4, 5).In photoreceptors, the RGS9⅐G␤5 complex is tightly associated with the transmembrane protein R9AP (RGS9 anchor protein), which anchors RGS9⅐G␤5 on the surface of the disc membranes of the outer segment, which is the subcellular compartment where visual transduction occurs (6 -8). R9AP is a 25-kDa protein structurally related to members of the SNARE (N-ethylmaleimide-sensitive factor attachment protein receptor) protein family, which are involved in vesicular trafficking and exocytosis (8 -10). In mammals, R9AP is expressed predominantly in the retina (6, 9), whereas in chicken it is also present in cochlear hair cells and dorsal root ganglion neurons (9). R9AP dramatically enhances the ability of RGS9⅐G␤5 to stimulate transducin GTPase (7,8,10) and participates in the delivery of RGS9⅐G␤5 to photoreceptor outer segment (10).In this study, we analyzed visual signaling in rods of R9AP knockout mice. The knockout did not affect the overall retinal morphology or photoreceptor development. However, light responses from R9AP knockout rods were very slow to recover and were indistinguishable from those of RGS9 or G␤5 knockout rods. The effect of the R9AP knockout on the photoresponse recovery was explained by a...

Background: Mutations in the transmembrane cochlear expressed gene 1 (TMC1) cause deafness in human and mouse. Mutations in two homologous genes, EVER1 and EVER2 increase the susceptibility to infection with certain human papillomaviruses resulting in high risk of skin carcinoma. Here we report that TMC1, EVER1 and EVER2 (now TMC6 and TMC8) belong to a larger novel gene family, which is named TMC for trans membrane channel-like gene family.

Auditory neuropathy is a hearing disorder characterized by normal outer hair cell function and abnormal neural conduction of the auditory pathway. Aetiology and clinical presentation of congenital or early-onset auditory neuropathy are heterogeneous, and their correlations are not well understood. Genetic backgrounds and associated phenotypes of congenital or early-onset auditory neuropathy were investigated by systematically screening a cohort of 23 patients from unrelated Japanese families. Of the 23 patients, 13 (56.5%) had biallelic mutations in OTOF, whereas little or no association was detected with GJB2 or PJVK, respectively. Nine different mutations of OTOF were detected, and seven of them were novel. p.R1939Q, which was previously reported in one family in the United States, was found in 13 of the 23 patients (56.5%), and a founder effect was determined for this mutation. p.R1939Q homozygotes and compound heterozygotes of p.R1939Q and truncating mutations or a putative splice site mutation presented with stable, and severe-to-profound hearing loss with a flat or gently sloping audiogram, whereas patients who had non-truncating mutations except for p.R1939Q presented with moderate hearing loss with a steeply sloping, gently sloping or flat audiogram, or temperature-sensitive auditory neuropathy. These results support the clinical significance of comprehensive mutation screening for auditory neuropathy.