Alström Syndrome protein ALMS1 localizes to basal bodies of cochlear hair cells and regulates cilium-dependent planar cell polarity

Abstract

Alström Syndrome is a life-threatening disease characterized primarily by numerous metabolic abnormalities, retinal degeneration, cardiomyopathy, kidney and liver disease, and sensorineural hearing loss. The cellular localization of the affected protein, ALMS1, has suggested roles in ciliary function and/or ciliogenesis. We have investigated the role of ALMS1 in the cochlea and the pathogenesis of hearing loss in Alström Syndrome. In neonatal rat organ of Corti, ALMS1 was localized to the basal bodies of hair cells and supporting cells. ALMS1 was also evident at the basal bodies of differentiating fibrocytes and marginal cells in the lateral wall. Centriolar ALMS1 expression was retained into maturity. In Alms1-disrupted mice, which recapitulate the neurosensory deficits of human Alström Syndrome, cochleae displayed several cyto-architectural defects including abnormalities in the shape and orientation of hair cell stereociliary bundles. Developing hair cells were ciliated, suggesting that ciliogenesis was largely normal. In adult mice, in addition to bundle abnormalities, there was an accelerated loss of outer hair cells and the progressive appearance of large lesions in stria vascularis. Although the mice progressively lost distortion product otoacoustic emissions, suggesting defects in outer hair cell amplification, their endocochlear potentials were normal, indicating the strial atrophy did not affect its function. These results identify previously unrecognized cochlear histopathologies associated with this ciliopathy that (i) implicate ALMS1 in planar cell polarity signaling and (ii) suggest that the loss of outer hair cells causes the majority of the hearing loss in Alström Syndrome.

Basal body proteins regulate Notch signaling via endosomal trafficking

“…To determine whether our observations extended to other basal body proteins, we investigated the role of BBS3, a BBS protein that is not a core member of the BBSome but that associates with it (Jin et al, 2010), and ALMS1, a basal body ciliopathy protein that is not related to the BBSome but that is important for regulation of developmental signaling (Hearn et al, 2005;Jagger et al, 2011). Suppression of either protein by short hairpin treatment in HEK293 cells increased HES5 expression, as detected by qRT-PCR (1.8-fold and 1.2-fold, respectively; Fig.…”

Ick Ciliary Kinase Is Essential for Planar Cell Polarity Formation in Inner Ear Hair Cells and Hearing Function

“…As HCs begin to differentiate, the kinocilium moves to the periphery and the stereocilia nearest to the kinocilium begin to elongate (Tilney et al, 1992). By E18.5, the kinocilium reaches the lateral position along the mediolateral axis and stereociliary bundles are regularly organized (Kelly and Chen, 2007). Postnatally, kinocilia regress and disappear until postnatal day 21 (P21) Figure 1.…”

“…In addition, Mkks Ϫ / Ϫ mutants display detachment of the kinocilium from sterociliary bundles (Ross et al, 2005). Mutant mice for Mks1 and Alsm1, causative genes for Meckel-Gruber syndrome and Alström syndrome in humans, respectively, exhibit misorientation of sterociliary bundles and abnormal localization of kinocilia (Cui et al, 2011;Jagger et al, 2011). Furthermore, mice defective in Ift88 or Kif3a, both of which are components of the intraflagellar transport (IFT) machinery, lack kinocilia and display misorientation or shape defects of stereociliary bundles (Jones et al, 2008;Sipe and Lu, 2011).…”

Kif3a regulates planar polarization of auditory hair cells through both ciliary and non-ciliary mechanisms

“…In particular, an isoform-specific knockout of protocadherin 15 (PCDH15-CD2) caused disruption of the kinociliary links that connect the kinocilium to the adjacent stereocilia, leading to hair bundle orientation and polarity defects (Webb et al, 2011). Moreover, the Alström syndrome protein ALMS1 has been shown to localize to basal bodies of cochlear hair cells and regulate hair bundle shape and orientation (Jagger et al, 2011). Finally, a role for the kinocilium in hair cell PCP regulation has been demonstrated by genetic ablation of the kinocilium (Jones et al, 2008).…”