Knockdown of Bardet-Biedl Syndrome Gene <em>BBS9/PTHB1</em> Leads to Cilia Defects

<div><p>Bardet-Biedl Syndrome (BBS, MIM#209900) is a genetically heterogeneous disorder with pleiotropic phenotypes that include retinopathy, mental retardation, obesity and renal abnormalities. Of the 15 genes identified so far, seven encode core proteins that form a stable complex called BBSome, which is implicated in trafficking of proteins to cilia. Though BBS9 (also known as PTHB1) is reportedly a component of BBSome, its direct function has not yet been elucidated. Using zebrafish as a model, we show that knockdown of <em>bbs9</em> with specific antisense morpholinos leads to developmental abnormalities in retina and brain including hydrocephaly that are consistent with the core phenotypes observed in syndromic ciliopathies. Knockdown of <em>bbs9</em> also causes reduced number and length of cilia in Kupffer's vesicle. We also demonstrate that an orthologous human <em>BBS9</em> mRNA, but not one carrying a missense mutation identified in BBS patients, can rescue the <em>bbs9</em> morphant phenotype. Consistent with these findings, knockdown of <em>Bbs9</em> in mouse IMCD3 cells results in the absence of cilia. Our studies suggest a key conserved role of BBS9 in biogenesis and/or function of cilia in zebrafish and mammals.</p>