SCAPER mutation affects cilia length, causing Bardet-Biedl syndrome.

Studies of ciliopathies have served in elucidating much of our knowledge of structure and function of primary cilia. We demonstrate through linkage analysis and exome sequencing studies of two remotely related large consanguineous families, that an autosomal recessive Bardet-Biedl syndrome of intellectual disability, retinitis pigmentosa, obesity, short stature and brachydactyly, stems from a homozyogous truncation mutation in SCAPER, a gene previously associated with mitotic progression. Our findings are in line with recent reports of SCAPER variants associated with intellectual disability and retinitis pigmentosa. Through immuno-fluorescence and live cell imaging in NIH/3T3 fibroblasts and SH-SY5Y neuroblastoma cell lines over-expressing SCAPER, we show that both wild type and mutant SCAPER are expressed in primary cilia and co-localize with tubulin, forming bundles of microtubules. While wild type SCAPER was rarely localized along the ciliary axoneme and basal body, the aberrant protein remained sequestered to the cilia, mostly at the ciliary tip. Longer cilia were demonstrated both in human affected fibroblasts compared to controls, as well as in NIH/3T3 cells transfected with mutant versus wildtype SCAPER. As SCAPER expression is known to peak at late G1 and S phase, overlapping the timing of ciliary resorption, our data suggest a possible role of SCAPER in ciliary dynamics and disassembly, also affecting microtubule-related mitotic progression. Thus, we outline a human ciliopathy syndrome and demonstrate that it is caused by a mutation in SCAPER, affecting primary cilia.