SCAPER localizes to primary cilia and its mutation affects cilia length, causing Bardet-Biedl syndrome

Abstract

Studies of ciliopathies have served in elucidating much of our knowledge of structure and function of primary cilia. We report humans with Bardet-Biedl syndrome who display intellectual disability, retinitis pigmentosa, obesity, short stature and brachydactyly, stemming from a homozyogous truncation mutation in SCAPER, a gene previously associated with mitotic progression. Our findings, based on linkage analysis and exome sequencing studies of two remotely related large consanguineous families, are in line with recent reports of SCAPER variants associated with intellectual disability and retinitis pigmentosa. Using immuno-fluorescence and live cell imaging in NIH/3T3 fibroblasts and SH-SY5Y neuroblastoma cell lines over-expressing SCAPER, we demonstrate 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. Notably, 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.

Meta‐analysis of genotype‐phenotype associations in Bardet‐Biedl syndrome uncovers differences among causative genes

“…BBS is an autosomal recessive disorder caused by loss‐of‐function (LOF) mutations in at least 24 genes ( BBS1‐21 , Forsythe, Kenny, Bacchelli, & Beales, ; NPHP1 , Lindstrand et al, ; IFT74 , Lindstrand et al, ; and SCAPER , Wormser et al, ), whose function is closely related to the primary cilium. Most of the BBS patients have mutations in one of the eight genes encoding for the subunits of the octameric protein complex, BBSome ( BBS1 , 2 , 4 , 5 , 7 , 8 , 9 , 18 ; Nachury et al, ).…”

Exploring Key Challenges of Understanding the Pathogenesis of Kidney Disease in Bardet–Biedl Syndrome

“…16 Notably, several other BBS genes were later implicated in other ciliopathies and vice versa; for example, CEP290/NPHP6 mutations are associated with BBS and other ciliopathies, such as Meckel-Gruber, Joubert, Senior-Løcken, nephronophtisis, and Leber congenital amaurosis syndromes. 11 The advent of next-generation sequencing has led to the discovery of an increasing number of pathogenic loci; to date, up to 24 genes have been described 10,[17][18][19] (Supplementary Table S1). BBS1, BBS2, and BBS10 are the most commonly mutated genes and account for almost 50% of diagnoses.…”

Delineating the expanding phenotype associated with SCAPER gene mutation

“…In the current study, we describe clinical and genetic findings, including seven novel SCAPER variants, in six individuals of Amish, Caucasian, and South Asian descent. Together with our molecular data, our comprehensive phenotypic assessments enable a more detailed clinical comparison to be drawn between the patient cohort described here (including previously published individual G001284; Patient 3 in this study, (Carss et al, ) with the 17 individuals in whom SCAPER variants were recently defined (Hu et al, ; Jauregui et al, ; Najmabadi et al, ; Tatour et al, ; Wormser et al, ), permitting a more precise definition of the clinical phenotype arising from pathogenic SCAPER variation.…”

“…Biallelic LOF variants have since been associated with ID with or without retinitis pigmentosa (RP) in seven individuals from five families from Spain, Israel, and Iran (Hu et al, ; Tatour et al, ); in one individual from a Jordanian Arab family, a homozygous SCAPER gene variant was identified as the cause of nonsyndromic RP (Jauregui et al, ). More recently, Wormser et al () described a SCAPER gene variant associated with a Bardet–Biedl syndrome (BBS)‐like presentation comprising of ID, RP, short stature, obesity, and brachydactyly in eight individuals from two consanguineous Bedouin families belonging to the same tribe in southern Israel, alongside preliminary functional studies suggesting a possible role for SCAPER in ciliary dynamics and disassembly. In the current study, we describe clinical and genetic findings, including seven novel SCAPER variants, in six individuals of Amish, Caucasian, and South Asian descent.…”