Mutations in the Cilia Gene ARL13B Lead to the Classical Form of Joubert Syndrome

Abstract

Joubert syndrome (JS) and related disorders are a group of autosomal-recessive conditions sharing the "molar tooth sign" on axial brain MRI, together with cerebellar vermis hypoplasia, ataxia, and psychomotor delay. JS is suggested to be a disorder of cilia function and is part of a spectrum of disorders involving retinal, renal, digital, oral, hepatic, and cerebral organs. We identified mutations in ARL13B in two families with the classical form of JS. ARL13B belongs to the Ras GTPase family, and in other species is required for ciliogenesis, body axis formation, and renal function. The encoded Arl13b protein was expressed in developing murine cerebellum and localized to the cilia in primary neurons. Overexpression of human wild-type but not patient mutant ARL13B rescued the Arl13b scorpion zebrafish mutant. Thus, ARL13B has an evolutionarily conserved role mediating cilia function in multiple organs.

Identification of a novel ARL13B variant in a Joubert syndrome-affected patient with retinal impairment and obesity

“…Even if Y86 is not conserved in C.reinhardtii (Figure 2a), this is the only ARL13B structure published to date. In contrast to the previously identified ARL13B variant at R79, which normally establishes a hydrogen bond with D30 from the GTP binding domain, 9 Y86 appears not directly involved in GTP binding but in the switch II region (Figure 2b). In addition, we have identified two other aromatic residues: H117 and W82 located o5.5 Å from the Y86, contributing to Van der Walls forces stabilizing this region of the protein.…”

“…We have shown that this variant is hypomorphic, as it is unable to rescue efficiently either the arl13b sco zebrafish phenotype or the deficiencies in Arl13b hnn MEFs. This variant is the first novel ARL13B variant reported since the original publication by Cantagrel et al 9 reporting three variants in two families. Thus, these results confirm the involvement of ARL13B in JS with retinopathy and suggest the extension of the phenotypic spectrum of ARL13B variants to obesity.…”

“…Novel ARL13B variant in Joubert syndrome S Thomas et al reported, 9 supporting a minor contribution of ARL13B to JS. In this previous study, no patient had renal involvement, and one patient displayed evidence of mild nonspecific pigmentary retinopathy on clinical examination, although electroretinogram was normal in the affected siblings, and therefore ARL13B involvement in retinal function was not clear.…”

“…Wild-type human ARL13B can rescue the arl13b sco phenotype. 9 We thus tested the ability of human ARL13B synthetic mRNA with the Y86C variant to rescue the arl13b sco phenotype. We found that mutated mRNA is not able to efficiently rescue the phenotype as compared to WT human ARL13B synthetic mRNA.…”

“…Three ARL13B variants (R79C, R200C and W82X) were previously reported in two families with JS associated or not with retinal anomalies. 9 ARL13B is a member of the ADP-ribosylation factor-like (ARL) family of small GTPases of the RAS superfamily. In model organisms, variants in ARL13B have been linked to cilia assembly and kidney cyst formation.…”