Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes

Abstract

Joubert syndrome (JBTS), related disorders (JSRD) and Meckel syndrome (MKS) are ciliopathies. We now report that MKS2 and JBTS2 loci are allelic and due to mutations in TMEM216, encoding an uncharacterized tetraspan transmembrane protein. JBTS2 patients displayed frequent nephronophthisis and polydactytly, and two cases conformed to the Oro-Facio-Digital type VI phenotype, whereas skeletal dysplasia was common in MKS fetuses. A single p.R73L mutation was identified in all patients of Ashkenazi Jewish descent (n=10). TMEM216 localized to the base of primary cilia, and loss of TMEM216 in patient fibroblasts or following siRNA knockdown caused defective ciliogenesis and centrosomal docking, with concomitant hyperactivation of RhoA and Dishevelled. TMEM216 complexed with Meckelin, encoded by a gene also mutated in JSRD and MKS. Abrogation of tmem216 expression in zebrafish led to gastrulation defects that overlap with other ciliary morphants. The data implicate a new family of proteins in the ciliopathies, and further support allelism between ciliopathy disorders.

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

“…Despite two patients displaying an occipital encephalocele, no ARL13B variants have been found in Meckel syndrome fetuses (Cantagrel et al 9 and personal data), although Meckel syndrome has been shown to be the extreme lethal phenotype of JS for other genes. [29][30][31][32][33] In conclusion, we have identified a novel homozygous missense variant in ARL13B/JBTS8 in a JS patient with retinal involvement and obesity. 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.…”

Phenotypic spectrum and prevalence of INPP5E mutations in Joubert Syndrome and related disorders

“…The INPP5E phenotypic spectrum appears to largely overlap with that related to AHI1 mutations; 18 conversely, none of the INPP5E-mutated patients presented polydactyly or encephalocele, two features that are often associated with mutations in genes also causative of MKS, such as TMEM216, CEP290, TMEM67 or RPGRIP1L. 5,[19][20][21] In one patient with pure JS (COR28), only a single heterozygous INPP5E mutation could be detected, despite complete sequencing of the coding regions and canonical splice sites, and search for genomic rearrangements. Although we cannot exclude the possibility that a second pathogenic mutation resides within intronic or regulatory regions of the gene, it is also plausible that the identified change could act as a genetic modifier of the clinical phenotype in an oligogenic context, and that digenic mutations may reside in another gene.…”

Far from solved: A perspective on what we know about early mechanisms of left–right asymmetry

“…Further weakening the causal connection between ciliary function and LR asymmetry are studies in the mouse model (where the cilia link is expected to be the strongest) on genes such as Inturned, which regulate cilia formation but do not randomize asymmetry when disrupted (Zeng et al, 2010). Mutations in TMEM216 also result in ciliopathies but no LR defects in both mice and zebrafish (Valente et al, 2010). While it has been suggested that the dissociation of ciliary mutants and LR phenotypes could be due to a maternal protein that can somehow rescue early defects (Serluca et al, 2009), together these examples demonstrate that ciliary defects can indeed be separated from LR patterning errors, and cast considerable doubt on the idea that ciliary motion is a required component of vertebrate asymmetry; these examples also confirm that LR phenotypes observed in genetic mutations of ''ciliary'' genes do not establish a causal link.…”