Mutations in CCDC11 cause aberrant placement of internal organs and congenital heart disease in humans. Ccdc11 is a novel component of centriolar satellites and plays a critical role in motile and sensory ciliogenesis. The results implicate centriolar satellites in the pathology of left–right patterning and heart disease.

SUMMARY SYNE1 (Synaptic nuclear envelope 1) encodes multiple isoforms of Nesprin1 (Nuclear Envelope Spectrin 1) that associate with the nuclear envelope (NE) through a C-terminal KASH (Klarsicht/Anc1/Syne homology) domain (Figure 1A) [1–4]. This domain interacts directly with the SUN (Sad1/Unc84) domain of Sun proteins [5–7], a family of transmembrane proteins of the inner nuclear membrane (INM) [8, 9], to form the so-called LINC complexes (Linkers of the Nucleoskeleton and the Cytoskeleton) that span the whole NE and mediate nuclear positioning [10–12]. In a stark departure from this classical depiction of Nesprin1 in the context of the NE, we report that rootletin recruits Nesprin1α at the ciliary rootlets of photoreceptors and identified asymmetric NE aggregates of Nesprin1α and Sun2 that dock filaments of rootletin at the nuclear surface. In NIH3t3 cells, we show that recombinant rootletin filaments also dock to the NE through the specific recruitment of a ~600 kDa endogenous isoform of Nesprin1 (Nes1600kDa) and of Sun2. In agreement with the association of Nesprin1α with photoreceptor ciliary rootlets and the functional interaction between rootletin and Nesprin1 in fibroblasts, we demonstrate that multiple isoforms of Nesprin1 are integral components of ciliary rootlets of multiciliated ependymal and tracheal cells. Together, these data provide a novel functional paradigm for Nesprin1 at ciliary rootlets and suggest that the wide spectrum of human pathologies linked to truncating mutations of SYNE1 [13–15] may in part originate from ciliary defects.

The GTPase Arl13b participates in ciliary protein transport, but its contribution to intraflagellar transport (IFT), the main motor-based protein shuttle of cilia, remains largely unknown. Chlamydomonas arl13 mutant cilia were characterized by both abnormal reduction and accumulation of select membrane-associated proteins. With respect to the latter, a similar set of proteins including phospholipase D (PLD) also accumulated in BBSome-deficient cilia. IFT and BBSome traffic were apparently normal in arl13. However, transport of PLD, which in control cells moves by BBSome-dependent IFT, was impaired in arl13, causing PLD to accumulate in cilia. ARL13 only rarely and transiently traveled by IFT, indicating that it is not a co-migrating adapter securing PLD to IFT trains. In conclusion, the loss of Chlamydomonas ARL13 impedes BBSome-dependent protein transport, resulting in overlapping biochemical defects in arl13 and bbs mutant cilia.

A recent study reveals that the large coiled-coil protein CEP290 is an integral component of the transition zone between the cell body and the cilium and functions as a gatekeeper to regulate trafficking of ciliary proteins.

BackgroundBiallelic deleterious variants in RTTN, which encodes rotatin, are associated with primary microcephaly, polymicrogyria, seizures, intellectual disability, and primordial dwarfism in human infants.Methods and ResultsWe performed exome sequencing of an infant with primary microcephaly, pontocerebellar hypoplasia, and intractable seizures and his healthy, unrelated parents. We cultured the infant’s fibroblasts to determine primary ciliary phenotype.ResultsWe identified biallelic variants in RTTN in the affected infant: a novel missense variant and a rare, intronic variant that results in aberrant transcript splicing. Cultured fibroblasts from the infant demonstrated reduced length and number of primary cilia.ConclusionBiallelic variants in RTTN cause primary microcephaly in infants. Functional characterization of primary cilia length and number can be used to determine pathogenicity of RTTN variants.