Skeletal ciliopathies are a heterogeneous group of autosomal recessive osteochondrodysplasias caused by defects in formation, maintenance and function of the primary cilium. Mutations in the underlying genes affect the molecular motors, intraflagellar transport complexes (IFT), or the basal body. The more severe phenotypes are caused by defects of genes of the dynein-2 complex, where mutations in DYNC2H1, WDR34 and WDR60 have been identified. In a patient with a Jeune-like phenotype we performed exome sequencing and identified compound heterozygous missense and nonsense mutations in DYNC2LI1 segregating with the phenotype. DYNC2LI1 is ubiquitously expressed and interacts with DYNC2H1 to form the dynein-2 complex important for retrograde IFT. Using DYNC2LI1 siRNA knockdown in fibroblasts we identified a significantly reduced cilia length proposed to affect cilia function. In addition, depletion of DYNC2LI1 induced altered cilia morphology with broadened ciliary tips and accumulation of IFT-B complex proteins in accordance with retrograde IFT defects. Our results expand the clinical spectrum of ciliopathies caused by defects of the dynein-2 complex.

Ciliopathies are caused by defects in formation, maintenance and function of the primary cilium and underlying genes affect the dynein motor, intraflagellar transport complexes, or the basal body. In a patient of non-consanguineous parents presenting an intermediate phenotype between asphyxiating thoracic dystrophy and Ellis-van Crefeld syndrome we performed exome sequencing. Variants were selected based on potential ciliary function as identified in a yeast two-hybrid screen with NEK1, a basal body protein involved in short ribpolydactyly type Majeweski (SRPSII). We identified compound heterozygous nonsense (p.R208X) and missense (p.T221I) mutations in DYNC2LI1 segregating in the family. DYNC2LI1 is ubiquitously expressed and interacts with DYNC2H1 to form the dynein 2 complex important for retrograde intraflagellar transport. The hypothetical protein caused by the nonsense mutation lacks the coiledcoil domain involved in protein interaction and dimerization. The mutation p.T221I affects a highly conserved nucleoside triphosphate hydrolase domain responsible for GTPase driven dynein protein localization. Mutations in both DYNC2LI1 interacting partners DYNC2H1 and NEK1 are associated with ATD and SRPSs. We screened further patients of our short stature cohort and identified in two siblings heterozygous mutations in DYNC2LI1 (p. M1T) and its interaction partner DYNC2H1 (p.K495T). The DYNC2H1 mutation was previously reported by El Hokayem et al. compound heterozygous with a splice site mutation in a patient with SRPSII. Our results might indicate a possible digenic diallelic inheritance in our patients. This is the first report of mutations in DYNC2LI1 as part of the dynein 2 complex further expanding the clinical spectrum of ciliopathies.