Joubert Syndrome 35

A number sign (#) is used with this entry because of evidence that Joubert syndrome-35 (JBTS35) is caused by homozygous mutation in the ARL3 gene (604695) on chromosome 10q24.

For a discussion of genetic heterogeneity of Joubert syndrome, see JBTS1 (213300).

Clinical Features

Alkanderi et al. (2018) reported 1 patient from a consanguineous Saudi Arabian family and 3 sisters from a consanguineous Pakistani family with Joubert syndrome. The patients ranged in age from 5 to 21 years. Common features included developmental delay, hypotonia, ataxia, and retinal rod-cone dystrophy with night blindness and progressive visual impairment. One patient had oculomotor apraxia. Brain imaging showed the molar tooth sign with cerebellar vermis hypoplasia and elongation of the superior cerebellar peduncles in all patients. Three of the 4 patients had variable renal involvement; 2 had recurrent urinary tract infections, and each of the 3 had 1 of the following: multicystic dysplastic kidney with hydronephrosis, renal scarring, or unequal kidney size. Two sisters had abnormalities of thermoregulation, suggestive of brainstem involvement. The boy from the Saudi Arabian family had dysmorphic facial features, including depressed nasal bridge, upturned nares, ptosis, arched eyebrows, telecanthus, and low-set ears.

Inheritance

The transmission pattern of JBTS35 in the families reported by Alkanderi et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 patients from 2 unrelated consanguineous families with JBTS35, Alkanderi et al. (2018) identified homozygous missense mutations affecting the same residue in the ARL3 gene (R149C, 604695.0001 and R149H, 604695.0002). The mutations, which were found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in both families. In vitro functional expression assays using murine Arl3 showed that the R149H variant disrupted the interaction with ARL13B (608922) and resulted in impaired ARL13B-assisted GTP-nucleotide exchange. Patient fibroblasts did not show abnormal ciliary length or structural appearance, but cilia showed a significant loss of both INPP5E (613037) and NPHP3 (608002) content, indicating that wildtype ARL3 is required for normal release of these cargoes into the ciliary axoneme. There was a defect in both prenylated and myristoylated ciliary cargo delivery compared to wildtype.

Animal Model

Schrick et al. (2006) found that while Arl3 +/- mice appeared normal, Arl3 -/- mice were obtained at a submendelian ratio, were small and sickly, and had markedly swollen abdomens. Arl3 -/- mice failed to thrive and all died by 3 weeks of age. They exhibited abnormal development of renal, hepatic, and pancreatic epithelial tubule structures, with abnormal epithelial cell proliferation and cyst formation characteristic of ARPKD (263200). Moreover, mice lacking Arl3 exhibited photoreceptor degeneration as early as postnatal day 14. Schrick et al. (2006) concluded that absence of Arl3 causes a ciliary disease affecting the kidney, biliary tract, pancreas, and retina. Alkanderi et al. (2018) noted that the Arl3-null mouse phenotype described by Schrick et al. (2006) is consistent with a ciliopathy.