Joubert Syndrome 22

A number sign (#) is used with this entry because of evidence that Joubert syndrome-22 (JBTS22) is caused by homozygous mutation in the PDE6D gene (602676) on chromosome 2q37. One such family has been reported.

For a phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see 213300.

Clinical Features

Thomas et al. (2014) reported a consanguineous family in which 2 sibs had Joubert syndrome. An infant girl presented with intrauterine growth retardation, facial dysmorphism, postaxial polydactyly of feet, syndactyly, renal hypoplasia, microphthalmia, and an extinguished electroretinogram. Brain MRI confirmed the diagnosis of Joubert syndrome. Her brother had polydactyly, microphthalmia, and coloboma. A third sib was a male fetus terminated at 14 weeks' gestation following the observation of brain anomalies and polydactyly. Fetal examination showed severe retinal dysplasia.

Inheritance

The transmission pattern of Joubert syndrome in the family reported by Thomas et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 sibs, born of consanguineous parents, with Joubert syndrome, Thomas et al. (2014) identified a homozygous splice site mutation in the PDE6D gene (602676.0001). The mutation, which was found using homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. The mutant protein localized normally to the basal body of primary cilia in patient fibroblasts, and the morphology of cilia was normal. The mutant mRNA did not adequately rescue a knockdown zebrafish mutant, although there was some partial rescue of abnormal eye development. Coimmunoprecipitation assays showed that the mutant PDE6D protein was unable to bind to INPP5E (613037), and that siRNA-mediated depletion of PDE6D led to a complete loss of ciliary INPP5E. Patient fibroblasts showed abnormal accumulation of INPP5E at the apical pole of epithelial tubule cells and loss of INPP5E at the cilia. These findings indicated that PDE6D is indispensable for proper ciliary INPP5E trafficking and targeting. Screening the PDE6D gene in 940 patients with variable ciliopathy syndromes did not identify any mutations.

Animal Model

Thomas et al. (2014) found that morpholino knockdown of pde6d in zebrafish embryos resulted in microphthalmia, pericardial edema, distended and blocked renal pronephric openings, proximal tubule cysts, and disorganized retinal cell layers.