Joubert Syndrome 20

A number sign (#) is used with this entry because of evidence that Joubert syndrome-20 (JBTS20) is caused by compound heterozygous mutation in the TMEM231 gene (614949) on chromosome 16q23.

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

Clinical Features

Srour et al. (2012) reported 3 patients from 2 unrelated French Canadian families with Joubert syndrome. The patients were 14, 9, and 4 years old, respectively. All had developmental delay and were nonverbal and nonambulatory. Other features included oculomotor apraxia, breathing abnormalities, and the molar tooth sign on brain MRI. Two had postaxial polydactyly, 2 had retinal involvement, and 2 had renal cysts with normal renal function. Two sibs in 1 family showed significant aggressive behavior and self-mutilation.

Inheritance

The transmission pattern of JBTS20 in the families reported by Srour et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 patients from 2 French Canadian families with Joubert syndrome-20, Srour et al. (2012) identified compound heterozygosity for 2 mutations in the TMEM231 gene (614949.0001 and 614949.0002). The mutations were identified by exome sequencing and confirmed by Sanger sequencing. The TMEM231 gene is a component of a protein complex in the basal body, a ring-like structure that functions in the transition zone at the base of cilia (Chih et al., 2012).

Animal Model

Chih et al. (2012) found that knockout of Tmem231 in mice led to lethality around embryonic day 15.5 with severe vascular defects. The phenotype included microphthalmia and polydactyly, and defects in patterning of the ventral spinal cord, consistent with a ciliopathy. Tmem231 -/- embryos showed loss of cilia and altered Shh (600725) gene expression, including absence of Shh-positive floorplate cells.