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Results Core JS diagnostic features (hypotonia, ataxia, cognitive dysfunction, oculo-motor apraxia) were present in >80% of individuals, while abnormal breathing pattern was reported in 60%. Frequently associated features included retinal dystrophy (31.4%), renal disease (20.9%), coloboma (17.7%), polydactyly (15.3%), liver fibrosis (15.2%) and encephalocele (8%). Liver fibrosis and coloboma were strongly associated with each other (Odds Ratio 7.0, 95% Confidence Interval = 3.0-13.2), while retinal dystrophy and renal disease were weakly associated (O.R. 2.2, 95%C. I. = 1.7-5.6). Additional clinical features included other brain abnormalities (n = 73), seizures (n = 49), cleft palate (n = 16), hearing loss (n = 14) and psychiatric problems (n = 45). The genetic cause was identified in 60% of families, with 5 genes accounting for the majority of patients (C5ORF42, CEP290, CC2D2A, AHI1, TMEM67). Bi-allelic causal mutations in B9D2 and C2CD3 were identified in 2 families each. Bi-allelic mutations in 2 different genes were identified in 4 families and heterozygous mutations (in addition to the causal mutation) were present in 62 individuals. Significant (p

We have identified a complex of proteins that form part of the transition zone, a region at the base of the cilium. This complex includes the three members of the Tectonic family, extracytosolic glycoproteins that interact with transmembrane components of the transition zone such as Tmem67, Tmem216, and Tmem231. These transmembrane proteins connect to an intracellular transition zone complex comprised of many known Joubert- and Meckel-associated proteins including Cc2d2a, B9d1, B9d2, Mks1. Loss of components of this transition zone complex in mice compromise ciliogenesis in some tissues, and deregulate ciliary protein composition in others. In particular, the ciliary localization of Smoothened (Smo), a central component of the Hedgehog pathway, depends on this complex. As Smo functions at the cilium, many mouse transition zone mutants show deregulation of Hh signaling, resulting in ventralization of the neural tube and polydactyly. Defining the components of the transition zone has led to the identification of additional genes underlying Joubert and Meckel syndromes including Tctn1, Tctn2 and B9d2. We hypothesize that Joubert and Meckel syndromes are caused by transition zone dysfunction that disrupts intercellular signaling, leading to developmental defects.

Background Understanding the pathogenesis of the autosomal recessive cystic kidney disease, nephronophthisis (NPHP) remains a challenge. NPHP is associated with extra-renal disease in 10-15%, including abnormal eye and cerebellar development, this combination of problems is called Joubert Syndrome, JS. NPHP and JS are ciliopathies because the encoded proteins of all mutated genes are found in primary cilia/associated architecture. NPHP and JS are genetically heterogenous, with mutations in a single gene such as NPHP6, AHI1 or CC2D2A being sufficient to cause disease. Although homozygous mutations are identified in most cases, some patients have an additional heterozygous mutation in another gene, leading to hypotheses of epistasis modifying the clinical phenotype.