CC2D2A Is Mutated in Joubert Syndrome and Interacts with the Ciliopathy-Associated Basal Body Protein CEP290

Abstract

Joubert syndrome and related disorders (JSRD) are primarily autosomal-recessive conditions characterized by hypotonia, ataxia, abnormal eye movements, and intellectual disability with a distinctive mid-hindbrain malformation. Variable features include retinal dystrophy, cystic kidney disease, and liver fibrosis. JSRD are included in the rapidly expanding group of disorders called ciliopathies, because all six gene products implicated in JSRD (NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67, and ARL13B) function in the primary cilium/basal body organelle. By using homozygosity mapping in consanguineous families, we identify loss-of-function mutations in CC2D2A in JSRD patients with and without retinal, kidney, and liver disease. CC2D2A is expressed in all fetal and adult tissues tested. In ciliated cells, we observe localization of recombinant CC2D2A at the basal body and colocalization with CEP290, whose cognate gene is mutated in multiple hereditary ciliopathies. In addition, the proteins can physically interact in vitro, as shown by yeast two-hybrid and GST pull-down experiments. A nonsense mutation in the zebrafish CC2D2A ortholog (sentinel) results in pronephric cysts, a hallmark of ciliary dysfunction analogous to human cystic kidney disease. Knockdown of cep290 function in sentinel fish results in a synergistic pronephric cyst phenotype, revealing a genetic interaction between CC2D2A and CEP290 and implicating CC2D2A in cilium/basal body function. These observations extend the genetic spectrum of JSRD and provide a model system for studying extragenic modifiers in JSRD and other ciliopathies.

Genomic analysis of Meckel–Gruber syndrome in Arabs reveals marked genetic heterogeneity and novel candidate genes

“…15 In fact, mutations in MKS genes have been reported to cause other ciliopathies, for example, MKS1 and BardetBiedl syndrome, 16 TMEM216 and Joubert syndrome, 17 TMEM67 and Joubert syndrome and nephrophthisis, 18,19 CEP290 in non-syndromic retinal dystrophy, Senior-Loken syndrome, nephronophthisis, Joubert syndrome, and Bardet-Biedl syndrome, 20 RPGRIP1L and Joubert syndrome, 21 and CC2D2A and Joubert syndrome. 22 The factors that determine the ultimate clinical phenotype are not completely understood but there is growing evidence that ciliopathies represent a spectrum of clinical severity that correlates to some extent with the severity of the ciliary defect. Consistent with MKS being at the severe end of the clinical spectrum, most causative mutations are truncating in nature while hypomorphic mutations in the same genes cause less severe phenotypes.…”

The role of primary cilia in the development and disease of the retina

“…43 Mutations in CC2D2A in humans lead to RP, often as part of multi-organ syndromes. [44][45][46] Growth of the microtubule axoneme is dependent on chaperone proteins such as prefoldin-5 that, when mutated in mice, leads to photoreceptor degeneration. 47 Other chaperones including HSC70 (Hspa8) have also been found to be associated with photoreceptor axonemal proteins.…”

Structural abnormalities of the brain other than molar tooth sign in joubert syndrome related disorders

“…Today, JSRDs are included in the rapidly expanding group of disorders called ciliopathies, because all six gene products implicated in JSRD (NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67, and ARL13B) function in the primary cilium/basal body organelle (14). Recently Gorden et al (14) identified lossof-function mutations in CC2D2A in JSRD patients with and without retinal, kidney, and liver disease. Conventional cranial MRI features of JSRD are well known today.…”

“…It is concluded that genetic and environmental factors during this developmental period (most probably between 3 weeks and 26 weeks of gestation) may cause embryological abnormalities, affecting both supra-and infratentorial structures (7). Today, JSRDs are included in the rapidly expanding group of disorders called ciliopathies, because all six gene products implicated in JSRD (NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67, and ARL13B) function in the primary cilium/basal body organelle (14). Recently Gorden et al (14) identified lossof-function mutations in CC2D2A in JSRD patients with and without retinal, kidney, and liver disease.…”