CC2D2Amutations in Meckel and Joubert syndromes indicate a genotype-phenotype correlation

Abstract

The Meckel syndrome (MKS) is a lethal fetal disorder characterized by diffuse renal cystic dysplasia, polydactyly, a brain malformation that is usually occipital encephalocele and/or vermian agenesis, with intrahepatic biliary duct proliferation. Joubert syndrome (JBS) is a viable neurological disorder with a characteristic "molar tooth sign" (MTS) on axial images reflecting cerebellar vermian hypoplasia/dysplasia. Both conditions are classified as ciliopathies with an autosomal recessive mode of inheritance. Allelism of MS and JBS has been reported for TMEM67/MKS3, CEP290/MKS4, and RPGRIP1L/MKS5. Recently, one homozygous splice mutation with a founder effect was reported in the CC2D2A gene in Finnish fetuses with MKS, defining the 6 th locus for MKS. Shortly thereafter, CC2D2A mutations were reported in JBS also. The analysis of the CC2D2A gene in our series of MKS fetuses, identified 14 novel truncating mutations in 11 cases. These results confirm the involvement of CC2D2A in MKS and reveal a major contribution of CC2D2A to the disease. We also identified three missense CC2D2A mutations in two JBS cases. Therefore and in accordance with the data reported regarding RPGRIP1L, our results indicate phenotype-genotype correlations, as missense and presumably hypomorphic mutations lead to JBS while all null alleles lead to MKS.

Joubert syndrome: genotyping a Northern European patient cohort

“…19 This would be in line with the observation that mild mutations in MKS-associated genes can cause JBS, for example, RPGRIP1L/MKS5 and CC2D2A/MKS6. 35,36 The patient presented with a mild classic JBS phenotype without renal, retinal, or hepatic disease (at age 10 years), similar to the phenotype of two JBS cases with B9D1 mutations described recently. 19 The percentage of JBS cases with a heterozygous mutation in a known JBS gene (53%) is much higher than expected in a rare autosomal recessive disease (the estimated birth prevalence of JBS is 1 in 80 000 to 1 in 100 000); 2,7 however, we cannot exclude that a second pathogenic mutation is present but missed by our detection method.…”

Identification of a novel ARL13B variant in a Joubert syndrome-affected patient with retinal impairment and obesity

“…Despite two patients displaying an occipital encephalocele, no ARL13B variants have been found in Meckel syndrome fetuses (Cantagrel et al 9 and personal data), although Meckel syndrome has been shown to be the extreme lethal phenotype of JS for other genes. [29][30][31][32][33] In conclusion, we have identified a novel homozygous missense variant in ARL13B/JBTS8 in a JS patient with retinal involvement and obesity. We have shown that this variant is hypomorphic, as it is unable to rescue efficiently either the arl13b sco zebrafish phenotype or the deficiencies in Arl13b hnn MEFs.…”

A coiled-coil- and C2-domain-containing protein is required for FAZ assembly and cell morphology in Trypanosoma brucei

“…This protein was therefore named CC2D, standing for coiled-coil-and C2-domain-containing protein. Proteins with similar domain organization have also been found in other organisms, and the human CC2D2A protein has been located to the cilia basal bodies and been implicated in ciliogenesis and human ciliary diseases (Doherty, 2009;Gorden et al, 2008;Mougou-Zerelli et al, 2009;Noor et al, 2008;Tallila et al, 2008).…”