* 612013

COILED-COIL AND C2 DOMAINS-CONTAINING PROTEIN 2A; CC2D2A


Alternative titles; symbols

KIAA1345


HGNC Approved Gene Symbol: CC2D2A

Cytogenetic location: 4p15.32     Genomic coordinates (GRCh38): 4:15,469,865-15,601,557 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
4p15.32 COACH syndrome 2 619111 AR 3
Joubert syndrome 9 612285 AR 3
Meckel syndrome 6 612284 AR 3
Retinitis pigmentosa 93 619845 AR 3

TEXT

Description

CC2D2A 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. This complex acts as a barrier to restrict protein diffusion between plasma and ciliary membranes (Chih et al., 2012).


Cloning and Expression

By sequencing clones obtained from a size-fractionated human fetal brain cDNA library, Nagase et al. (2000) cloned CC2D2A, which they designated KIAA1345. The deduced protein contains 1,532 amino acids. RT-PCR detected moderate CC2D2A expression in ovary, lung, brain, liver, kidney, testis, and all specific adult brain regions examined. Low expression was detected in fetal brain and adult heart, and little to no expression was detected in fetal liver and adult skeletal muscle, pancreas, and spleen. In vitro-translated CC2D2A had an apparent molecular mass of more than 100 kD by SDS-PAGE.

By RT-PCR analysis of human tissues, Noor et al. (2008) detected strong CC2D2A expression in prostate, pancreas, kidney, lung, and liver with lower expression in spleen, small intestine, colon, skeletal muscle, ovary, thymus, and heart. CC2D2A contains 3 putative coiled-coil domains, a C-terminal C2 domain, and potential CaMKII recognition sites, PKC phosphorylation sites, and 2 putative nuclear localization signals. CC2D2A shares 84.8% amino acid identity with its rodent homologs. In COS-7 cells, overexpressed CC2D2A-GFP fusion protein localized almost exclusively to the cytoplasmic fraction, despite the predicted presence of potential nuclear localization signals.

Tallila et al. (2008) determined that full-length CC2D2A encodes a 1,620-residue protein. The longer transcript was present in all normal fetal tissues examined.


Gene Structure

Noor et al. (2008) determined that the CC2D2A gene contains 37 exons spanning 131.5 kb.

Tallila et al. (2008) identified an additional exon in the CC2D2A gene located after exon 29, which brought the total number of exons to 38.


Mapping

Noor et al. (2008) stated that the CC2D2A gene maps to chromosome 4p15.3.


Gene Function

Gorden et al. (2008) found that CC2D2A colocalized and interacted with CEP290 (610142) at the basal body in cultured ciliary cells.

Williams et al. (2011) showed that the conserved proteins Mks1 (609883), Mksr1 (B9D1), Mksr2 (B9D2; 611951), Tmem67 (609884), Rpgrip1l (610937), Cc2d2a, Nphp1 (607100), and Nphp4 (607215) functioned at an early stage of ciliogenesis in C. elegans. These 8 proteins localized to the ciliary transition zone and established attachments between the basal body and transition zone membrane. They also provided a docking site that restricted vesicle fusion to vesicles containing ciliary proteins.

Using tandem affinity purification and mass spectrometry to isolate proteins that purified with B9d1 (614144) in mouse IMCD3 cells and embryonic fibroblasts, Chih et al. (2012) identified several components of the B9d1-containing ciliary complex, including Tmem231 (614949), Tmem17 (614950), B9d2 (611951), Tctn1 (609863), Tctn2 (613846), Mks1 (609883), Ahi1 (608894), Cc2d2a, and Kctd10 (613421).


Molecular Genetics

Joubert Syndrome 9

In a consanguineous Pakistani family with mental retardation and retinitis pigmentosa consistent with Joubert syndrome (JBTS9; 612285) mapping to chromosome 4p15.33-p15.2, Noor et al. (2008) sequenced genes within an 11.2-Mb critical region and identified homozygosity for a splice site mutation in the CC2D2A gene (612013.0001).

Gorden et al. (2008) identified 6 different mutations in the CC2D2A gene (see, e.g., 612013.0003-612013.0005) in 5 (9%) of 70 families with clinical features consistent with Joubert syndrome. There was a wide range of phenotypic features.

Meckel Syndrome 6

In 11 unrelated Finnish fetuses with Meckel syndrome (MKS6; 612284), Tallila et al. (2008) identified a homozygous mutation in the CC2D2A gene (612013.0001). All parents were heterozygous for the mutation. There were 6 fetuses with Meckel syndrome that did not have CC2D2A mutations. Analysis of 575 healthy controls indicated that the carrier frequency of the CC2D2A mutation was 0.5% in the Finnish population.

COACH Syndrome 2

In a patient (UW49) with features of Joubert syndrome and hepatic fibrosis requiring liver transplantation at age 10 years (COACH2; 619111), Gorden et al. (2008) identified compound heterozygous mutations in the CC2D2A gene (612013.0004 and 612013.0006). Doherty et al. (2010) reported further on this patient.

In a 3-year-old boy (UW67) with COACH2, defined as Joubert syndrome with liver disease, Doherty et al. (2010) identified compound heterozygosity for 2 mutations in the CC2D2A gene (612013.0007 and 612013.0008). The findings indicated that COACH syndrome can be considered a subtype of Joubert syndrome with liver involvement, as also noted by Gorden et al. (2008). The proposed ciliary function for CC2D2A supported a unifying underlying pathophysiology for liver disease in these disorders.

Retinitis Pigmentosa 93

In 3 brothers of Senegalese ancestry with nonsyndromic retinitis pigmentosa (RP93; 619845), Mejecase et al. (2019) identified compound heterozygosity for a missense mutation (R925P; 612013.0010) and a deletion/insertion (612013.0011) in the CC2D2A gene. Analysis of targeted next-generation sequencing data from 1,056 cases of nonsyndromic retinal dystrophy identified a 36-year-old woman from Central Africa who was compound heterozygous for the R925P mutation and a 16,145-bp deletion (612013.0012) in the CC2D2A gene.


Animal Model

Gorden et al. (2008) found that 33% of Cc2d2a-null zebrafish ('sentinel'; snl) developed pronephric cysts by 6 days postfertilization, compared to none of wildtype zebrafish. Some of the mutant fish also developed a pericardial effusion. However, there were no overt differences with respect to cilium number or morphology between mutant and wildtype zebrafish.

Garcia-Gonzalo et al. (2011) found that Cc2d2a-null mice embryos showed randomized left-right axes, holoprosencephaly, microphthalmia, and a variably expressive curved body axis. The embryos also had cilia defects, although embryonic fibroblasts could generate cilia, indicating tissue-specific ciliary functions. The findings were similar to those observed in Tctn1 (609863)-null and Tctn2 (613846)-null mice. Garcia-Gonzalo et al. (2011) also demonstrated that Cc2d2a interacts with Tctn1 and Tctn2 and other proteins in a large complex localized to the transition zone between the ciliary axoneme and the basal body.


ALLELIC VARIANTS ( 12 Selected Examples):

.0001 JOUBERT SYNDROME 9

CC2D2A, IVS19DS, G-C, +1
  
RCV000000777

In a consanguineous Pakistani family with mental retardation and retinitis pigmentosa, Noor et al. (2008) identified homozygosity for a +1G-C transversion in intron 19 (IVS19DS+1G-C) of the CC2D2A gene, resulting in skipping of exon 19, a frameshift, and premature termination after amino acid 740, which abolishes the C2 domain. The mutation was not found in 460 Pakistani control chromosomes. Gorden et al. (2008) reviewed the brain MRIs of the patients reported by Noor et al. (2008) and concluded that they both had Joubert syndrome (JBTS9; 612285). In an erratum, Noor et al. (2008) agreed.


.0002 MECKEL SYNDROME, TYPE 6

CC2D2A, 1762C-T
  
RCV000000778...

In 11 of 17 unrelated Finnish fetuses with Meckel syndrome type 6 (MKS6; 612284), Tallila et al. (2008) identified a homozygous 1762C-T transition at the end of exon 16 of the CC2D2A gene, resulting in the creation of a new donor splice site, the deletion of 4 bp at the end of exon 16, and premature termination of the protein. All fetuses had occipital encephalocele and large cystic kidneys. Most also had polydactyly of the hands and feet, clubfeet, fibrotic or cystic changes in the liver, and hypoplastic lungs. Fibroblasts isolated from 1 fetus showed no detectable cilia, although there was normal cellular localization of centrioles. Analysis of 575 healthy controls indicated that the carrier frequency of the CC2D2A mutation was 0.5% in the Finnish population.


.0003 JOUBERT SYNDROME 9

CC2D2A, PRO1122SER
  
RCV000000779...

In 2 patients from 2 different consanguineous Saudi Arabian families with Joubert syndrome (JBTS9; 612285), Gorden et al. (2008) identified a homozygous 3364C-T transition in the CC2D2A gene, resulting in a pro1122-to-ser (P1122S) substitution. Both patients had the molar tooth sign on brain MRI, but only 1 had additional features, including retinal dystrophy, and hepatosplenomegaly. Haplotype analysis indicated that the families were related.


.0004 JOUBERT SYNDROME 9

COACH SYNDROME 2, INCLUDED
CC2D2A, ARG1528CYS
  
RCV000000780...

Joubert Syndrome 9

In 2 patients from a consanguineous Levanten Arab family with Joubert syndrome (JBTS9; 612285), Gorden et al. (2008) identified a homozygous 4582C-T transition in the CC2D2A gene, resulting in an arg1528-to-cys (R1528C) substitution.

COACH Syndrome 2

Gorden et al. (2008) identified the R1528C mutation in compound heterozygosity with a 1-bp deletion (612013.0006) in the CC2D2A gene in a woman (UW49) with COACH syndrome-2 (COACH2; 619111), defined by Doherty et al. (2010) as Joubert syndrome with liver disease.


.0005 JOUBERT SYNDROME 9

CC2D2A, ARG950TER
  
RCV000000781...

In a patient, born of consanguineous parents, with Joubert syndrome (JBTS9; 612285), Gorden et al. (2008) identified a homozygous 2848C-T transition in the CC2D2A gene, resulting in an arg950-to-ter (R950X) substitution. The patient had the molar tooth sign on brain MRI and retinal dystrophy.


.0006 COACH SYNDROME 2

CC2D2A, 1-BP DEL, 3289G
  
RCV000049715...

In a 22-year-old woman (UW49) with features of Joubert syndrome and liver disease (COACH2; 619111), defined as Joubert syndrome with liver disease by Doherty et al. (2010), Gorden et al. (2008) identified compound heterozygosity for 2 mutations in the CC2D2A gene: a 1-bp deletion (3289delG), resulting in a frameshift and premature termination, and the R1528C mutation (612013.0004). The patient had agenesis of the corpus callosum, hydrocephalus, cerebellar vermis hypoplasia, abnormal eye movements, coloboma, mild renal disease, and hepatic fibrosis requiring liver transplant at age 10 years. Gorden et al. (2008) noted that the features in this patient were reminiscent of COACH syndrome, which in some cases may be a variant representing a transitional phenotype between Joubert syndrome and Meckel syndrome. Two additional sibs with Joubert syndrome without liver disease, renal fibrosis, or polydactyly were found to be heterozygous for the 3289delG mutation; however, a second mutation was not identified.


.0007 COACH SYNDROME 2

JOUBERT SYNDROME 9/15, DIGENIC, INCLUDED
CC2D2A, ARG1049TER
  
RCV000000783...

In a 3-year-old boy (UW67) with COACH syndrome-2 (COACH2; 619111), defined as Joubert syndrome with liver involvement, Doherty et al. (2010) identified compound heterozygosity for 2 mutations in the CC2D2A gene: a 3145C-T transition, resulting in an arg1049-to-ter (R1049X) substitution, and a 3347C-T transition, resulting in a thr1116-to-met (T1116M; 612013.0008) substitution. The patient had abnormal respiratory control, molar tooth sign on brain MRI, elevated liver enzymes, congenital hepatic fibrosis, impaired intellectual development, and echogenic kidneys with hypertension.

In a Spanish patient with digenic inheritance of Joubert syndrome, Lee et al. (2012) identified a heterozygous R1049X substitution, consistent with JBTS9 (612285) and a heterozygous mutation in the CEP41 gene (M36T; 610523.0005), consistent with JBTS15 (614464). She had hypotonia, ataxia, mental retardation, and the molar tooth sign on brain MRI, but no liver, renal, or retinal involvement.


.0008 COACH SYNDROME 2

CC2D2A, THR1116MET
  
RCV000000784...

For discussion of the thr1116-to-met (T1116M) mutation in the CC2D2A gene that was found in compound heterozygous state in a boy with COACH syndrome-2 (COACH2; 619111) by Doherty et al. (2010), see 612013.0007.


.0009 JOUBERT SYNDROME 9/15, DIGENIC

CC2D2A, GLU1447ALA
  
RCV000023923...

In a Swiss patient with digenic inheritance of Joubert syndrome, Lee et al. (2012) identified a heterozygous 4340A-C transversion in exon 35 of the CC2D2A gene, resulting in a glu1447-to-ala (E1447A) substitution predicted to be a potentially deleterious sequence variant and consistent with JBTS9 (612285) and a heterozygous mutation in the CEP41 gene (R360C; 610523.0006), consistent with JBTS15 (614464). She had hypotonia, ataxia, mental retardation, oculomotor apraxia, bilateral preaxial polydactyly, and the molar tooth sign on brain MRI, but no liver, renal, or retinal involvement.


.0010 RETINITIS PIGMENTOSA 93

CC2D2A, ARG925PRO (rs200707391)
  
RCV001207137...

In 3 brothers of Senegalese ancestry (CIC02584, CIC02585, and CIC02583) with nonsyndromic retinitis pigmentosa (RP93; 619845), Mejecase et al. (2019) identified compound heterozygosity for a c.2774G-C transversion (chr4.15557452G-C, GRCh38) in exon 24 of the CC2D2A gene, resulting in an arg925-to-pro (R925P) substitution at a highly conserved residue, and a deletion/insertion (c.4730_4731delinsTGTATA; 612013.0011) in exon 38, causing a frameshift predicted to result in a premature termination codon (Ala1577ValfsTer5). The mutations segregated with disease in the family. The R925P variant was present in the African population at a minor allele frequency of 0.00006693. In an unrelated 36-year-old woman from Central Africa with inherited retinal dystrophy, the authors identified compound heterozygosity for the R925P mutation and a 16,145-bp deletion (c.3182+355_3825del; 612013.0012), encompassing intron 25 to exon 33 of the CC2D2A gene. Her family members were unavailable for segregation analysis. The youngest Senegalese brother (CIC02583), who exhibited a more severe ocular phenotype, was found to be homozygous for a frameshift mutation in the achromatopsia-associated CNGA3 gene (600053.0011), which likely accounted for his early-onset cone dysfunction (ACHM2; 216900).


.0011 RETINITIS PIGMENTOSA 93

CC2D2A, 6-BP DEL/INS, 4730TGTATA
  
RCV002248374

For discussion of the deletion/insertion (c.4730_4731delinsTGTATA; chr4.15601292_15601293delinsTGTATA, GRCh38) in exon 38 of the CC2D2A gene, causing a frameshift predicted to result in a premature termination codon (Ala1577ValfsTer5), that was found in compound heterozygous state in 3 brothers of Senegalese ancestry with retinitis pigmentosa (RP93; 619845) by Mejecase et al. (2019), see 612013.0010.


.0012 RETINITIS PIGMENTOSA 93

CC2D2A, 16-KB DEL, IVS25-EX33
   RCV002248372

For discussion of the 16,145-bp deletion (chr4.15563877_15580021del, GRCh38), encompassing intron 25 to exon 33 of the CC2D2A gene, that was found in compound heterozygous state in a 36-year-old woman from Central Africa with retinitis pigmentosa (RP93; 619845) by Mejecase et al. (2019), see 612013.0010.


REFERENCES

  1. Chih, B., Liu, P., Chinn, Y., Chalouni, C., Komuves, L. G., Hass, P. E., Sandoval, W., Peterson, A. S. A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain. Nature Cell Biol. 14: 61-72, 2012. [PubMed: 22179047, related citations] [Full Text]

  2. Doherty, D., Parisi, M. A., Finn, L. S., Gunay-Aygun, M., Al-Mateen, M., Bates, D., Clericuzio, C., Demir, H., Dorschner, M., van Essen, A. J., Gahl, W. A., Gentile, M., and 11 others. Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis). J. Med. Genet. 47: 8-21, 2010. [PubMed: 19574260, images, related citations] [Full Text]

  3. Garcia-Gonzalo, F. R., Corbit, K. C., Sirerol-Piquer, M. S., Ramaswami, G., Otto, E. A., Noriega, T. R., Seol, A. D., Robinson, J. F., Bennett, C. L., Josifova, D. J., Garcia-Verdugo, J. M., Katsanis, N., Hildebrandt, F., Reiter, J. F. A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nature Genet. 43: 776-784, 2011. [PubMed: 21725307, images, related citations] [Full Text]

  4. Gorden, N. T., Arts, H. H., Parisi, M. A., Coene, K. L. M., Letteboer, S. J. F., van Beersum, S. E. C., Mans, D. A., Hikida, A., Eckert, M., Knutzen, D., Alswaid, A. F., Ozyurek, H., and 23 others. CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290. Am. J. Hum. Genet. 83: 559-571, 2008. [PubMed: 18950740, images, related citations] [Full Text]

  5. Lee, J. E., Silhavy, J. L., Zaki, M. S., Schroth, J., Bielas, S. L., Marsh, S. E., Olvera, J., Brancati, F., Iannicelli, M., Ikegami, K., Schlossman, A. M., Merriman, B., and 18 others. CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium. Nature Genet. 44: 193-199, 2012. [PubMed: 22246503, images, related citations] [Full Text]

  6. Mejecase, C., Hummel, A., Mohand-Said, S., Andrieu, C., El Shamieh, S., Antonio, A., Condroyer, C., Boyard, F., Foussard, M., Blanchard, S., Letexier, M., Saraiva,, J.-P., Sahel, J.-A., Zeitz, C., Audo, I. Whole exome sequencing resolves complex phenotype and identifies CC2D2A mutations underlying non-syndromic rod-cone dystrophy. Clin. Genet. 95: 329-333, 2019. [PubMed: 30267408, related citations] [Full Text]

  7. Nagase, T., Kikuno, R., Ishikawa, K., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 65-73, 2000. [PubMed: 10718198, related citations] [Full Text]

  8. Noor, A., Windpassinger, C., Patel, M., Stachowiak, B., Mikhailov, A., Azam, M., Irfan, M., Siddiqui, Z. K., Naeem, F., Paterson, A. D., Lutfullah, M., Vincent, J. B., Ayub, M. CC2D2A, encoding a coiled-coil and C2 domain protein, causes autosomal-recessive mental retardation with retinitis pigmentosa. Am. J. Hum. Genet. 82: 1011-1018, 2008. Note: Erratum: Am. J. Hum. Genet. 83: 656 only, 2008. [PubMed: 18387594, images, related citations] [Full Text]

  9. Tallila, J., Jakkula, E., Peltonen, L., Salonen, R., Kestila, M. Identification of CC2D2A as a Meckel syndrome gene adds an important piece to the ciliopathy puzzle. Am. J. Hum. Genet. 82: 1361-1367, 2008. [PubMed: 18513680, images, related citations] [Full Text]

  10. Williams, C. L., Li, C., Kida, K., Inglis, P. N., Mohan, S., Semenec, L., Bialas, N. J., Stupay, R. M., Chen, N., Blacque, O. E., Yoder, B. K., Leroux, M. R. MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis. J. Cell. Biol. 192: 1023-1041, 2011. [PubMed: 21422230, images, related citations] [Full Text]


Marla J. F. O'Neill - updated : 04/19/2022
Patricia A. Hartz - updated : 11/27/2012
Cassandra L. Kniffin - updated : 2/1/2012
Cassandra L. Kniffin - updated : 8/18/2011
Patricia A. Hartz - updated : 4/29/2011
Cassandra L. Kniffin - updated : 6/16/2010
Cassandra L. Kniffin - updated : 11/26/2008
Cassandra L. Kniffin - updated : 9/15/2008
Marla J. F. O'Neill - updated : 9/12/2008
Creation Date:
Patricia A. Hartz : 4/25/2008
carol : 04/19/2022
carol : 12/03/2020
carol : 12/02/2020
carol : 12/01/2020
alopez : 05/14/2019
carol : 01/30/2017
carol : 09/12/2013
alopez : 11/27/2012
terry : 11/27/2012
carol : 2/2/2012
ckniffin : 2/1/2012
alopez : 8/23/2011
ckniffin : 8/18/2011
mgross : 5/19/2011
mgross : 5/19/2011
terry : 4/29/2011
wwang : 6/25/2010
ckniffin : 6/25/2010
wwang : 6/24/2010
ckniffin : 6/16/2010
terry : 1/21/2010
carol : 12/4/2008
ckniffin : 11/26/2008
wwang : 9/16/2008
ckniffin : 9/15/2008
wwang : 9/12/2008
terry : 9/12/2008
mgross : 4/25/2008

* 612013

COILED-COIL AND C2 DOMAINS-CONTAINING PROTEIN 2A; CC2D2A


Alternative titles; symbols

KIAA1345


HGNC Approved Gene Symbol: CC2D2A

Cytogenetic location: 4p15.32     Genomic coordinates (GRCh38): 4:15,469,865-15,601,557 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
4p15.32 COACH syndrome 2 619111 Autosomal recessive 3
Joubert syndrome 9 612285 Autosomal recessive 3
Meckel syndrome 6 612284 Autosomal recessive 3
Retinitis pigmentosa 93 619845 Autosomal recessive 3

TEXT

Description

CC2D2A 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. This complex acts as a barrier to restrict protein diffusion between plasma and ciliary membranes (Chih et al., 2012).


Cloning and Expression

By sequencing clones obtained from a size-fractionated human fetal brain cDNA library, Nagase et al. (2000) cloned CC2D2A, which they designated KIAA1345. The deduced protein contains 1,532 amino acids. RT-PCR detected moderate CC2D2A expression in ovary, lung, brain, liver, kidney, testis, and all specific adult brain regions examined. Low expression was detected in fetal brain and adult heart, and little to no expression was detected in fetal liver and adult skeletal muscle, pancreas, and spleen. In vitro-translated CC2D2A had an apparent molecular mass of more than 100 kD by SDS-PAGE.

By RT-PCR analysis of human tissues, Noor et al. (2008) detected strong CC2D2A expression in prostate, pancreas, kidney, lung, and liver with lower expression in spleen, small intestine, colon, skeletal muscle, ovary, thymus, and heart. CC2D2A contains 3 putative coiled-coil domains, a C-terminal C2 domain, and potential CaMKII recognition sites, PKC phosphorylation sites, and 2 putative nuclear localization signals. CC2D2A shares 84.8% amino acid identity with its rodent homologs. In COS-7 cells, overexpressed CC2D2A-GFP fusion protein localized almost exclusively to the cytoplasmic fraction, despite the predicted presence of potential nuclear localization signals.

Tallila et al. (2008) determined that full-length CC2D2A encodes a 1,620-residue protein. The longer transcript was present in all normal fetal tissues examined.


Gene Structure

Noor et al. (2008) determined that the CC2D2A gene contains 37 exons spanning 131.5 kb.

Tallila et al. (2008) identified an additional exon in the CC2D2A gene located after exon 29, which brought the total number of exons to 38.


Mapping

Noor et al. (2008) stated that the CC2D2A gene maps to chromosome 4p15.3.


Gene Function

Gorden et al. (2008) found that CC2D2A colocalized and interacted with CEP290 (610142) at the basal body in cultured ciliary cells.

Williams et al. (2011) showed that the conserved proteins Mks1 (609883), Mksr1 (B9D1), Mksr2 (B9D2; 611951), Tmem67 (609884), Rpgrip1l (610937), Cc2d2a, Nphp1 (607100), and Nphp4 (607215) functioned at an early stage of ciliogenesis in C. elegans. These 8 proteins localized to the ciliary transition zone and established attachments between the basal body and transition zone membrane. They also provided a docking site that restricted vesicle fusion to vesicles containing ciliary proteins.

Using tandem affinity purification and mass spectrometry to isolate proteins that purified with B9d1 (614144) in mouse IMCD3 cells and embryonic fibroblasts, Chih et al. (2012) identified several components of the B9d1-containing ciliary complex, including Tmem231 (614949), Tmem17 (614950), B9d2 (611951), Tctn1 (609863), Tctn2 (613846), Mks1 (609883), Ahi1 (608894), Cc2d2a, and Kctd10 (613421).


Molecular Genetics

Joubert Syndrome 9

In a consanguineous Pakistani family with mental retardation and retinitis pigmentosa consistent with Joubert syndrome (JBTS9; 612285) mapping to chromosome 4p15.33-p15.2, Noor et al. (2008) sequenced genes within an 11.2-Mb critical region and identified homozygosity for a splice site mutation in the CC2D2A gene (612013.0001).

Gorden et al. (2008) identified 6 different mutations in the CC2D2A gene (see, e.g., 612013.0003-612013.0005) in 5 (9%) of 70 families with clinical features consistent with Joubert syndrome. There was a wide range of phenotypic features.

Meckel Syndrome 6

In 11 unrelated Finnish fetuses with Meckel syndrome (MKS6; 612284), Tallila et al. (2008) identified a homozygous mutation in the CC2D2A gene (612013.0001). All parents were heterozygous for the mutation. There were 6 fetuses with Meckel syndrome that did not have CC2D2A mutations. Analysis of 575 healthy controls indicated that the carrier frequency of the CC2D2A mutation was 0.5% in the Finnish population.

COACH Syndrome 2

In a patient (UW49) with features of Joubert syndrome and hepatic fibrosis requiring liver transplantation at age 10 years (COACH2; 619111), Gorden et al. (2008) identified compound heterozygous mutations in the CC2D2A gene (612013.0004 and 612013.0006). Doherty et al. (2010) reported further on this patient.

In a 3-year-old boy (UW67) with COACH2, defined as Joubert syndrome with liver disease, Doherty et al. (2010) identified compound heterozygosity for 2 mutations in the CC2D2A gene (612013.0007 and 612013.0008). The findings indicated that COACH syndrome can be considered a subtype of Joubert syndrome with liver involvement, as also noted by Gorden et al. (2008). The proposed ciliary function for CC2D2A supported a unifying underlying pathophysiology for liver disease in these disorders.

Retinitis Pigmentosa 93

In 3 brothers of Senegalese ancestry with nonsyndromic retinitis pigmentosa (RP93; 619845), Mejecase et al. (2019) identified compound heterozygosity for a missense mutation (R925P; 612013.0010) and a deletion/insertion (612013.0011) in the CC2D2A gene. Analysis of targeted next-generation sequencing data from 1,056 cases of nonsyndromic retinal dystrophy identified a 36-year-old woman from Central Africa who was compound heterozygous for the R925P mutation and a 16,145-bp deletion (612013.0012) in the CC2D2A gene.


Animal Model

Gorden et al. (2008) found that 33% of Cc2d2a-null zebrafish ('sentinel'; snl) developed pronephric cysts by 6 days postfertilization, compared to none of wildtype zebrafish. Some of the mutant fish also developed a pericardial effusion. However, there were no overt differences with respect to cilium number or morphology between mutant and wildtype zebrafish.

Garcia-Gonzalo et al. (2011) found that Cc2d2a-null mice embryos showed randomized left-right axes, holoprosencephaly, microphthalmia, and a variably expressive curved body axis. The embryos also had cilia defects, although embryonic fibroblasts could generate cilia, indicating tissue-specific ciliary functions. The findings were similar to those observed in Tctn1 (609863)-null and Tctn2 (613846)-null mice. Garcia-Gonzalo et al. (2011) also demonstrated that Cc2d2a interacts with Tctn1 and Tctn2 and other proteins in a large complex localized to the transition zone between the ciliary axoneme and the basal body.


ALLELIC VARIANTS 12 Selected Examples):

.0001   JOUBERT SYNDROME 9

CC2D2A, IVS19DS, G-C, +1
SNP: rs2109050324, ClinVar: RCV000000777

In a consanguineous Pakistani family with mental retardation and retinitis pigmentosa, Noor et al. (2008) identified homozygosity for a +1G-C transversion in intron 19 (IVS19DS+1G-C) of the CC2D2A gene, resulting in skipping of exon 19, a frameshift, and premature termination after amino acid 740, which abolishes the C2 domain. The mutation was not found in 460 Pakistani control chromosomes. Gorden et al. (2008) reviewed the brain MRIs of the patients reported by Noor et al. (2008) and concluded that they both had Joubert syndrome (JBTS9; 612285). In an erratum, Noor et al. (2008) agreed.


.0002   MECKEL SYNDROME, TYPE 6

CC2D2A, 1762C-T
SNP: rs116358011, gnomAD: rs116358011, ClinVar: RCV000000778, RCV001385996

In 11 of 17 unrelated Finnish fetuses with Meckel syndrome type 6 (MKS6; 612284), Tallila et al. (2008) identified a homozygous 1762C-T transition at the end of exon 16 of the CC2D2A gene, resulting in the creation of a new donor splice site, the deletion of 4 bp at the end of exon 16, and premature termination of the protein. All fetuses had occipital encephalocele and large cystic kidneys. Most also had polydactyly of the hands and feet, clubfeet, fibrotic or cystic changes in the liver, and hypoplastic lungs. Fibroblasts isolated from 1 fetus showed no detectable cilia, although there was normal cellular localization of centrioles. Analysis of 575 healthy controls indicated that the carrier frequency of the CC2D2A mutation was 0.5% in the Finnish population.


.0003   JOUBERT SYNDROME 9

CC2D2A, PRO1122SER
SNP: rs118204051, gnomAD: rs118204051, ClinVar: RCV000000779, RCV000730543, RCV001329602, RCV001851514

In 2 patients from 2 different consanguineous Saudi Arabian families with Joubert syndrome (JBTS9; 612285), Gorden et al. (2008) identified a homozygous 3364C-T transition in the CC2D2A gene, resulting in a pro1122-to-ser (P1122S) substitution. Both patients had the molar tooth sign on brain MRI, but only 1 had additional features, including retinal dystrophy, and hepatosplenomegaly. Haplotype analysis indicated that the families were related.


.0004   JOUBERT SYNDROME 9

COACH SYNDROME 2, INCLUDED
CC2D2A, ARG1528CYS
SNP: rs118204052, gnomAD: rs118204052, ClinVar: RCV000000780, RCV000445290, RCV001269034, RCV003234885, RCV003390630, RCV003764503

Joubert Syndrome 9

In 2 patients from a consanguineous Levanten Arab family with Joubert syndrome (JBTS9; 612285), Gorden et al. (2008) identified a homozygous 4582C-T transition in the CC2D2A gene, resulting in an arg1528-to-cys (R1528C) substitution.

COACH Syndrome 2

Gorden et al. (2008) identified the R1528C mutation in compound heterozygosity with a 1-bp deletion (612013.0006) in the CC2D2A gene in a woman (UW49) with COACH syndrome-2 (COACH2; 619111), defined by Doherty et al. (2010) as Joubert syndrome with liver disease.


.0005   JOUBERT SYNDROME 9

CC2D2A, ARG950TER
SNP: rs118204053, gnomAD: rs118204053, ClinVar: RCV000000781, RCV000727257, RCV001266487, RCV002512617, RCV003398404

In a patient, born of consanguineous parents, with Joubert syndrome (JBTS9; 612285), Gorden et al. (2008) identified a homozygous 2848C-T transition in the CC2D2A gene, resulting in an arg950-to-ter (R950X) substitution. The patient had the molar tooth sign on brain MRI and retinal dystrophy.


.0006   COACH SYNDROME 2

CC2D2A, 1-BP DEL, 3289G
SNP: rs386833751, ClinVar: RCV000049715, RCV000201550, RCV000727050, RCV000817119, RCV002227058, RCV002266895, RCV002513687, RCV003398639

In a 22-year-old woman (UW49) with features of Joubert syndrome and liver disease (COACH2; 619111), defined as Joubert syndrome with liver disease by Doherty et al. (2010), Gorden et al. (2008) identified compound heterozygosity for 2 mutations in the CC2D2A gene: a 1-bp deletion (3289delG), resulting in a frameshift and premature termination, and the R1528C mutation (612013.0004). The patient had agenesis of the corpus callosum, hydrocephalus, cerebellar vermis hypoplasia, abnormal eye movements, coloboma, mild renal disease, and hepatic fibrosis requiring liver transplant at age 10 years. Gorden et al. (2008) noted that the features in this patient were reminiscent of COACH syndrome, which in some cases may be a variant representing a transitional phenotype between Joubert syndrome and Meckel syndrome. Two additional sibs with Joubert syndrome without liver disease, renal fibrosis, or polydactyly were found to be heterozygous for the 3289delG mutation; however, a second mutation was not identified.


.0007   COACH SYNDROME 2

JOUBERT SYNDROME 9/15, DIGENIC, INCLUDED
CC2D2A, ARG1049TER
SNP: rs386833750, gnomAD: rs386833750, ClinVar: RCV000000783, RCV000023922, RCV000199602, RCV000578695, RCV002251848, RCV002476904

In a 3-year-old boy (UW67) with COACH syndrome-2 (COACH2; 619111), defined as Joubert syndrome with liver involvement, Doherty et al. (2010) identified compound heterozygosity for 2 mutations in the CC2D2A gene: a 3145C-T transition, resulting in an arg1049-to-ter (R1049X) substitution, and a 3347C-T transition, resulting in a thr1116-to-met (T1116M; 612013.0008) substitution. The patient had abnormal respiratory control, molar tooth sign on brain MRI, elevated liver enzymes, congenital hepatic fibrosis, impaired intellectual development, and echogenic kidneys with hypertension.

In a Spanish patient with digenic inheritance of Joubert syndrome, Lee et al. (2012) identified a heterozygous R1049X substitution, consistent with JBTS9 (612285) and a heterozygous mutation in the CEP41 gene (M36T; 610523.0005), consistent with JBTS15 (614464). She had hypotonia, ataxia, mental retardation, and the molar tooth sign on brain MRI, but no liver, renal, or retinal involvement.


.0008   COACH SYNDROME 2

CC2D2A, THR1116MET
SNP: rs267606709, gnomAD: rs267606709, ClinVar: RCV000000784, RCV000201781, RCV000729670, RCV001383566

For discussion of the thr1116-to-met (T1116M) mutation in the CC2D2A gene that was found in compound heterozygous state in a boy with COACH syndrome-2 (COACH2; 619111) by Doherty et al. (2010), see 612013.0007.


.0009   JOUBERT SYNDROME 9/15, DIGENIC

CC2D2A, GLU1447ALA
SNP: rs387907058, gnomAD: rs387907058, ClinVar: RCV000023923, RCV000594523, RCV001852033, RCV003390699

In a Swiss patient with digenic inheritance of Joubert syndrome, Lee et al. (2012) identified a heterozygous 4340A-C transversion in exon 35 of the CC2D2A gene, resulting in a glu1447-to-ala (E1447A) substitution predicted to be a potentially deleterious sequence variant and consistent with JBTS9 (612285) and a heterozygous mutation in the CEP41 gene (R360C; 610523.0006), consistent with JBTS15 (614464). She had hypotonia, ataxia, mental retardation, oculomotor apraxia, bilateral preaxial polydactyly, and the molar tooth sign on brain MRI, but no liver, renal, or retinal involvement.


.0010   RETINITIS PIGMENTOSA 93

CC2D2A, ARG925PRO ({dbSNP rs200707391})
SNP: rs200707391, gnomAD: rs200707391, ClinVar: RCV001207137, RCV002251560

In 3 brothers of Senegalese ancestry (CIC02584, CIC02585, and CIC02583) with nonsyndromic retinitis pigmentosa (RP93; 619845), Mejecase et al. (2019) identified compound heterozygosity for a c.2774G-C transversion (chr4.15557452G-C, GRCh38) in exon 24 of the CC2D2A gene, resulting in an arg925-to-pro (R925P) substitution at a highly conserved residue, and a deletion/insertion (c.4730_4731delinsTGTATA; 612013.0011) in exon 38, causing a frameshift predicted to result in a premature termination codon (Ala1577ValfsTer5). The mutations segregated with disease in the family. The R925P variant was present in the African population at a minor allele frequency of 0.00006693. In an unrelated 36-year-old woman from Central Africa with inherited retinal dystrophy, the authors identified compound heterozygosity for the R925P mutation and a 16,145-bp deletion (c.3182+355_3825del; 612013.0012), encompassing intron 25 to exon 33 of the CC2D2A gene. Her family members were unavailable for segregation analysis. The youngest Senegalese brother (CIC02583), who exhibited a more severe ocular phenotype, was found to be homozygous for a frameshift mutation in the achromatopsia-associated CNGA3 gene (600053.0011), which likely accounted for his early-onset cone dysfunction (ACHM2; 216900).


.0011   RETINITIS PIGMENTOSA 93

CC2D2A, 6-BP DEL/INS, 4730TGTATA
SNP: rs2148497420, ClinVar: RCV002248374

For discussion of the deletion/insertion (c.4730_4731delinsTGTATA; chr4.15601292_15601293delinsTGTATA, GRCh38) in exon 38 of the CC2D2A gene, causing a frameshift predicted to result in a premature termination codon (Ala1577ValfsTer5), that was found in compound heterozygous state in 3 brothers of Senegalese ancestry with retinitis pigmentosa (RP93; 619845) by Mejecase et al. (2019), see 612013.0010.


.0012   RETINITIS PIGMENTOSA 93

CC2D2A, 16-KB DEL, IVS25-EX33
ClinVar: RCV002248372

For discussion of the 16,145-bp deletion (chr4.15563877_15580021del, GRCh38), encompassing intron 25 to exon 33 of the CC2D2A gene, that was found in compound heterozygous state in a 36-year-old woman from Central Africa with retinitis pigmentosa (RP93; 619845) by Mejecase et al. (2019), see 612013.0010.


REFERENCES

  1. Chih, B., Liu, P., Chinn, Y., Chalouni, C., Komuves, L. G., Hass, P. E., Sandoval, W., Peterson, A. S. A ciliopathy complex at the transition zone protects the cilia as a privileged membrane domain. Nature Cell Biol. 14: 61-72, 2012. [PubMed: 22179047] [Full Text: https://doi.org/10.1038/ncb2410]

  2. Doherty, D., Parisi, M. A., Finn, L. S., Gunay-Aygun, M., Al-Mateen, M., Bates, D., Clericuzio, C., Demir, H., Dorschner, M., van Essen, A. J., Gahl, W. A., Gentile, M., and 11 others. Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis). J. Med. Genet. 47: 8-21, 2010. [PubMed: 19574260] [Full Text: https://doi.org/10.1136/jmg.2009.067249]

  3. Garcia-Gonzalo, F. R., Corbit, K. C., Sirerol-Piquer, M. S., Ramaswami, G., Otto, E. A., Noriega, T. R., Seol, A. D., Robinson, J. F., Bennett, C. L., Josifova, D. J., Garcia-Verdugo, J. M., Katsanis, N., Hildebrandt, F., Reiter, J. F. A transition zone complex regulates mammalian ciliogenesis and ciliary membrane composition. Nature Genet. 43: 776-784, 2011. [PubMed: 21725307] [Full Text: https://doi.org/10.1038/ng.891]

  4. Gorden, N. T., Arts, H. H., Parisi, M. A., Coene, K. L. M., Letteboer, S. J. F., van Beersum, S. E. C., Mans, D. A., Hikida, A., Eckert, M., Knutzen, D., Alswaid, A. F., Ozyurek, H., and 23 others. CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290. Am. J. Hum. Genet. 83: 559-571, 2008. [PubMed: 18950740] [Full Text: https://doi.org/10.1016/j.ajhg.2008.10.002]

  5. Lee, J. E., Silhavy, J. L., Zaki, M. S., Schroth, J., Bielas, S. L., Marsh, S. E., Olvera, J., Brancati, F., Iannicelli, M., Ikegami, K., Schlossman, A. M., Merriman, B., and 18 others. CEP41 is mutated in Joubert syndrome and is required for tubulin glutamylation at the cilium. Nature Genet. 44: 193-199, 2012. [PubMed: 22246503] [Full Text: https://doi.org/10.1038/ng.1078]

  6. Mejecase, C., Hummel, A., Mohand-Said, S., Andrieu, C., El Shamieh, S., Antonio, A., Condroyer, C., Boyard, F., Foussard, M., Blanchard, S., Letexier, M., Saraiva,, J.-P., Sahel, J.-A., Zeitz, C., Audo, I. Whole exome sequencing resolves complex phenotype and identifies CC2D2A mutations underlying non-syndromic rod-cone dystrophy. Clin. Genet. 95: 329-333, 2019. [PubMed: 30267408] [Full Text: https://doi.org/10.1111/cge.13453]

  7. Nagase, T., Kikuno, R., Ishikawa, K., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVI. The complete sequences of 150 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 65-73, 2000. [PubMed: 10718198] [Full Text: https://doi.org/10.1093/dnares/7.1.65]

  8. Noor, A., Windpassinger, C., Patel, M., Stachowiak, B., Mikhailov, A., Azam, M., Irfan, M., Siddiqui, Z. K., Naeem, F., Paterson, A. D., Lutfullah, M., Vincent, J. B., Ayub, M. CC2D2A, encoding a coiled-coil and C2 domain protein, causes autosomal-recessive mental retardation with retinitis pigmentosa. Am. J. Hum. Genet. 82: 1011-1018, 2008. Note: Erratum: Am. J. Hum. Genet. 83: 656 only, 2008. [PubMed: 18387594] [Full Text: https://doi.org/10.1016/j.ajhg.2008.01.021]

  9. Tallila, J., Jakkula, E., Peltonen, L., Salonen, R., Kestila, M. Identification of CC2D2A as a Meckel syndrome gene adds an important piece to the ciliopathy puzzle. Am. J. Hum. Genet. 82: 1361-1367, 2008. [PubMed: 18513680] [Full Text: https://doi.org/10.1016/j.ajhg.2008.05.004]

  10. Williams, C. L., Li, C., Kida, K., Inglis, P. N., Mohan, S., Semenec, L., Bialas, N. J., Stupay, R. M., Chen, N., Blacque, O. E., Yoder, B. K., Leroux, M. R. MKS and NPHP modules cooperate to establish basal body/transition zone membrane associations and ciliary gate function during ciliogenesis. J. Cell. Biol. 192: 1023-1041, 2011. [PubMed: 21422230] [Full Text: https://doi.org/10.1083/jcb.201012116]


Contributors:
Marla J. F. O'Neill - updated : 04/19/2022
Patricia A. Hartz - updated : 11/27/2012
Cassandra L. Kniffin - updated : 2/1/2012
Cassandra L. Kniffin - updated : 8/18/2011
Patricia A. Hartz - updated : 4/29/2011
Cassandra L. Kniffin - updated : 6/16/2010
Cassandra L. Kniffin - updated : 11/26/2008
Cassandra L. Kniffin - updated : 9/15/2008
Marla J. F. O'Neill - updated : 9/12/2008

Creation Date:
Patricia A. Hartz : 4/25/2008

Edit History:
carol : 04/19/2022
carol : 12/03/2020
carol : 12/02/2020
carol : 12/01/2020
alopez : 05/14/2019
carol : 01/30/2017
carol : 09/12/2013
alopez : 11/27/2012
terry : 11/27/2012
carol : 2/2/2012
ckniffin : 2/1/2012
alopez : 8/23/2011
ckniffin : 8/18/2011
mgross : 5/19/2011
mgross : 5/19/2011
terry : 4/29/2011
wwang : 6/25/2010
ckniffin : 6/25/2010
wwang : 6/24/2010
ckniffin : 6/16/2010
terry : 1/21/2010
carol : 12/4/2008
ckniffin : 11/26/2008
wwang : 9/16/2008
ckniffin : 9/15/2008
wwang : 9/12/2008
terry : 9/12/2008
mgross : 4/25/2008