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Results: 6

1.
Figure 3

Figure 3. From: CC2D2A Is Mutated in Joubert Syndrome and Interacts with the Ciliopathy-Associated Basal Body Protein CEP290.

Sequence Tracings of CC2D2A Mutations
Numerical designations are based on NM_001080522.1 with the addition of exon 29a from genomic sequence (see Figure 2).

Nicholas T. Gorden, et al. Am J Hum Genet. 2008 November 17;83(5):559-571.
2.
Figure 6

Figure 6. From: CC2D2A Is Mutated in Joubert Syndrome and Interacts with the Ciliopathy-Associated Basal Body Protein CEP290.

Zebrafish sentinel Phenotype and Synergistic Genetic Interaction with cep290
(A) cc2d2a expression is greatly reduced in snl/snl fish versus their snl/+ and +/+ siblings. The odc1 gene was used as a template control.
(B and C) Tail and pronephros phenotype in snl/snl fish (B) and snl/snl fish injected with cep290splMO (C) at 4 dpf. snl/snl fish (B) have a sinusoidal-shaped tail and develop pronephric cysts (arrows) starting at 4 dpf, whereas snl/snl fish injected with cep290splMO (C) develop larger pronephric cysts starting at 2 dpf. Some of these fish also develop pericardial effusion (asterisk).
(D) AB wild-type fish for comparison.
(E) Frequency of pronephric cysts in snl/snl fish and their wild-type siblings (snl/+ and +/+) with and without cep290splMO. Brackets indicate 95% confidence intervals (p < 0.0001 for comparison between snl/snl fish and their wild-type siblings [snl/+ and +/+] injected with either CEP290 morpholino; chi-square test). dpf, days postfertilization; cep290splMO, cep290 splice-blocking morpholino.

Nicholas T. Gorden, et al. Am J Hum Genet. 2008 November 17;83(5):559-571.
3.
Figure 4

Figure 4. From: CC2D2A Is Mutated in Joubert Syndrome and Interacts with the Ciliopathy-Associated Basal Body Protein CEP290.

Segregation Analysis and MRI Images in Additional Families with CC2D2A Mutations
(A–E) Sagittal (A–E) and axial (A′–E′) MRI images of subjects UW46 II:1 (A, A′), UW46 II:2 (B, B′), UW47 II:1 (C, C′), UW41 II:1 (D, D′), and Noor et al. subject 36 22 (E, E′), revealing cerebellar vermis hypoplasia (arrowhead) and thick, horizontally oriented superior cerebellar peduncles (arrows). Mildly prominent temporal horns are bracketed in several axial images, consistent with mild ventriculomegaly. The cerebellar hemispheres in subject 36 appear atrophic (E′). (A–D, B′) T1-weighted images; (E) a T2/FLAIR-weighted image; (A′, C′–E′) T2-weighted images.
(F–H) Chromosome 4p15 could not be excluded by segregation of microsatellite markers in families UW46, UW47, and UW49.
(I) Pedigree for consanguineous family F871.

Nicholas T. Gorden, et al. Am J Hum Genet. 2008 November 17;83(5):559-571.
4.
Figure 2

Figure 2. From: CC2D2A Is Mutated in Joubert Syndrome and Interacts with the Ciliopathy-Associated Basal Body Protein CEP290.

CC2D2A Locus, Gene, Predicted Protein, and Expression
(A) Map of chromosome 4p15 locus with the regions of homozygosity in affected members of families UW36, UW48, and UW50 indicated by horizontal lines. The genes within this interval are indicated by arrows.
(B) 37 predicted CC2D2A exons based on the UCSC genome browser. The position of the homozygous nonsense mutation in exon 23 (c.2848C → T p.R950X) is marked with an ×. Note that exon 29a (asterisk) is not included in the RefSeq gene sequence, but is found in at least two spliced ESTs and is highly conserved.
(C) The CC2D2A gene encodes a protein with three predicted coiled-coil domains (cylinders), as well as a single C2 domain (pentagon). Missense mutations (gray arrows) were present in the C2 domain and the highly conserved C-terminal region (broken bar), whereas protein-truncating mutations (black arrows) precede the C2 domain.
(D) Phylogenetic tree of the CC2D2A C2 domain reveals orthologs in diverse species and a CC2D2B paralog that is restricted to mammals.
(E) RT-PCR analysis of CC2D2A, CC2D2B, and RPGRIP1L expression in adult and fetal tissues. The HPRT (hypoxanthine phosphoribosyl-transferase) gene was used as a template control.

Nicholas T. Gorden, et al. Am J Hum Genet. 2008 November 17;83(5):559-571.
5.
Figure 1

Figure 1. From: CC2D2A Is Mutated in Joubert Syndrome and Interacts with the Ciliopathy-Associated Basal Body Protein CEP290.

Homozygosity Mapping in Consanguineous Families with Joubert Syndrome
(A and B) Sagittal (A) and axial (B) MRI images of subject UW50 VI:3 revealing cerebellar vermis hypoplasia (arrowhead) and thick horizontally oriented superior cerebellar peduncles (arrow). (A) T2-weighted image; (B) T1-weighted image.
(C–E) Sagittal (C) and axial (D, E) MRI images of subject UW50 VI:1 revealing findings similar to subject UW50 VI:3. The midline tissue on the sagittal views (plus signs) is cerebellar hemisphere rather than vermis. Note the lack of corpus callosum (asterisk in [C]) and colpocephalic configuration of the lateral ventricles (brackets in [E]). T1-weighted images.
(F and G) Haplotypes at chromosome 4p15 locus in families UW50, UW48, UW36, and UW41. Mutations in CC2D2A are indicated by asterisks and known carriers are marked /+.
(F) Affected cousins in family UW50 share a haplotype of 242 consecutive homozygous SNPs (boxes) between SNP_A-1651302 and SNP_A-1718863 (9.6 Mb).
(G) Affected individuals in Saudi Arabian families UW36 and UW48 share a region of homozygosity (larger boxes) and a haplotype of 62 consecutive homozygous SNPs between SNP_A-1714400 and SNP_A-1738845 (2.3 Mb, smaller boxes). Unaffected siblings in UW48 are heterozygous in this region.
(H) The affected individual in family UW41 has a region of homozygosity between the 4p-terminus and D4S419. Note that only markers demarcating the regions of homozygosity and/or shared haplotypes are shown.

Nicholas T. Gorden, et al. Am J Hum Genet. 2008 November 17;83(5):559-571.
6.
Figure 5

Figure 5. From: CC2D2A Is Mutated in Joubert Syndrome and Interacts with the Ciliopathy-Associated Basal Body Protein CEP290.

CC2D2A and CEP290 Colocalize at the Basal Body and Interact in Yeast Two-Hybrid Assay and GST Pull-Down
(A–C) Colocalization of eCFP-tagged CC2D2A (green) and ciliary marker GT-335, a mouse monoclonal antibody against polyglutaminated tubulin (red), in cultured retinal pigment epithelial cells (hTERT-RPE1). In addition to the specific localization to the basal body (arrows), eCFP-CC2D2A is also in the cytoplasm, possibly because of overexpression ([A and C], green).
(D–F) Colocalization of eCFP-tagged CC2D2A (green) and CEP290 (red) to the basal bodies (arrows) of cultured hTERT-RPE1 cells.
(G) CC2D2A interaction with CEP290 in a yeast two-hybrid assay. Bait plasmids expressing different fragments of CC2D2A as binding domain (BD)-fusion proteins were cotransformed in the PJ69-4 alpha yeast strain together with prey plasmids expressing CEP290 fragment CC4-6 (aa 703–1130) as activation domain (AD)-fusion proteins. Plates lacking the amino acids Leu and Trp (-LW, top) selected for cotransformants, whereas additional omission of His and Ade from the plates (-LWHA, middle) selected for activation of the cognate reporter genes. A blue color in the β-galactosidase filter lift assay (bottom) indicates activation of the LacZ reporter gene. All reporter genes were only activated by the interaction of the CC2D2A fragment Nterm-C2 (aa 1–998). The rightmost column (+) represents a positive control of the wild-type AD and BD domains.
(H–J) GST pull-down analysis of recombinant CC2D2A and CEP290 fragments.
(H) Expression of GST-alone (∼26 kDa, lane 1) and GST-CEP290CC4-6 (amino acids 703–1030, which encode coiled-coil domains 4-6, ∼78 kDa, lane 2). The Simply Blue-stained gel shows 10% of the input that was used in the GST pull-down experiment.
(I) Expression of 3xFlag-tagged CC2D2ANterm-C2 (amino acids 1–998, which encode the N-terminal domain until the C2 domain; lanes 1 and 2). The blot shows 10% of the input that was used in the GST pull-down.
(J) GST-CEP290CC4-6 specifically pulls down 3xFlag-CC2D2ANterm-C2 (band at 150 kDa, lane 2), whereas GST alone does not (lane 1).

Nicholas T. Gorden, et al. Am J Hum Genet. 2008 November 17;83(5):559-571.

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