Alternative titles; symbols
HGNC Approved Gene Symbol: CEP290
Cytogenetic location: 12q21.32 Genomic coordinates (GRCh38): 12:88,049,016-88,142,088 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q21.32 | ?Bardet-Biedl syndrome 14 | 615991 | Autosomal recessive | 3 |
| Joubert syndrome 5 | 610188 | Autosomal recessive | 3 | |
| Leber congenital amaurosis 10 | 611755 | 3 | ||
| Meckel syndrome 4 | 611134 | Autosomal recessive | 3 | |
| Senior-Loken syndrome 6 | 610189 | Autosomal recessive | 3 |
The CEP290 gene encodes a centrosomal protein involved in ciliary assembly and ciliary trafficking (summary by Coppieters et al., 2010).
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1997) cloned KIAA0373. The deduced protein contains 1,539 amino acids. RT-PCR detected intermediate expression in kidney and ovary and low expression in thymus, prostate, and testis. Little to no expression was detected in other tissues examined.
By proteomic analysis of centrosomes isolated from a human lymphoblastic cell line, followed by database analysis, Andersen et al. (2003) identified KIAA0373, which they termed CEP290. The deduced protein contains 9 coiled-coil domains and has a calculated molecular mass of 290 kD. Fluorescence- and epitope-tagged CEP290 associated with centrosomes in a transfected human osteoblastoma cell line.
Monoclonal antibody 3H11 binds to cancer cells from various tissues. By screening a gastric cancer cell line expression library with 3H11, followed by RACE and nested PCR, Chen and Shou (2001) cloned CEP290, which they called 3H11 antigen (3H11Ag). The deduced protein contains 589 amino acids. Northern blot analysis detected a 2.3-kb 3H11Ag transcript. Expression was widespread in cancerous tissues, but was not detected in corresponding normal tissues. RT-PCR detected expression in normal embryonic tissues and placenta. Western blot analysis revealed a 70-kD protein.
Sayer et al. (2006) analyzed the deduced CEP290 protein sequence and described 13 putative coiled-coil domains, a region with homology to SMC (structural maintenance of chromosomes) chromosome segregation ATPases, a bipartite nuclear localization signal, 6 RepA/Rep+ protein KID motifs (KID), 3 tropomyosin homology domains, and an ATP/GTP binding site motif A (P loop). Using RNA blot analysis, Sayer et al. (2006) demonstrated a major CEP290 transcript of approximately 8 kb that was expressed strongly in placenta and weakly in brain. The 290-kD NPHP6 protein (2,479 amino acid residues) is encoded within the human full-length CEP290 mRNA of 7,951 nucleotides.
Papon et al. (2010) analyzed CEP290 expression by real-time PCR of human tissues and found highest expression in neural retina and nasal epithelium with significant expression in spinal cord, thyroid gland, testis, heart, lung, bone marrow, cerebellum, and uterus. Weaker expression was detected in whole brain, fetal brain, and kidney with very low levels in trachea, thymus, muscle, salivary gland, liver, and placenta.
Sayer et al. (2006) stated that the CEP290 gene, which encodes nephrocystin-6 (NPHP6), spans 55 exons and 93.2 kb.
By radiation hybrid analysis, Nagase et al. (1997) mapped the CEP290 gene to chromosome 12. Using a positional cloning strategy, Sayer et al. (2006) and Valente et al. (2006) identified the CEP290 gene on chromosome 12q21.32.
Guo et al. (2004) identified sites for N-glycosylation, tyrosine sulfation, phosphorylation, N-myristoylation, and amidation in 3H11Ag. The protein was predicted to have 8 coiled-coil domains and to form dimeric coiled coils. Transfected COS-7 cells expressed 3H11Ag in the cytoplasm and nucleus. Extraction experiments suggested that, in the nucleus, 3H11Ag is a peripheral membrane protein associated with the nuclear membrane, and 3H11Ag appeared to bind DNA. Truncation experiments showed that the 150 C-terminal amino acids of 3H11Ag directed subcellular localization.
To identify direct interaction partners of NPHP6 (CEP290), Sayer et al. (2006) performed a yeast 2-hybrid screen of a human fetal brain expression library, showing ATF4 (604064) as a direct interaction partner of NPHP6. The protein-interaction domains mapped to the N-terminal third of NPHP6, encoded by exons 2 through 21, and the C-terminal two-thirds of ATF4. To confirm that NPHP6 and ATF4 interact physiologically in vivo, Sayer et al. (2006) performed coimmunoprecipitation experiments using bovine retina extracts. Immunoblot analysis demonstrated that endogenous ATF4 can be immunoprecipitated using an antibody to NPHP6 but not using a control IgG. Reverse coimmunoprecipitation experiments showed that antibody to ATF4 can also precipitate endogenous NPHP6.
Valente et al. (2006) detected CEP290 expression mostly in proliferating cerebellar granule neuron populations and showed centrosome and ciliary localization.
McEwen et al. (2007) provided evidence that CEP290 may mediate G protein trafficking in certain tissues. Rd16 mice and humans with CEP290 mutations were found to have severe olfactory dysfunction, which in the mice was characterized by defective ciliary localization of the olfactory G proteins G-olf (GNAL; 139312) and G-gamma-13 (GNG13; 607298) in olfactory sensory neurons. Other components of the olfactory signaling pathway appeared to be unaffected, suggesting that these components likely enter the cilia independently and assemble within the cilia.
Using yeast 2-hybrid analysis, Tsang et al. (2008) found that CP110 (609544) interacted with CEP290 from human brain. Both proteins migrated in a high molecular mass complex in human embryonic kidney cell lysates, but they did not coelute with a pericentriolar matrix protein. In G0-phase cells, CP110 localized to the daughter centriole, and CEP290 localized to both the mother and daughter centrioles. Knockdown of CEP290 suppressed ciliogenesis in differentiating human REP1 retinal pigment epithelial cells and interfered with localization of the small GTPase RAB8A (165040) to centrosomes and cilia. Conversely, knockdown of CP110 resulted in aberrant formation of primary cilia. Tsang et al. (2008) concluded that CEP290 cooperates with RAB8A to promote ciliogenesis, and that this function is antagonized by CP110.
By coimmunoprecipitation of proteins from the human TERT-RPE1 cell line, Kim et al. (2008) found that CEP290 interacted with PCM1 (600299). Both proteins showed extensive overlap in their localization near centriolar satellites. Knockdown and biochemical studies revealed that localization of CEP290 to centriolar satellites was dependent on PCM1 and microtubules. Conversely, depletion of CEP290 disrupted subcellular distribution and protein complex formation of PCM1 and caused disorganization of the cytoplasmic microtubule network. Both CEP290 and PCM1 were required for ciliogenesis and ciliary targeting of RAB8A, a small GTPase that promotes ciliogenesis in conjunction with the BBS protein complex (see BBS1, 209901).
By coimmunoprecipitation analysis, Stowe et al. (2012) found that CEP72 (616475) interacted directly with PCM1 (600299) and CEP290 in polarized mouse and human cells. Depletion of PCM1 in both ciliated and nonciliated cells resulted in microtubule-independent relocalization of CEP72 and CEP290 from centrosomal satellites to centrosomes. Depletion of either CEP72 or CEP290 reduced pericentrosomal PCM1 and reduced cilium formation in RPE1 cells. Reduced cilium formation in ciliated mouse and human cells coincided with reduced ciliary recruitment of BBS4 (600374) and BBS8 (TTC8; 608132), subunits of the BBS protein complex required for formation of primary cilia. Overexpression of CEP72 disrupted organization of centriolar satellites and interfered with formation of the primary cilium.
Rachel et al. (2012) found that Cep290 and Mkks (604896) localized to adjacent regions in ciliated sensory cells in mice. Yeast 2-hybrid and coimmunoprecipitation analyses showed that full-length human MKKS interacted with the C-terminal domain of human CEP290 corresponding to the region deleted in rd16 mice, as well as with full-length CEP290. Some Bardet-Biedl syndrome (BBS; see 605231)-associated MKKS mutants showed weak or nonexistent interaction with the CEP290 C-terminal domain in yeast 2-hybrid analysis.
Coppieters et al. (2010) provided a review of the mutational spectrum of the CEP290 gene and of the different ciliopathies resulting from these mutations. No clear genotype/phenotype correlations were apparent.
Joubert and Senior-Loken Syndromes
Using a positional cloning strategy followed by direct sequencing, Sayer et al. (2006) detected CEP290 mutations in 1 family with Senior-Loken syndrome (SLSN6; 610189) and 7 families with Joubert syndrome (JBTS5; 610188). Sayer et al. (2006) identified an identical homozygous nonsense mutation, 5668G-T (G1890X; 610142.0001) in 2 kindreds. In subsequent studies they identified 9 distinct CEP290 mutations in 7 families with JBTS and 1 family with SLSN. All sequence changes were nonsense or frameshift mutations. In 2 families, they found only 1 heterozygous mutation in each. All of the affected individuals, with the exception of 1 family with SLSN, showed renal ultrasonographic and clinical features of JBTS.
Investigating from the neurologic point of view in an international group studying Joubert syndrome-related disorders, Valente et al. (2006) identified mutations in the CEP290 gene in 5 families with variable neurologic, retinal, and renal manifestations. Valente et al. (2006) found 3 nonsense mutations resulting in premature protein termination, a 1-bp deletion generating a frameshift and a premature stop codon, and a missense mutation (W7C; 610142.0003).
Joubert syndrome-related disorders (JSRDs) are a group of clinically and genetically heterogeneous conditions that share a midbrain-hindbrain malformation, the molar tooth sign (MTS) visible on brain imaging, with variable neurologic, ocular, and renal manifestations. Mutations in the CEP290 gene occur in families with the MTS-related neurologic features, many of which show oculorenal involvement typical of Senior-Loken syndrome (JSRD-SLS phenotype); see 610142.0004. Brancati et al. (2007) performed comprehensive CEP290 mutation analysis in 2 nonoverlapping cohorts of JSRD-affected patients with a proven molar tooth sign. They identified mutations in 19 of 44 patients with JSRD-SLS. The second cohort consisted of 84 patients representing the spectrum of other JSRD subtypes, with mutations identified in only 2 patients. The data suggested that CEP290 mutations are frequently encountered and are largely specific to the JSRD-SLS subtype. One patient with mutation displayed complete situs inversus, confirming the clinical and genetic overlap between JSRDs and other ciliopathies.
Helou et al. (2007) performed mutation analysis on a worldwide cohort of 75 families with Senior-Loken syndrome, 99 families with Joubert syndrome, and 21 families with isolated nephronophthisis. Six novel and 6 known truncating mutations, 1 known missense mutation, and 1 novel 3-bp in-frame deletion were identified in a total of 7 families with Joubert syndrome, 2 families with Senior-Loken syndrome, and 1 family with isolated nephronophthisis. The mutation in the patient with isolated nephronophthisis was found in heterozygosity, and it was suggested that this mutation was not disease-causing in itself but could be disease-causing in combination with mutations in other genes; it was classified as a variant 'of unknown significance' in a table.
Leber Congenital Amaurosis
Den Hollander et al. (2006) ascertained a consanguineous French Canadian family with 4 sibs affected by Leber congenital amaurosis (LCA10; see 611755). Linkage analysis assigned the gene to 12q21-q22, in a region containing 15 genes, including CEP290. Joubert syndrome-5, which is due to mutations in the CEP290 gene, is associated in all patients with congenital amaurosis or retinitis pigmentosa. An in-frame deletion in the Cep290 gene was found in association with early onset in the rd16 mouse (Chang et al., 2006). After extensive evaluation, no gross brain or kidney pathology could be detected in these mice. Because of its function and the phenotype of the rd16 mice, den Hollander et al. (2006) considered CEP290 to be an excellent candidate gene for LCA in the French Canadian family. The authors detected an A-to-G transition 5 bp downstream of a cryptic exon (2991+1655A-G; 610142.0005) as the cause of the disorder. To determine whether this mutation could be a common cause of LCA, den Hollander et al. (2006) screened 76 unrelated patients with LCA for the 2991+1655A-G mutation by allele-specific PCR. Four patients were found to be homozygous for the mutation, and 12 were heterozygous.
Meckel Syndrome Type 4
To identify new Meckel syndrome (see MKS1, 249000) loci, Baala et al. (2007) performed a genomewide linkage scan in 8 families unlinked to MKS1, MKS2 (603194), or MKS3 (607361) and found linkage to chromosome 12. The interval was narrowed to an 8-Mb region containing the CEP290 gene which, in view of the phenotypic overlap between Joubert syndrome (213300) and Meckel syndrome, and the finding of Baala et al. (2007) of allelism of these 2 phenotypes at the MKS3 locus, was considered an excellent candidate gene. Sequencing of the 53 coding exons revealed homozygous truncating mutations in 3 families and compound heterozygous mutations in a fourth family (MKS4; 611134). Sequencing of 20 additional MKS cases identified 2 additional MKS-affected families with affected individuals carrying compound heterozygous mutations of CEP290. Baala et al. (2007) also identified CEP290 mutations in 4 families presenting a cerebrorenodigital syndrome (see 611134), with a phenotype between that of Meckel syndrome and Joubert syndrome and thus representing the continuum of the clinical spectrum between these 2 disorders.
Frank et al. (2008) identified a homozygous mutation in the CEP290 gene (610142.0012) in 4 fetuses with Meckel syndrome type 4 from 2 consanguineous families of Kosovar origin. Common features included large cystic, dysplastic kidneys, postaxial polydactyly, occipital meningoencephalocele, and hepatobiliary ductal plate malformations. No clear-cut genotype/phenotype correlations were apparent in a review of CEP290 mutations reported to date.
Bardet-Biedl Syndrome 14
The identification of mutations in the MKS1 gene (609883) in patients with clinical diagnoses of Bardet-Biedl syndrome (BBS13; 615990) led Leitch et al. (2008) to investigate other Meckel syndrome genes as contributors to the BBS phenotype. Leitch et al. (2008) identified an individual with Bardet-Biedl syndrome (BBS14; 615991) who was homozygous for a nonsense mutation in CEP290 (E1903X; 610142.0013) and who also carried a complex heterozygous mutation in TMEM67 (609884.0012).
In an analogy to genes previously identified as mutated in nephronophthisis (NPHP; see 256100), Sayer et al. (2006) referred to the CEP290 gene as NPHP6, SLSN6, and JBTS6, depending on the predominant clinical features.
Chang et al. (2006) identified an in-frame deletion in the Cep290 gene in association with a mouse model of early-onset retinal degeneration, 'rd16.' No gross brain or kidney pathology was detected in these mice.
McEwen et al. (2007) found that patients with LCA10 and rd16 mice have severe olfactory dysfunction. Detailed examination of olfactory cilia from rd16 mice showed an intact cilia layer and normal localization of the mutant Cep290 protein to dendritic knobs underlying the cilia. However, rd16 olfactory sensory neurons showed defective ciliary localization of the olfactory G proteins Gnal (139312) and Gng13 (607298). Other components of the olfactory signaling pathway appeared to be unaffected, suggesting that these components likely enter the cilia independently and assemble within the cilia. The findings indicated that CEP290 is a mediator of G protein trafficking, and that the olfactory phenotype is due to defective transport of olfactory G proteins.
An animal model of autosomal recessive retinitis pigmentosa, designated rdAc, has been developed in Abyssinian cats. Affected cats have normal vision at birth, but develop ophthalmic and morphologic changes by 7 months and complete photoreceptor degeneration and blindness at the end stage, usually at 3 to 5 years of age. Menotti-Raymond et al. (2007) determined that rdAc is due to a SNP in intron 50 of the Cep290 gene (IVS50+9T-G) that creates a strong canonical splice donor site, resulting in a 4-bp insertion and frameshift in the mRNA transcript and premature termination of the protein.
Schafer et al. (2008) found that depletion of either Nphp5 (IQCB1; 609237) or Nphp6 in zebrafish embryos caused almost identical abnormalities, including hydrocephalus, developmental eye defects, and pronephric cysts. Combined knockdown of Nphp5 and Nphp6 synergistically augmented these phenotypes. Nphp5 directly bound Nphp6 in vitro. Expression of the Nphp5-binding domain of Nphp6 inhibited neural tube closure during early Xenopus embryogenesis, and a similar phenotype was observed after knockdown of Nphp5 in Xenopus oocytes.
Lancaster et al. (2011) found that Cep290-null mouse embryos showed defective midline fusion of the cerebellum at E16.5, as observed in Joubert syndrome. Adult Cep290 mutants showed a mild foliation defect, although the vermis was not statistically smaller than that in controls.
Rachel et al. (2012) demonstrated that the rd16 mutation removes a domain of Cep290 that interacts with Mkks (see GENE FUNCTION). They found that haploinsufficiency of Mkks at least partly rescued ciliary pathology in some mice homozygous for the rd16 mutation. Likewise, haploinsufficiency of Cep290 partly rescued ciliary pathology in Mkks -/- mice. In contrast, haploinsufficiency of both proteins in zebrafish exacerbated ciliary defects found in single-mutant animals.
In 2 consanguineous Turkish families whose phenotype was linked to the NPHP6 genetic interval, Sayer et al. (2006) found that Joubert syndrome (JBTS5; 610188) was associated with homozygosity for a 5668G-T transversion in exon 41 of the CEP290 gene, resulting in a gly1890-to-ter (G1890X) substitution. Mutation screening of 96 additional JBTS families identified the G1890X mutation in compound heterozygosity with a 1-bp deletion (610142.0002) in a nonconsanguineous German family.
Valente et al. (2006) found the G1890X mutation in homozygosity in a Turkish JBTS family.
Brancati et al. (2007) found that the G1890X mutation of CEP290 had been observed in 10 families and that affected individuals in these families had Joubert syndrome-related disorders only, i.e., no Leber congenital amaurosis.
Sayer et al. (2006) found this mutation, a 1-bp deletion in exon 36 of the CEP290 gene (4656delA) in compound heterozygosity with the G1890X mutation (610142.0001) in a German family with Joubert syndrome (JBTS5; 610188). The deletion resulted in frameshift and premature termination of the protein (Lys1552fsTer1556).
In a Pakistani family with Joubert syndrome (JBTS5; 610188), Valente et al. (2006) detected a 21G-T transversion in the first exon of the CEP290 gene, resulting in a trp7-to-cys (W7C) substitution.
In a Turkish family with Senior-Loken syndrome (SLSN6; 610189), Sayer et al. (2006) found homozygosity for a 5-bp deletion in the CEP290 gene, 2218-2222delccagATAGA. The mutation altered the splice donor site of exon 23.
In a consanguineous French Canadian family with 4 sibs affected by Leber congenital amaurosis-10 (LCA10; 611755), den Hollander et al. (2006) found that the affected individuals had a splice defect in the CEP290 gene caused by an intronic mutation (2991+1655A-G) that created a strong splice donor site and inserted a cryptic exon in the CEP290 mRNA. This mutation was detected in 16 (21%) of 76 unrelated patients with LCA, either homozygously or in combination with a second deleterious mutation on the other allele.
Brancati et al. (2007) found that the 2991+1655A-G mutation, resulting in a C998X protein alteration, is associated with LCA only and is by far the most frequently observed mutation in the CEP290 gene, having been observed in 44 families.
Gene Therapy
Pierce et al. (2024) performed a phase 1-2, open-label, single-ascending-dose study in which persons 3 years of age or older with LCA10 caused by a homozygous or compound heterozygous CEP290 intron 26 variant received a subretinal injection of EDIT-101, a CRISPR-Cas9 gene editing complex designed to treat this specific damaging variant, in the worse (study) eye. The primary outcome was safety, which included adverse events and dose-limiting toxic effects. Key secondary efficacy outcomes were the change from baseline in the best corrected visual acuity, the retinal sensitivity detected with the use of full-field stimulus testing (FST), the score on the Ora-Visual Navigation Challenge mobility test, and the vision-related quality of life score on the National Eye Institute Visual Function Questionnaire-25 (in adults) or the Children's Visual Function Questionnaire (in children). EDIT-101 was injected in 12 adults aged 17 to 63 years (median, 37 years) at a low, intermediate, or high dose, and in 2 children aged 9 and 14 years at the intermediate dose. No serious adverse events related to the treatment or procedure and no dose-limiting toxic effects were recorded. Six participants had a meaningful improvement from baseline in cone-mediated vision as assessed with the use of FST, of whom 5 had improvement in at least 1 other key secondary outcome. Nine participants (64%) had a meaningful improvement from baseline in the best corrected visual acuity, the sensitivity to red light as measured with FST, or the score on the mobility test. Six participants had a meaningful improvement from baseline in the vision-related quality-of-life score.
In a German patient with Leber congenital amaurosis-10 (LCA10; 611755), den Hollander et al. (2006) identified compound heterozygosity for 2 mutations in the CEP290 gene: the frequent mutation found in all families (610142.0005) and a nonsense mutation, 2249T-G, predicting a leu759-to-stop (L750X) protein change.
Among the families in which mutations of the CEP290 gene were associated with both Joubert syndrome (JBTS5; 610188) and Leber congenital amaurosis-10 (LCA10; 611755), the nonsense mutation lys1575-to-ter (K1575X) was the most frequent mutation, having been observed in 8 families (Brancati et al., 2007). The K1575X mutation arises from a 4723A-T transversion in exon 36.
In 2 families with Meckel syndrome (MKS4; 611134), Baala et al. (2007) found a 4-bp deletion in exon 6 of the CEP290 gene (384_387TAGA, Asp128GlufsTer34). In the family of Tunisian origin, the mutation occurred in homozygosity; in the French/Tunisian family, it occurred in compound heterozygosity with a splice site mutation (610142.0009) and was inherited from the mother, of French origin. Haplotype analysis suggested a recurrent mutation rather than a founder effect.
This mutation was reported in a patient with Leber congenital amaurosis (LCA10; 611755) by Perrault et al. (2007).
In a family with Meckel syndrome (MKS4; 611134), Baala et al. (2007) found a splice site mutation, 180+2T-A, affecting exon 3 of the CEP290 gene. The mutation, inherited from the Tunisian father, occurred in compound heterozygosity with a deletion (610142.0008).
In 2 sibs from a Moroccan family with Meckel syndrome (MKS4; 611134), Baala et al. (2007) found homozygosity for a 613C-T transition in exon 9 of the CEP290 gene, resulting in an arg205-to-ter (R205X) substitution.
In a patient with Leber congenital amaurosis (LCA10; 611755), Cideciyan et al. (2007) identified compound heterozygosity for 2 mutations in the CEP290 gene: the common splice site defect (610142.0005) and a 5-bp deletion (1260delTAAAG), resulting in a frameshift and premature termination.
In affected fetuses from 2 consanguineous families with Meckel syndrome type 4 (MKS4; 611134), Frank et al. (2008) identified a homozygous 1-bp deletion (5489delA) in exon 40 of the CEP290 gene, resulting in a frameshift and likely loss of protein function. The phenotype in both families was characterized by large cystic, dysplastic kidneys, postaxial polydactyly, and occipital meningoencephalocele. Three of the 4 affected fetuses also had hepatobiliary ductal plate malformations. Both families were of Kosovar origin, and haplotype analysis indicated a founder effect.
In an 11-year-old female with Bardet-Biedl syndrome-14 (BBS14; 615991) manifesting retinitis pigmentosa, obesity, mental retardation, and nystagmus, Leitch et al. (2008) identified homozygosity for a glu1903-to-ter (E1903X) mutation in CEP290 gene. This patient also carried a complex heterozygous mutation in TMEM67 (609884.0012).
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