Alternative titles; symbols
HGNC Approved Gene Symbol: CEP104
Cytogenetic location: 1p36.32 Genomic coordinates (GRCh38) : 1:3,812,086-3,857,211 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.32 | Intellectual developmental disorder, autosomal recessive 77 | 619988 | Autosomal recessive | 3 |
| Joubert syndrome 25 | 616781 | Autosomal recessive | 3 |
CEP104 localizes on the distal ends of both centrioles of nondividing cells until the mother centriole forms a cilium and then localizes at the tip of the elongating cilium. It appears to be required for both ciliogenesis and for structural integrity at the ciliary tip (Satish Tammana et al., 2013).
Using polyclonal antibodies to immunopurify a protein with ligand recognition sites similar to those of brain NMDA receptors (see GRIN1, 138249) from rat brain synaptic membrane, followed by screening a rat hippocampus cDNA expression library, Kumar et al. (1995) cloned Cep104, which they called Glybp. The deduced 470-amino acid protein contains 2 glycosylation sites, 3 hydrophobic regions, 4 cys-rich motifs, and 2 regions of homology with Grin1. Northern blot analysis revealed expression of a 1.9-kb transcript in rat cortex, hippocampus, cerebellum, and brainstem.
By screening for large proteins expressed in brain, Nagase et al. (1998) cloned human CEP104, which they called KIAA0562. The predicted 925-amino acid protein shares significant homology with rat Glybp. RT-PCR analysis detected variable expression in all human tissues examined, with highest levels in kidney and skeletal muscle and lowest levels in testis and spleen.
Using confocal microscopy of human RPE1 retinal pigment epithelial cells starved to induce cilia formation, Satish Tammana et al. (2013) demonstrated localization of CEP104 to the tip of the primary cilium as well as at the distal end in the daughter centriole, but not the mother centriole. CEP104 remained at the ciliary tip during ciliary resorption and localized to centrioles during cell division. RNA interference experiments showed that CEP104 was required for ciliogenesis in RPE1 cells, similar to findings for its Chlamydomonas ortholog, Fap256. Satish Tammana et al. (2013) proposed that CEP104 has functions at the centriole to initiate ciliogenesis and at the ciliary tip, where it is required for formation or stability of specializations characteristic of the tip.
By radiation hybrid analysis, Nagase et al. (1998) mapped the CEP104 gene to chromosome 1. Gross (2015) mapped the CEP104 gene to chromosome 1p36.32 based on an alignment of the CEP104 sequence (GenBank BC047450) with the genomic sequence (GRCh38).
Joubert Syndrome 25
In 3 unrelated children with Joubert syndrome-25 (JBTS25; 616781), Srour et al. (2015) identified homozygous or compound heterozygous mutations in the CEP104 gene (616690.0001-616690.0003). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies and studies on patient cells were not performed.
Autosomal Recessive Intellectual Developmental Disorder 77
In 4 patients from 2 unrelated consanguineous Iranian families (families 8800138 and 9100012), with autosomal recessive intellectual developmental disorder-77 (MRT77; 619988), Khoshbakht et al. (2021) identified homozygous frameshift mutations in the CEP104 gene (616690.0005 and 616690.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Neither was present in the ClinVar, 1000 Genomes Project, or ExAC databases. Patient-derived lymphoblastoid cells showed a significant reduction in CEP104 transcripts, although Western blot analysis was consistent with low expression of a truncated protein, suggesting incomplete nonsense-mediated mRNA decay. Additional functional studies were not performed. The patients had global developmental delay with normal brain imaging, thus distinguishing the phenotype from Joubert syndrome.
In a 7.5-year-old girl, born of consanguineous Iranian parents, with MRT77, Badv et al. (2022) identified a homozygous nonsense mutation in the CEP104 gene (R215X; 616690.0007). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. It was not reported in the 1000 Genomes Project database. Functional studies of the variant and studies of patient cells were not performed. The patient had global developmental delay with normal brain imaging.
In a 2.5-year-old girl (patient 1763.618) of French Canadian descent with Joubert syndrome-25 (JBTS25; 616781), Srour et al. (2015) identified a homozygous T-to-C transition in intron 7 of the CEP104 gene (c.735+2T-C, NM_014704.3), predicted to result in a splice site aberration and skipping of exon 7. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases, or in 201 in-house control exomes. Functional studies and studies on patient cells were not performed.
In a 3.5-year-old boy (patient 842629), born of consanguineous Arab-Israeli parents, with Joubert syndrome-25 (JBTS25; 616781), Srour et al. (2015) identified a homozygous 1-bp insertion (c.1328_1329insT, NM_014704.3) in the CEP104 gene, resulting in a frameshift and premature termination (Tyr444fsTer3). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was nor found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases, or in 350 in-house ethnically matched exomes. Functional studies and studies on patient cells were not performed.
In a 28-month-old boy (patient GeneDX01) with Joubert syndrome-25 (JBTS25; 616781), Srour et al. (2015) identified compound heterozygous mutations in the CEP104 gene: a c.496C-T transition (c.496C-T, NM014704.3), resulting in an arg166-to-ter (R166X) substitution, and an A-to-G transition in intron 20 (c.2572-2A-G; 616690.0004), predicted to result in a splice site mutation. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The R166X mutation was inherited from the unaffected mother, whereas the splice site mutation occurred de novo. The R166X variant was found at very low frequencies in the Exome Variant Server and ExAC databases, whereas the splice site mutation was not found in either of these databases. Functional studies and studies on patient cells were not performed.
For discussion of the A-to-G transition in intron 20 of the CEP104 gene (c.2572-2A-G, NM_014704.3), predicted to result in a splice site mutation, that was found in compound heterozygous state in a patient with Joubert syndrome-25 (JBTS25; 616781) by Srour et al. (2015), see 616690.0003.
In a 10-year-old boy, born of consanguineous Iranian parents (family 8800138), with autosomal recessive intellectual developmental disorder-77 (MRT77; 619988), Khoshbakht et al. (2021) identified a homozygous 2-bp insertion (c.2356_2357insTT, NM_014704) in the CEP104 gene, resulting in a frameshift and premature termination (Cys786PhefsTer11) in the C-terminal domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the ClinVar, 1000 Genomes Project, or ExAC databases. Patient-derived lymphoblastoid cells showed a significant reduction in CEP104 transcripts, and Western blot analysis was consistent with low expression of a truncated protein, suggesting incomplete nonsense-mediated mRNA decay. Additional functional studies were not performed. The patient had global developmental delay with normal brain imaging.
In 3 sibs, born of consanguineous Iranian parents (family 9100012), with autosomal recessive intellectual developmental disorder-77 (MRT77; 619988), Khoshbakht et al. (2021) identified a homozygous 1-bp insertion (c.1901_1902insT, NM_014704) in the CEP104 gene, resulting in a frameshift and premature termination (Leu634PhefsTer33) in the central alpha-helical TOG domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the ClinVar, 1000 Genomes Project, or ExAC databases. Patient-derived lymphoblastoid cells showed a significant reduction in CEP104 transcripts, and Western blot analysis was consistent with low expression of a truncated protein, suggesting incomplete nonsense-mediated mRNA decay. Additional functional studies were not performed. The patient had global developmental delay with normal brain imaging.
In a 7.5-year-old girl, born of consanguineous Iranian parents, with autosomal recessive intellectual developmental disorder-77 (MRT77; 619988), Badv et al. (2022) identified a homozygous c.643C-T transition (c.643C-T, NM_014704.3) in the CEP104 gene, resulting in an arg215-to-ter (R215X) substitution. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. It was not reported in the 1000 Genomes Project database. Functional studies of the variant and studies of patient cells were not performed. The patient had global developmental delay with normal brain imaging.
Badv, R. S., Mahdiannasser, M., Rasoulinezhad, M., Habibi, L., Rashidi-Nezhad, A. CEP104 gene may involve in the pathogenesis of a new developmental disorder other than joubert (sic) syndrome. Molec. Biol. Rep. 49: 7231-7237, 2022. [PubMed: 35359234] [Full Text: https://doi.org/10.1007/s11033-022-07353-w]
Gross, M. B. Personal Communication. Baltimore, Md. 12/11/2015.
Khoshbakht, S., Beheshtian, M., Fattahi, Z., Bazazzadegan, N., Parsimehr, E., Fadaee, M., Vazehan, R., Faraji Zonooz, M., Abolhassani, A., Makvand, M., Kariminejad, A., Celik, A., Kahrizi, K., Najmabadi, H. CEP104 and CEP290; genes with ciliary functions cause intellectual disability in multiple families. Arch. Iran. Med. 24: 364-373, 2021. [PubMed: 34196201] [Full Text: https://doi.org/10.34172/aim.2021.53]
Kumar, K. N., Babcock, K. K., Johnson, P. S., Ahmad, C. M., Michaelis, E. K. Cloning of the cDNA for brain glycine-, glutamate- and thienylcyclohexylpiperidine-binding protein. Biochem. Biophys. Res. Commun. 216: 390-398, 1995. [PubMed: 7488117] [Full Text: https://doi.org/10.1006/bbrc.1995.2636]
Nagase, T., Ishikawa, K., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 5: 31-39, 1998. [PubMed: 9628581] [Full Text: https://doi.org/10.1093/dnares/5.1.31]
Satish Tammana, T. V., Tammana, D., Diener, D. R., Rosenbaum, J. Centrosomal protein CEP104 (Chlamydomonas FAP256) moves to the ciliary tip during ciliary assembly. J. Cell Sci. 126: 5018-5029, 2013. [PubMed: 23970417] [Full Text: https://doi.org/10.1242/jcs.133439]
Srour, M., Hamdan, F. F., McKnight, D., Davis, E., Mandel, H., Schwartzentruber, J., Martin, B., Patry, L., Nassif, C., Dionne-Laporte, A., Ospina, L. H., Lemyre, E., and 22 others. Joubert syndrome in French Canadians and identification of mutations in CEP104. Am. J. Hum. Genet. 97: 744-753, 2015. [PubMed: 26477546] [Full Text: https://doi.org/10.1016/j.ajhg.2015.09.009]