Alternative titles; symbols
HGNC Approved Gene Symbol: CPLANE1
SNOMEDCT: 721873007;
Cytogenetic location: 5p13.2 Genomic coordinates (GRCh38) : 5:37,075,669-37,249,376 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5p13.2 | Joubert syndrome 17 | 614615 | Autosomal recessive | 3 |
| Orofaciodigital syndrome VI | 277170 | Autosomal recessive | 3 |
Srour et al. (2012) stated that the deduced 3,198-amino acid C5ORF42 protein exhibits features of a transmembrane protein and has a putative coiled-coil region. Analysis of EST, microarray, and other databases predicted widespread expression of C5ORF42, including in brain. Srour et al. (2012) identified an alternative exon, exon 40a, and RNA sequencing data suggested elevated expression of C5ORF42 transcripts containing exon 40a in brain and testis. Close orthologs of C5ORF42 were detected in several vertebrates.
By immunohistochemical analysis of mouse embryonic fibroblasts and IMCD3 collecting duct cells, Damerla et al. (2015) found that C5orf42, which they called Jbts17, colocalized with Nphp1 (607100) in the ciliary transition zone.
Srour et al. (2012) determined that the C5ORF42 gene contains at least 53 exons, including an alternative exon, exon 40a, located between exons 40 and 41.
Hartz (2012) mapped the C5ORF42 gene to chromosome 5p13.2 based on an alignment of the C5ORF42 sequence (GenBank AL832176) with the genomic sequence (GRCh37).
Damerla et al. (2015) mapped the mouse C5orf42 gene to chromosome 15.
In Xenopus embryos in which C5orf42 had been knocked down by morpholino oligonucleotides (MOs), Toriyama et al. (2016) observed ciliopathy-related developmental defects, including failure of neural tube closure, defective Hedgehog (see 600725) signaling, and defective left-right patterning. Immunostaining demonstrated that ciliogenesis was disrupted in the developing neural tube, in the node, and in multiciliated cells. CRISPR-based disruption of C5orf42 also disrupted ciliogenesis, and coinjection with wildtype C5orf42 mRNA rescued both the neural tube and ciliogenesis defects resulting from MO-based knockdown. In mice, Toriyama et al. (2016) showed that C5orf42 knockdown specifically disrupted recruitment of peripheral IFTA subunits to the basal body, but recruitment of IFTA core proteins or IFTB components was not affected. Kymography showed that both peripheral and core components of IFTB formed stationary accumulations, and quantitative microscopy confirmed significant enrichment of total IFTB levels in the axoneme. Peripheral IFTA proteins that were not recruited to basal bodies were absent from axonemes after C5orf42 knockdown, whereas IFTA core proteins were present at normal levels in axonemes and underwent bidirectional transport. The authors suggested that the so-called CPLANE (ciliogenesis and planar polarity effector) proteins, including C5ORF42, are involved in recruiting peripheral IFTA proteins to the basal body for assembly onto the IFTA core.
Using knockdown analysis, Hong et al. (2019) found that human JBTS17 was required for cilium assembly in ciliated cells. In nonciliated cycling cells, JBTS17 was detected in the nuclear envelope and nucleus of a subset of interphase cells. Upon entry into mitosis, JBTS17 localized to the kinetochore. JBTS17 protein levels were regulated by cell-cycle-dependent proteolysis. Immunoprecipitation analysis confirmed that C-terminal Joubert syndrome-associated conserved domain (JCD) of JBTS17 mediated JBTS17 kinetochore localization by interacting with the kinetochore component NDC80 (607272). JBTS17 was required for proper establishment of metaphase chromosome alignment, and knockdown of JBTS17 resulted in chromosome misalignment and delayed metaphase-anaphase transition in HeLa cells. JBTS17 also physically interacted with LIS1 via its JCD and contributed to the localization and stability of LIS1, thereby maintaining normal spindle orientation during mitosis. Knockdown of Jbts17 caused mitotic arrest of progenitor cells and defects in neuronal migration in cerebral cortex in developing mouse brain, and overexpression of Lis1 partially rescued the defects.
Joubert Syndrome 17
In affected individuals from 7 French Canadian families with Joubert syndrome-17 (JBTS17; 614615), Srour et al. (2012) identified 6 different potentially pathogenic mutations in the C5ORF42 gene (614571.0001-614571.0006). The mutations were found by exome sequencing and confirmed by Sanger sequencing. All patients showed global developmental delay, with the onset of independent walking between 30 months and 8 years of age. Cognitive impairment was present in all individuals but was variable, ranging from borderline intelligence to mild intellectual disability. Most also showed oculomotor apraxia and breathing abnormalities, mainly episodic hyperventilation. Two individuals showed limb abnormalities; 1 had preaxial and postaxial polydactyly, and another had syndactyly of the third and fourth fingers on 1 hand. None had evidence of retinal or kidney involvement. Three of the mutations were found in multiple families, and haplotype analysis showed that each was linked to a distinct haplotype. The higher frequency of these mutations in the Lower St. Lawrence region might be explained by a founder effect with the coincidental occurrence of the 3 mutations in the same group of settlers, or by multiple regional founder effects corresponding to sequential pioneer fronts.
Orofaciodigital Syndrome VI
In 12 patients from 9 of 11 unrelated families with orofaciodigital syndrome VI (OFD6; 277170), Lopez et al. (2014) identified 14 different homozygous or compound heterozygous mutations in the C5ORF42 gene (see, e.g., 614571.0007-614571.0011). Mutations in the first 6 families were found by exome sequencing; in the remaining 3 families, they were found by direct sequencing of the C5ORF42 gene in 9 additional probands with a clinical diagnosis of OFD6 or a similar disorder. There were 4 frameshift, 3 nonsense, 5 missense, and 2 splice site mutations, suggesting that at least 1 truncating mutation is necessary to induce the phenotype. However, functional studies of the variants were not performed.
Associations Pending Confirmation
For discussion of a possible association between variation in the C5ORF42 gene and monomelic amyotrophy, see 602440.
Using fetal ultrasound biomicroscopy, Damerla et al. (2015) screened N-ethylnitrosourea-generated mouse mutants for congenital heart disease and identified 'heart under glass' (hug) mutant mice with agenesis of the rib cage. Hug mutants had multiple developmental defects that caused prenatal mortality, including skeletal dysplasia, craniofacial defects, polydactyly, cystic kidneys, and cerebellar hypoplasia. Hug mutants and cultured fibroblasts showed perturbed hedgehog signaling (see SHH, 600725). However, hug cochlea had normal stereocilia and kinocilia, and hug neural tube had normal dorsoventral patterning. Damerla et al. (2015) identified the hug mutation as a homozygous 757T-C transition in the C5orf42 gene that results in a ser253-to-phe (S253F) substitution in a highly conserved residue in the Jbts17 protein.
In 5 French Canadian patients with Joubert syndrome-17 (JBTS17; 614615), Srour et al. (2012) identified a heterozygous 4006C-T transition in the C5ORF42 gene, resulting in an arg1336-to-trp (R1336W) substitution in a highly conserved residue. Each patient was compound heterozygous for R1336W and another pathogenic mutation in the C5ORF42 gene. Three families, including 2 sibs from the original family reported by Joubert et al. (1969), carried a G-to-A transition in intron 35 on the other allele (7400+1G-A; 614571.0002), which was demonstrated to cause skipping of exon 35 and premature termination. A fourth patient carried R1336W and a 1-bp deletion (6407del; 614571.0003) on the other allele, which was predicted to cause a frameshift and premature termination. The fifth patient carried R1336W and a 4804C-T transition resulting in an arg1602-to-ter (R1602X; 614571.0004) substitution on the other allele. All the variants were identified by whole-exome sequencing and confirmed by Sanger sequencing. None of the mutations were found in 261 control exomes, in the 1,000 Genomes Browser, or in 477 French Canadian controls. R1336W was found in the heterozygous state in the National Heart, Lung, and Blood Institute (NHLBI) Go Exome Sequencing Project dataset, with a minor allele frequency of 0.0186% (2 of 10,754 alleles).
Damerla et al. (2015) showed that fibroblasts cultured from a compound heterozygous JBTS17 patient with the R1336W substitution and 7400+1G-A failed to develop cilia upon serum withdrawal.
For discussion of the donor splice site mutation (7411+1G-A) in intron 35 of the C5ORF42 gene that was found in compound heterozygous state in 3 families with Joubert syndrome-17 (JBTS17; 614615) by Srour et al. (2012), see 614571.0001.
For discussion of the 1-bp deletion (6407del) in the C5ORF42 gene that was found in compound heterozygous state in a patient with Joubert syndrome-17 (JBTS17; 614615) by Srour et al. (2012), see 614571.0001.
For discussion of the 4804C-T transition in the C5ORF42 gene, resulting in an arg1602-to-ter (R1602X) substitution, that was found in compound heterozygous state in a patient with Joubert syndrome-17 (JBTS17; 614615) by Srour et al. (2012), see 614571.0001.
Toriyama et al. (2016) analyzed the Xenopus cognate of the human R1602X mutation, R1569X, and found that the mutant C5orf42 failed to localize to basal bodies and could not rescue neural tube defects that were rescued by wildtype C5orf42. Unlike the wildtype protein, the R1569 mutant could not rescue basal body recruitment of Intu (610621) after C5orf42 knockdown. The authors concluded that this JBTS-associated variant fails to support localization and function of the so-called CPLANE (ciliogenesis and planar polarity effector) proteins.
In a French Canadian patient with Joubert syndrome-17 (JBTS17; 614615), Srour et al. (2012) identified compound heterozygosity for 2 variations in the C5ORF42 gene: a 7477C-T transition, resulting in an arg2493-to-ter (R2493X) substitution, and A1564T (614571.0006). The R2493X mutation was not found in 261 control exomes, in the 1000 Genomes Project database, or in 477 French Canadian controls. However, it was found in the heterozygous state in the National Heart, Lung, and Blood Institute (NHLBI) Go Exome Sequencing Project dataset, with a minor allele frequency of 0.009% (1 of 10,755 alleles), and designated rs139675596.
This variant is classified as a variant of unknown significance because its contribution to the phenotype of Joubert syndrome (JBTS17; 614615) has not been confirmed.
In 4 patients from 3 unrelated French Canadian families with Joubert syndrome, Srour et al. (2012) identified a heterozygous 4690G-A transition in exon 40a of the C5ORF42 gene, resulting in an ala1564-to-thr (A1564T) substitution. Each patient carried another pathogenic mutation in the C5ORF42 gene on the other allele (see, e.g., 614571.0001). The A1564T substitution was not found in 261 control exomes, in the 1000 Genomes Project database, or in 477 French Canadian controls. However, it was found in heterozygous state in the National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project database, with a minor allele frequency of 0.262% (12 of 4,574 alleles). This variant has been designated rs111294855. It was not possible to predict the effect of the A1564T substitution because the corresponding exon was not annotated across species, and Srour et al. (2012) noted that it is possible that this variant may be linked to another pathogenic mutation.
In 2 Iraqi Kurdish sisters with orofaciodigital syndrome VI (OFD6; 277170), Lopez et al. (2014) identified a homozygous G-to-T transversion (c.3150-1G-T) in a splice acceptor site in exon 18 of the C5ORF42 gene. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.
In a 10-year-old girl of French and Portuguese descent with orofaciodigital syndrome VI (OFD6; 277170), originally reported by Darmency-Stamboul et al. (2013), Lopez et al. (2014) identified compound heterozygous mutations in the C5ORF42 gene: a 1-bp deletion (c.493delA) in exon 5, resulting in a frameshift and premature termination (Ile165TyrfsTer17), and an A-to-G transition (c.3290-2A-G; 614571.0009) in an acceptor splice site in intron 19. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.
For discussion of the acceptor splice site mutation (c.3290-2A-G) in the C5ORF42 gene that was found in compound heterozygous state in a patient with orofaciodigital syndrome VI (OFD6; 277170) by Lopez et al. (2014), see 614571.0008.
In 2 French sib fetuses with orofaciodigital syndrome VI (OFD6; 277170), Lopez et al. (2014) identified compound heterozygous mutations in the C5ORF42 gene: a c.3380C-T transition in exon 19, resulting in a ser1127-to-leu (S1127L) substitution, and a c.3859G-C transversion in exon 22, resulting in an asp1287-to-his (D1287H; 614571.0011) substitution. Each unaffected parent was heterozygous for 1 of the mutations. The S1127L mutation was found in compound heterozygosity with a truncating C5ORF42 mutation (614571.0008) in another French fetus with OFD6, and haplotype analysis suggested a founder effect for S1127L. Functional studies of the variants were not performed, but in silico analysis suggested that the missense mutations may affect splicing.
For discussion of the c.3859G-C transversion in exon 22 of the C5ORF42 gene, resulting in an asp1287-to-his (D1287H) substitution, that was found in compound heterozygous state in 2 sib fetuses with orofaciodigital syndrome VI (OFD6; 277170) by Lopez et al. (2014), see 614571.0010.
Damerla, R. R., Cui, C., Gabriel, G. C., Liu, X., Craige, B., Gibbs, B. C., Francis, R., Li, Y., Chatterjee, B., San Agustin, J. T., Eguether, T., Subramanian, R., Witman, G. B., Michaud, J. L., Pazour, G. J., Lo, C. W. Novel Jbts17 mutant mouse model of Joubert syndrome with cilia transition zone defects and cerebellar and other ciliopathy related anomalies. Hum. Molec. Genet. 24: 3994-4005, 2015. [PubMed: 25877302] [Full Text: https://doi.org/10.1093/hmg/ddv137]
Darmency-Stamboul, V., Burglen, L., Lopez, E., Mejean, N., Dean, J., Franco, B., Rodriguez, D., Lacombe, D., Desguerres, I., Cormier-Daire, V., Doray, B., Pasquier, L., and 10 others. Detailed clinical, genetic and neuroimaging characterization of OFD VI syndrome. Europ. J. Med. Genet. 56: 301-308, 2013. [PubMed: 23523602] [Full Text: https://doi.org/10.1016/j.ejmg.2013.03.004]
Hartz, P. A. Personal Communication. Baltimore, Md. 4/16/2012.
Hong, H., Joo, K., Park, S. M., Seo, J., Kim, M. H., Shin, E. Cheong, H. I., Lee, J. H., Kim, J. Extraciliary roles of the ciliopathy protein JBTS17 in mitosis and neurogenesis. Ann. Neurol. 86: 99-115, 2019. [PubMed: 31004438] [Full Text: https://doi.org/10.1002/ana.25491]
Joubert, M., Eisenring, J. J., Robb, J. P., Andermann, F. Familial agenesis of the cerebellar vermis: a syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation. Neurology 19: 813-825, 1969. Note: Reprinted in J. Child Neurol. 14: 554-564, 1999. [PubMed: 5816874] [Full Text: https://doi.org/10.1212/wnl.19.9.813]
Lopez, E., Thauvin-Robinet, C., Reversade, B., Khartoufi, N. E., Devisme, L., Holder, M., Ansart-Franquet, H., Avila, M., Lacombe, D., Kleinfinger, P., Kaori, I., Takanashi, J.-I., and 20 others. C5orf42 is the major gene responsible for OFD syndrome type VI. Hum. Genet. 133: 367-377, 2014. [PubMed: 24178751] [Full Text: https://doi.org/10.1007/s00439-013-1385-1]
Srour, M., Schwartzentruber, J., Hamdan, F. F., Ospina, L. H., Patry, L., Labuda, D., Massicotte, C., Dobrzeniecka, S., Cap-Chichi, J.-M., Papillon-Cavanagh, S., Samuels, M. E., Boycott, K. M., Shevell, M. I., Laframboise, R., Desilets, V., FORGE Canada Consortium, Maranda, B., Rouleau, G. A., Majewski, J., Michaud, J. L. Mutations in C5ORF42 cause Joubert syndrome in the French Canadian population. Am. J. Hum. Genet. 90: 693-700, 2012. [PubMed: 22425360] [Full Text: https://doi.org/10.1016/j.ajhg.2012.02.011]
Toriyama, M., Lee, C., Taylor, S. P., Duran, I., Cohn, D. H., Bruel, A.-L., Tabler, J. M., Drew, K., Kelly, M. R., Kim, S., Park, T. J., Braun, D. A., and 21 others. The ciliopathy-associated CPLANE proteins direct basal body recruitment of intraflagellar transport machinery. Nature Genet. 48: 648-656, 2016. Note: Erratum: Nature Genet. 48: 970 only, 2016. [PubMed: 27158779] [Full Text: https://doi.org/10.1038/ng.3558]