Online Mendelian Inheritance in Man (OMIM) (original) (raw)

Cytogenetic location: 22q13.31 Genomic coordinates (GRCh38) : 22:46,361,174-46,537,620 (from NCBI)

TEXT

Description

Planar cell polarity (PCP) is the term given to global cell polarization, such as the alignment of mammalian body hair along the anterior-posterior axis or the orientation of stereocilia bundles in the inner ear. CELSR1 is a PCP protein that is involved in the transmission of directional cues to align either individual cells within an epithelial sheet or multicellular clusters, which polarize as a group (Devenport and Fuchs, 2008).

Cloning and Expression

By screening a mouse embryonic cDNA library, Hadjantonakis et al. (1997, 1998) obtained a cDNA encoding a 3,034-amino acid 7-pass transmembrane G protein-coupled receptor, which they termed cadherin EGF LAG seven-pass G-type receptor-1 (Celsr1). Celsr1 contains motifs that are recognized as mediators of protein-protein interactions. In its extracellular region it has a block of contiguous cadherin repeats in the N terminus and then a region with 7 epidermal growth factor (EGF; 131530)-like repeats interrupted by 2 laminin A (150320) G-type (LAG) repeats. By in situ hybridization and RT-PCR analysis, Hadjantonakis et al. (1997) detected significant levels of Celsr1 in neural tube, brain, lung epithelium, and nascent eyelid in day 11.5 mouse embryos. In adult mice, expression was detected in spinal cord, eye, and brain, chiefly in ependymal cells lining the lateral, third, and fourth ventricles. The structure, putative G-linked signaling properties, and restricted expression of the Celsr1 protein suggest that it is a receptor involved in contact-mediated communication.

Gene Function

Devenport and Fuchs (2008) found that marked changes in cell shape and cytoskeletal polarization occurred in embryonic mouse skin as nascent hair follicles became anteriorly angled, morphologically polarized, and molecularly compartmentalized along the anterior-posterior axis. Using embryonic mice harboring point mutations in Vangl2 (600533) and Celsr1, they showed that these proteins were asymmetrically distributed within the embryonic epidermal basal layer, were codependent for their asymmetric distribution, and drove the orientation of hair follicles along the anterior-posterior axis. Fzd6 (603409) was also required for the orientation of adult hair follicles. Fzd6 asymmetrically localized in the epidermis and was recruited to cell contacts by Celsr1. Devenport and Fuchs (2008) concluded that PCP proteins operate early in the mammalian epidermis to coordinately polarize hair follicles across body axes.

Gene Structure

By genomic sequence analysis, Wu and Maniatis (2000) determined that the FMI2 gene, like the FMI1 gene (CELSR3; 604264), contains 35 exons. All 9 protocadherin ectodomain repeats are encoded by the large first exon. The FMI2 introns are larger than those of FMI1.

Mapping

By interspecific backcross analysis, Hadjantonakis et al. (1997) mapped the mouse Celsr1 gene to proximal chromosome 15. By FISH, they mapped the human CELSR1 gene to chromosome 22q13.3.

Molecular Genetics

Neural Tube Defects

Based on studies in mice by Curtin et al. (2003) (see ANIMAL MODEL), Robinson et al. (2012) sequenced the CELSR1 gene in 36 fetuses with craniorachischisis (CRN), the most severe type of neural tube defect (see 182940) in which the neural tube remains open from the midbrain or rostral hindbrain to the base of the spine. Missense variants were found in 6 patients, but only 3 variants (S2964L, R2438Q, and P2983A) were demonstrated to cause a decrease in proper membrane localization in cellular transfection studies. Robinson et al. (2012) suggested that some of the identified variants may alter planar cell polarity pathways and contribute to the development of CRN.

In a cohort of 473 patients affected with various forms of open and closed neural tube defects (182940) or caudal agenesis (600145), Allache et al. (2012) identified 13 novel missense variants in the CELSR1 gene in 12 patients, including 11 with neural tube defects and 1 with caudal agenesis. One nonsense variant and 1 in-frame deletion were also identified, but each was inherited from an unaffected parent. Novel and rare variants (frequency of less than 1%) were not found in 639 controls. Functional studies of the variants were not performed. Overall, potentially pathogenic CELSR1 variants were found in 2.9% of patients with neural tube defects and in 3.3% of patients with caudal agenesis. Allache et al. (2012) suggested that variation in the CELSR1 gene may contribute to the development of these disorders.

By direct sequencing of the CELSR1 gene, Lei et al. (2014) identified heterozygous frameshift mutations (604523.0001 and 604523.0002) in 2 (1%) of 192 patients from California with the neural tube defect spina bifida. In vitro functional analysis showed that both mutations changed subcellular localization of the CELSR1 protein and impaired the physical association between CELSR1 and VANGL2 (600533), diminishing the ability to recruit VANGL2 for cell-cell contact. Studies of patient tissue were not performed. Six additional heterozygous missense variants, 4 of which were predicted to be pathogenic (A1023G, I1124M, T1362M, and R2497C), were also found in patients but not in controls or in the Exome Variant Server database, but functional studies of these variants were not performed.

Lymphatic Malformation 9

In 5 affected women from a 3-generation family with lymphatic malformation-9 (LMPHM9; 619319), Gonzalez-Garay et al. (2016) identified a heterozygous nonsense mutation in the CELSR1 gene (W1957X; 604523.0003) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases. Functional studies of the variant were not performed, but it was predicted to result in a loss of function. The authors postulated that if the mutant truncated protein was expressed, it would lack several important functional domains, including the entire cadherin domain, 5 EGF domains, and the LamG domains. The findings suggested that defective planar cell polarity signaling pathways may contribute to the development of lymphedema.

In 5 unrelated patients with LMPHM9, Maltese et al. (2019) identified heterozygous loss-of-function mutations in the CELSR1 gene (see, e.g., 604523.0004-604523.0006). The mutations, which were found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families, with evidence of incomplete penetrance. Functional studies of the variants and studies of patient cells were not performed. The patients were part of a cohort of 95 probands with a similar phenotype; mutations in CELSR1 thus accounted for 5.3% of probands, and the authors recommended adding it to a diagnostic gene panel.

In 5 affected women from a large multigenerational family with LMPHM9, Erickson et al. (2019) identified a heterozygous frameshift mutation in the CELSR1 gene (604523.0007). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, but showed incomplete penetrance, particularly in male carriers, who were clinically unaffected. Functional studies of the variant and studies of patient cells were not performed. The authors noted that CELSR1 is involved in vascular endothelial cell migration and proliferation.

Animal Model

In independent mutagenesis experiments, Curtin et al. (2003) identified 2 novel mouse mutants with abnormal head-shaking behavior ('spin cycle' and 'crash') due to heterozygous mutations in the Celsr1 gene. Heterozygous mutant mice had defects in the orientation of sensory hair cells in the organ of Corti, indicating a defect in planar cell polarity. Homozygous mutants showed severe neural tube defects consistent with craniorachischisis resulting from a failure to initiate neural tube closure. The identification of mouse mutants of Celsr1 provided the first evidence for the function of the Celsr family in planar cell polarity in mammals, and supported the involvement of a planar cell polarity pathway in vertebrate neurulation.

Yates et al. (2010) showed that mutations in the planar cell polarity genes Celsr1 and Vangl2 led to disrupted lung development and defects in lung architecture in transgenic mice. Lungs from Celsr1(Crsh) and Vangl2(Lp) mouse mutants were small and misshapen with fewer branches, and by late gestation exhibited thickened interstitial mesenchyme and defective saccular formation. There was a recapitulation of these branching defects following inhibition of Rho kinase (601702), an important downstream effector of the PCP signaling pathway. Epithelial integrity was disrupted, cytoskeletal remodeling perturbed, and mutant endoderm did not branch normally in response to the chemoattractant FGF10 (602115). Celsr1 and Vangl2 proteins were present in restricted spatial domains within lung epithelium. The authors concluded that Celsr1 and Vangl2 are required for normal fetal lung development and may be key components of a novel signaling pathway critical for this process.

ALLELIC VARIANTS 7 Selected Examples):

.0001 NEURAL TUBE DEFECTS, SUSCEPTIBILITY TO

CELSR1, 2-BP INS, 5050TG
SNP: rs786201015, gnomAD: rs786201015, ClinVar: RCV000162244

In a patient with a neural tube defect (NTD; 182940) manifest as spina bifida, Lei et al. (2014) identified a heterozygous 2-bp insertion (c.5050_5051insTG) within a TG repeat in the CELSR1 gene, resulting in a frameshift and premature termination at residue 1706. The deletion was not found in 190 control samples.

.0002 NEURAL TUBE DEFECTS, SUSCEPTIBILITY TO

CELSR1, 2-BP DEL, 5719TG
SNP: rs786201016, ClinVar: RCV000162245

In a patient with a neural tube defect (NTD; 182940) manifest as spina bifida, Lei et al. (2014) identified a heterozygous 2-bp deletion (c.5719_5720delTG) within a TG repeat in the CELSR1 gene, resulting in a frameshift and premature termination at residue 1944. The deletion was not found in 190 control samples.

.0003 LYMPHATIC MALFORMATION 9

CELSR1, TRP1957TER
SNP: rs2147265140, ClinVar: RCV001418322

In 5 affected women from a 3-generation family with lymphatic malformation-9 (LMPHM9; 619319), Gonzalez-Garay et al. (2016) identified a heterozygous c.5871G-A transition (c.5871G-A, NM_014246.1) in the CELSR1 gene, resulting in a trp1957-to-ter (W1957X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in the 1000 Genomes Project, Exome Sequencing Project, and or ExAC databases. Functional studies of the variant were not performed, but it was predicted to result in a loss of function. The authors postulated that if the mutant truncated protein was expressed, it would lack several important functional domains, including the entire cadherin domain, 5 EGF domains, and the LamG domains. The findings suggested that defective planar cell polarity signaling pathways may contribute to the development of lymphedema.

.0004 LYMPHATIC MALFORMATION 9

CELSR1, IVSDS, T-A, +2
SNP: rs1569141899, ClinVar: RCV001418323, RCV001787356

In an 11-year-old girl (case 1) and her father with lymphatic malformation-9 (LMPHM9; 619319), Maltese et al. (2019) identified a heterozygous intronic T-to-A transversion in the CELSR1 gene (c.5226+2T-A, NM_014246.1), predicted to result in a splicing defect. The mutation was found by next-generation sequencing and confirmed by Sanger sequencing; functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function.

.0005 LYMPHATIC MALFORMATION 9

CELSR1, IVSDS, G-A, +1
SNP: rs1569124017, ClinVar: RCV001418325, RCV001787357

In a 32-year-old woman (case 2) and her affected mother with lymphatic malformation-9 (LMPHM9; 619319), Maltese et al. (2019) identified a heterozygous intronic G-to-A transition in the CELSR1 gene (c.6739+1G-A, NM_014246.1) predicted to result in a splicing defect and a loss of function. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing was inherited from her affected mother. Functional studies of the variant and studies of patient cells were not performed.

.0006 LYMPHATIC MALFORMATION 9

CELSR1, GLU290TER
SNP: rs1569227576, ClinVar: RCV001418327, RCV001787353

In a 14-year-old girl (case 3) with lymphatic malformation-9 (LMPHM9; 619319), Maltese et al. (2019) identified a heterozygous c.868G-T transversion (c.868G-T, NM_014246.1) in the CELSR1 gene, resulting in a glu290-to-ter (E290X) substitution. The mutation was found by next-generation sequencing and confirmed by Sanger sequencing. Her unaffected father and brother carried the mutation, indicating incomplete penetrance. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function.

.0007 LYMPHATIC MALFORMATION 9

CELSR1, 1-BP DUP, 5121C
SNP: rs2147324428, ClinVar: RCV001418328

In 5 affected women from a large multigenerational family with lymphatic malformation-9 (LMPHM9; 619319), Erickson et al. (2019) identified a heterozygous 1-bp duplication (c.5121dupC, NM_014246.1) in the CELSR1 gene, predicted to result in a frameshift and premature termination (Ile1708fsTer44). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, but showed incomplete penetrance, particularly in male carriers, who were clinically unaffected. Functional studies of the variant and studies of patient cells were not performed.

REFERENCES

  1. Allache, R., De Marco, P., Merello, E., Capra, V., Kibar, Z.Role of the planar cell polarity gene CELSR1 in neural tube defects and caudal agenesis. Birth Defects Res. A Clin. Molec. Teratol. 94: 176-181, 2012. [PubMed: 22371354] [Full Text: https://doi.org/10.1002/bdra.23002\]
  2. Curtin, J. A., Quint, E., Tsipouri, V., Arkell, R. M., Cattanach, B., Copp, A. J., Henderson, D. J., Spurr, N., Stanier, P., Fisher, E. M., Nolan, P. M., Steel, K. P., Brown, S. D. M., Gray, I. C., Murdoch, J. N.Mutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse. Curr. Biol. 13: 1129-1133, 2003. [PubMed: 12842012] [Full Text: https://doi.org/10.1016/s0960-9822(03)00374-9\]
  3. Devenport, D., Fuchs, E.Planar polarization in embryonic epidermis orchestrates global asymmetric morphogenesis of hair follicles. Nature Cell Biol. 10: 1257-1268, 2008. [PubMed: 18849982] [Full Text: https://doi.org/10.1038/ncb1784\]
  4. Erickson, R. P., Lai, L.-W., Mustacich, D. J., Bernas, M. J., Kuo, P. H., Witte, M. H.Sex-limited penetrance of lymphedema to females with CELSR1 haploinsufficiency: a second family. Clin. Genet. 96: 478-482, 2019. [PubMed: 31403174] [Full Text: https://doi.org/10.1111/cge.13622\]
  5. Gonzalez-Garay, M. L., Aldrich, M. B., Rasmussen, J. C., Guilliod, R., Lapinski, P. E., King, P. D., Sevick-Muraca, E. M.A novel mutation in CELSR1 is associated with hereditary lymphedema. Vasc. Cell 8: 1, 2016. [PubMed: 26855770] [Full Text: https://doi.org/10.1186/s13221-016-0035-5\]
  6. Hadjantonakis, A.-K., Formstone, C. J., Little, P. F. R.mCelsr1 is an evolutionarily conserved seven-pass transmembrane receptor and is expressed during mouse embryonic development. Mech. Dev. 78: 91-95, 1998. [PubMed: 9858697] [Full Text: https://doi.org/10.1016/s0925-4773(98)00153-1\]
  7. Hadjantonakis, A.-K., Sheward, W. J., Harmar, A. J., de Galan, L., Hoovers, J. M. N., Little, P. F. R.Celsr1, a neural-specific gene encoding an unusual seven-pass transmembrane receptor, maps to mouse chromosome 15 and human chromosome 22qter. Genomics 45: 97-104, 1997. [PubMed: 9339365] [Full Text: https://doi.org/10.1006/geno.1997.4892\]
  8. Lei, Y., Zhu, H., Yang, W., Ross, M. E., Shaw, G. M., Finnell, R. H.Identification of novel CELSR1 mutations in spina bifida. PLoS One 9: e92207, 2014. Note: Electronic Article. [PubMed: 24632739] [Full Text: https://doi.org/10.1371/journal.pone.0092207\]
  9. Maltese, P. E., Michelini, S., Ricci, M., Maitz, S., Fiorentino, A., Serrani, R., Lazzerotti, A., Bruson, A., Paolacci, S., Benedetti, S., Bertelli, M.Increasing evidence of hereditary lymphedema caused by CELSR1 loss-of-function variants. Am. J. Med. Genet. 179A: 1718-1724, 2019. [PubMed: 31215153] [Full Text: https://doi.org/10.1002/ajmg.a.61269\]
  10. Robinson, A., Escuin, S., Doudney, K., Vekemans, M., Stevenson, R. E., Greene, N. D. E., Copp, A. J., Stanier, P.Mutations in the planar cell polarity genes CELSR1 and SCRIB are associated with the severe neural tube defect craniorachischisis. Hum. Mutat. 33: 440-447, 2012. [PubMed: 22095531] [Full Text: https://doi.org/10.1002/humu.21662\]
  11. Wu, Q., Maniatis, T.Large exons encoding multiple ectodomains are a characteristic feature of protocadherin genes. Proc. Nat. Acad. Sci. 97: 3124-3129, 2000. [PubMed: 10716726] [Full Text: https://doi.org/10.1073/pnas.97.7.3124\]
  12. Yates, L. L., Schnatwinkel, C., Murdoch, J. N., Bogani, D., Formstone, C. J., Townsend, S., Greenfield, A., Niswander, L. A., Dean, C. H.The PCP genes Celsr1 and Vangl2 are required for normal lung branching morphogenesis. Hum. Molec. Genet. 19: 2251-2267, 2010. [PubMed: 20223754] [Full Text: https://doi.org/10.1093/hmg/ddq104\]