Alternative titles; symbols
HGNC Approved Gene Symbol: TSPAN12
Cytogenetic location: 7q31.31 Genomic coordinates (GRCh38) : 7:120,787,320-120,858,335 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q31.31 | Exudative vitreoretinopathy 5 | 613310 | Autosomal dominant | 3 |
Members of the tetraspanin superfamily, such as TSPAN12, are characterized by the presence of 4 transmembrane domains. Tetraspanins associate in large membrane complexes with other molecules, particularly integrins (see ITGB1; 135630), and function in cell adhesion, migration, and signaling (summary by Serru et al., 2000).
By searching an EST database for tetraspanin-like sequences, Serru et al. (2000) identified TSPAN12, which they called NET2. The deduced 305-amino acid protein contains 4 transmembrane segments, 4 cysteines in the second extracellular region, including the conserved CCG sequence, and a weakly conserved PxSC motif. Serru et al. (2000) also identified a TSPAN12 splice variant with a divergent 3-prime end. RT-PCR detected TSPAN12 expression in most human cell lines examined.
Using immunohistochemical analysis and in situ hybridization, Junge et al. (2009) found that Tspan12 was expressed in neonatal mouse retinal and meningeal vasculature and in intestinal smooth muscle cells.
Serru et al. (2000) determined that the TSPAN12 gene contains 8 exons.
Based on its inclusion in a PAC clone, Serru et al. (2000) mapped the TSPAN12 gene to chromosome 7q31.
Junge et al. (2009) mapped the mouse Tspan12 gene to chromosome 6.
Junge et al. (2009) found that the phenotype of Tspan12 -/- mice was similar to mouse models of familial exudative vitreoretinopathy (see 305390) caused by deletion of Fzd4 (604579), Lrp5 (603506), or norrin (NDP; 300658) (see ANIMAL MODEL). Using human retinal microvascular endothelial cells and cell lines, they showed that TSPAN12 associated with the norrin receptor complex and increased norrin/beta-catenin (CTNNB1; 116806) signaling, but not Wnt (see 164820)/beta-catenin signaling. Small interfering RNA directed to TSPAN12 abolished transcriptional responses to norrin, but not WNT3A (606359), in human retinal endothelial cells. Signaling defects due to norrin or FZD4 mutations that were predicted to impair receptor multimerization were rescued by overexpression of TSPAN12. Junge et al. (2009) concluded that TSPAN12 cooperates with norrin multimers to promote multimerization of FZD4 and its associated proteins, resulting in beta-catenin signaling.
Nikopoulos et al. (2010) analyzed the TSPAN12 gene in 2 large Dutch families with exudative vitreoretinopathy (FEVR) mapping to chromosome 7 (EVR5; 613310) and identified a heterozygous missense mutation in both probands and their affected relatives (A237P; 613138.0001). Analysis of the TSPAN12 gene in 9 additional Dutch FEVR probands revealed that the A237P change segregated with disease in 2 of the families, whereas a different missense mutation (G188R; 613138.0002) was found in 2 affected brothers from a third family.
In a cohort of 70 FEVR patients, Poulter et al. (2010) screened the TSPAN12 gene and identified 7 heterozygous mutations, including frameshift, splice site, nonsense, and missense mutations, that were not present in controls (see, e.g., 613138.0003-613138.0006). The authors stated that there was no correlation between particular mutations or mutation types and phenotypes, and that the variation in eye phenotypes was similar to that reported with other FEVR-causing genes.
Kondo et al. (2011) screened for mutations in the TSPAN12 gene in 90 Japanese probands with FEVR and identified a heterozygous mutation in 3: a previously reported L140X mutation (613136.0004) in 2 and a novel L245P mutation (613136.0007) in 1. Kondo et al. (2011) concluded that mutant TSPAN12 is responsible for approximately 3% of FEVR patients in Japan.
In 9 affected members of a large 4-generation Mexican family segregating autosomal dominant FEVR, Poulter et al. (2012) identified heterozygosity for a missense mutation in the TSPAN12 gene (Y138C; 613138.0008). Segregation analysis in the family showed that the 3 most severely affected individuals were homozygous for Y138C. Screening a panel of 10 severely affected FEVR/retinal dysplasia patients without mutations in known FEVR genes revealed a further 3 patients with homozygous or compound heterozygous mutations in TSPAN12 (see, e.g., 613138.0009-613138.0011). Poulter et al. (2012) suggested that the FEVR phenotype is sensitive to the dosage of TSPAN12.
In a large inbred Bedouin family with variable abnormal vitreoretinal vasculature, Gal et al. (2014) performed exome sequencing in the proband and identified homozygosity for a missense mutation in the TSPAN12 gene (C181F; 613138.0012). The authors noted that the TSPAN12 gene was located within a shared 58-Mb homozygous region with a lod score peak in chromosome 7. Sanger sequencing validated the mutation and its segregation with disease. There were 10 unaffected heterozygotes in the family, 6 of whom had been examined and showed no abnormalities of eye structure or function. The variant was not present in the dbSNP, 1000 Genomes Project, and ESP databases or in 63 ethnically matched controls. The authors noted that the lack of evidence for subclinical symptoms in heterozygotes in this family contrasted with the findings of Poulter et al. (2012). Gal et al. (2014) suggested that this might be a direct reflection of allelic dosage effect, but that there might also be contributions from modifier genes or environmental cues associated with the pathogenesis.
Junge et al. (2009) found that Tspan12 -/- mice were viable and fertile, but they developed abnormal retinal vascularization, with avascular outer plexiform layer, microaneurysms, vascular fenestrations, focal hemorrhage, and delayed hyaloid vessel regression. Mutant retinas also showed retinal glial cell activation. Vessels of the inner ear were also enlarged. The phenotype of Tspan12 -/- mice was similar to the phenotypes of mice lacking Fzd4, Lrp5, or norrin, which are models of exudative vitreoretinopathy (see 133780).
In affected members of 4 unrelated Dutch families segregating autosomal dominant exudative vitreoretinopathy-5 (EVR5; 613310), Nikopoulos et al. (2010) identified heterozygosity for a 709G-C transversion in exon 8 of the TSPAN12 gene, resulting in an ala237-to-pro (A237P) substitution at a highly conserved residue in an alpha-helical structure within the fourth transmembrane domain. The mutation was not detected in 140 ethnically matched controls, but was found in 3 relatives of uncertain clinical status and in 1 healthy individual, suggesting nonpenetrance. Genealogic analysis revealed that ancestors of 3 of the 4 families were born in the same eastern region of The Netherlands, and microsatellite marker analysis demonstrated a shared haplotype among all 4 families, suggesting that A237P is a regional founder mutation.
In 2 Dutch brothers with exudative vitreoretinopathy-5 (EVR5; 613310), Nikopoulos et al. (2010) identified heterozygosity for a 562G-C transversion in the TSPAN12 gene, resulting in a gly188-to-arg (G188R) substitution at a highly conserved residue in the extracellular loop between the third and fourth transmembrane domains. The mutation was not detected in 140 ethnically matched controls.
In the female proband of an Australian family of European descent with exudative vitreoretinopathy-5 (EVR5; 613310), Poulter et al. (2010) identified heterozygosity for a 7-bp insertion (218_219insGCTGTTT) in exon 4 of the TSPAN12 gene, causing a frameshift that results in 45 incorrect amino acids after codon 72, followed by premature termination at codon 118 (Phe73LeufsTer118). The proband exhibited macula ectopia, with a large retinal fold across the fovea of her right eye and fibrovascular changes in the temporal periphery of her left eye. Her asymptomatic father also carried the mutation, and was found to have bilateral peripheral retinal pigmentary disturbances in a bone-spicule pattern that was interpreted as being old exudative retinal detachments that had spontaneously resolved. The proband's asymptomatic 10-year-old brother also carried the mutation and showed no sign of disease on fundus examination; however, a mild phenotype that might be evident by fluorescein angiography could not be excluded.
In a father and daughter from a Japanese family with exudative vitreoretinopathy-5 (EVR5; 613310), Poulter et al. (2010) identified heterozygosity for a 419T-A transversion in exon 6 of the TSPAN12 gene, resulting in a leu140-to-ter (L140X) substitution. The female proband was diagnosed in infancy with bilateral retinal folds, whereas her mutation-positive but asymptomatic father had areas of avascularity and abnormal vessels in the peripheral retinal vasculature at the posterior pole.
Kondo et al. (2011) identified heterozygosity for the L140X mutation in 2 Japanese families with familial EVR. The mutation was not found in 380 chromosomes from 190 healthy volunteers.
In a Caucasian female British patient with exudative vitreoretinopathy-5 (EVR5; 613310), Poulter et al. (2010) identified heterozygosity for a 5-bp deletion in intron 5 (361-5_361-1delACCAG) of the TSPAN12 gene, removing the splice acceptor site including the consensus AG. The patient, who was diagnosed in the fifth decade of life and had no family history of the disease, had bilateral temporal retinal avascularity and associated areas of exudation visible with fundus fluorescein angiography, and both eyes showed traction of the retinal vasculature at the posterior pole.
In a father and son from a Caucasian British family with exudative vitreoretinopathy-5 (EVR5; 613310), Poulter et al. (2010) identified heterozygosity for a 302T-A transversion in exon 5 of the TSPAN12 gene, resulting in a leu101-to-his (L101H) substitution at a highly conserved residue. Both father and son had classic signs of FEVR, but the disease was severe in the son and mild in the father.
In affected members of a Japanese family segregating exudative vitreoretinopathy (EVR5; 613310), Kondo et al. (2011) identified a heterozygous 734T-C transition in the TSPAN12 gene, resulting in a leu245-to-pro (L245P) substitution. The mutation was not found in 380 chromosomes from 190 healthy volunteers.
In 9 affected members of a large 4-generation Mexican family segregating autosomal dominant exudative vitreoretinopathy (EVR5; 613310), originally studied by Toomes et al. (2005), Poulter et al. (2012) identified heterozygosity for a c.413A-G transition in exon 6 of the TSPAN12 gene, resulting in a tyr138-to-cys (Y138C) substitution at a highly conserved residue. The mutation was also detected in 3 asymptomatic younger family members, who showed no apparent signs of FEVR on indirect ophthalmoscopy performed in their home; however, the authors noted that without fluorescein angiography, subtle defects might have been missed. In addition, 3 severely affected family members were homozygous for Y138C; they presented in early childhood with tractional retinal detachments, in contrast to the heterozygous patients, who exhibited only retinal exudates or peripheral avascularity. The mutation was not found in 100 Hispanic or 400 Caucasian control chromosomes.
IN a 6-year-old Indian girl with severe exudative vitreoretinopathy (EVR5; 613310), Poulter et al. (2012) identified homozygosity for a c.67-1G-C transversion in the intron 2 splice acceptor site of the TSPAN12 gene. The patient presented as a neonate with very poor vision and roving eye movements; fundus examination showed bilateral retinal folds that remained stable over the years, with best-corrected visual acuity between 20/25 and 20/30, as well as myopia and astigmatism. Examination of her asymptomatic first-cousin parents, who were heterozygous for the mutation, revealed definite avascularity of the anterior retina bilaterally. Analysis of parental leukocyte RNA showed that the mutation resulted in deletion of exon 3, causing a frameshift followed by premature termination (Leu23GlyfsTer66). A 19-year-old male cousin of the parents, who was also found to be heterozygous for the mutation, had left-side congenital vision loss (light perception only) due to persistent hyperplastic vitreous, and visual acuity of approximately 20/30 with a -10D myopic correction in the right eye.
In a 23-year-old woman of Nigerian origin with severe exudative vitreoretinopathy (EVR5; 613310), Poulter et al. (2012) identified compound heterozygosity for a c.146C-T transition in exon 3 of the TSPAN12 gene, resulting in a thr49-to-met (T49M) substitution at a highly conserved residue, and a splice donor site mutation in intron 4 (c.285+1G-A; 613138.0011), predicted to cause deletion of exon 4 and a frameshift resulting in a premature termination codon (Arg50AspfsTer12). The missense mutation was not found in 340 African or 160 Caucasian control chromosomes. The patient was diagnosed with bilateral cataracts in infancy, and at age 2 was documented as having a phthisic right eye with chronic endophthalmitis due to perforation, with nystagmus of the left eye that precluded retinal examination. At 22 years of age, she had undergone a left pars plana vitrectomy for a reported diagnosis of persistent hyperplastic primary vitreous and had no light perception in the left aphakic eye, which showed corneal opacity and an elevated intraocular pressure of 34 mm Hg. Funduscopy suggested a large retinal fold traversing the posterior pole between the optic disc and temporal retinal periphery. No family members were available for study, although a sister was reported to have poor vision.
For discussion of the splice site mutation in the TSPAN12 gene (c.285+1G-A) that was found in compound heterozygous state in a patient with severe exudative vitreoretinopathy (EVR5; 613310) by Poulter et al. (2012), see 613138.0010.
In 9 affected members of a large inbred Bedouin family with variable abnormal vitreoretinal vasculature (EVR5; 613310), Gal et al. (2014) identified homozygosity for a c.542G-T transversion in the TSPAN12 gene, resulting in a cys181-to-phe (C181F) substitution. The authors noted that the TSPAN12 gene was located within a shared 58-Mb homozygous region with a lod score peak in chromosome 7. Sanger sequencing validated the mutation and its segregation with disease. There were 10 unaffected heterozygotes in the family, 6 of whom had been examined and showed no abnormalities of eye structure or function. The variant was not present in the dbSNP, 1000 Genomes Project, and ESP databases or in 63 ethnically matched controls.
Gal, M., Levanon, E. Y., Hujeirat, Y., Khayat, M., Pe'er, J., Shalev, S. Novel mutation in TSPAN12 leads to autosomal recessive inheritance of congenital vitreoretinal disease with intra-familial phenotypic variability. Am. J. Med. Genet. 164A: 2996-3002, 2014. [PubMed: 25250762] [Full Text: https://doi.org/10.1002/ajmg.a.36739]
Junge, H. J., Yang, S., Burton, J. B., Paes, K., Shu, X., French, D. M., Costa, M., Rice, D. S., Ye, W. TSPAN12 regulates retinal vascular development by promoting Norrin- but not Wnt-induced FZD4/beta-catenin signaling. Cell 139: 299-311, 2009. [PubMed: 19837033] [Full Text: https://doi.org/10.1016/j.cell.2009.07.048]
Kondo, H., Kusaka, S., Yoshinaga, A., Uchio, E., Tawara, A., Hayashi, K., Tahira, T. Mutations in the TSPAN12 gene in Japanese patients with familial exudative vitreoretinopathy. Am. J. Ophthal. 151: 1095-1100, 2011. [PubMed: 21334594] [Full Text: https://doi.org/10.1016/j.ajo.2010.11.026]
Nikopoulos, K., Gilissen, C., Hoischen, A., van Nouhuys, C. E., Boonstra, F. N., Blokland, E. A. W., Arts, P., Wieskamp, N., Strom, T. M., Ayuso, C., Tilanus, M. A. D., Bouwhuis, S., Mukhopadhyay, A., Scheffer, H., Hoefsloot, L. H., Veltman, J. A., Cremers, F. P. M., Collin, R. W. J. Next-generation sequencing of a 40 Mb linkage interval reveals TSPAN12 mutations in patients with familial exudative vitreoretinopathy. Am. J. Hum. Genet. 86: 240-247, 2010. [PubMed: 20159111] [Full Text: https://doi.org/10.1016/j.ajhg.2009.12.016]
Poulter, J. A., Ali, M., Gilmour, D. F., Rice, A., Kondo, H., Hayashi, K., Mackey, D. A., Kearns, L. S., Ruddle, J. B., Craig, J. E., Pierce, E. A., Downey, L. M., Mohamed, M. D., Markham, A. F., Inglehearn, C. F., Toomes, C. Mutations in TSPAN12 cause autosomal-dominant familial exudative vitreoretinopathy. Am. J. Hum. Genet. 86: 248-253, 2010. Note: Erratum: Am. J. Hum. Genet. 98: 592 only, 2016. [PubMed: 20159112] [Full Text: https://doi.org/10.1016/j.ajhg.2010.01.012]
Poulter, J. A., Davidson, A. E., Ali, M., Gilmour, D. F., Parry, D. A., Mintz-Hittner, H. A., Carr, I. M., Bottomley, H. M., Long, V. W., Downey, L. M., Sergouniotis, P. I., Wright, G. A., MacLaren, R. E., Moore, A. T., Webster, A. R., Inglehearn, C. F., Toomes, C. Recessive mutations in TSPAN12 cause retinal dysplasia and severe familial exudative vitreoretinopathy (FEVR). Invest. Ophthal. Vis. Sci. 53: 2873-2879, 2012. [PubMed: 22427576] [Full Text: https://doi.org/10.1167/iovs.11-8629]
Serru, V., Dessen, P., Boucheix, C., Rubinstein, E. Sequence and expression of seven new tetraspans. Biochim. Biophys. Acta 1478: 159-163, 2000. [PubMed: 10719184] [Full Text: https://doi.org/10.1016/s0167-4838(00)00022-4]
Toomes, C., Downey, L. M., Bottomley, H. M., Mintz-Hittner, H. A., Inglehearn, C. F. Further evidence of genetic heterogeneity in familial exudative vitreoretinopathy; exclusion of EVR1, EVR3, and EVR4 in a large autosomal dominant pedigree. Brit. J. Ophthal. 89: 194-197, 2005. [PubMed: 15665352] [Full Text: https://doi.org/10.1136/bjo.2004.042507]