HGNC Approved Gene Symbol: RS1
Cytogenetic location: Xp22.13 Genomic coordinates (GRCh38) : X:18,639,688-18,672,108 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp22.13 | Retinoschisis | 312700 | X-linked recessive | 3 |
The RS1 gene encodes retinoschisin, a secretory discoidin-domain protein expressed exclusively in retina that functions as an octamer and is implicated in cell-cell interactions and cell adhesion (summary by Sikkink et al., 2007).
By mapping and expression analysis of expressed sequence tags (ESTs), Sauer et al. (1997) identified a novel transcript, which they designated XLRS1, within the centromeric portion of the RS interval, and which was expressed exclusively in retina. The RS gene (XLRS1) encodes a 224-amino acid protein, processed by N-terminal cleavage into a mature protein with a calculated size of 23 kD (201 amino acids).
Using LacZ reporter analysis and in situ hybridization, Liu et al. (2019) showed that Rs1 was expressed primarily in photoreceptors of mice. Immunohistochemical analysis confirmed that Rs1 was present throughout mouse retina as a secreted protein, with prominent labeling in photoreceptor inner segments.
Sauer et al. (1997) determined that the RS1 gene is composed of 6 exons.
Sauer et al. (1997) identified the RS1 gene within the X-linked retinoschisis (312700) candidate region on chromosome Xp22.2 by positional cloning.
In humans, the proportion of male to female offspring at birth (the secondary sex ratio; SSR) is not 1:1, as would be expected from the equal number of X- and Y-bearing spermatozoa produced by males. The SSR is shifted slightly toward males with 5 to 7% more males than females being born, resulting in a value of 105-107. The primary sex ratio, i.e., the male/female rate at conception, is even more skewed than the SSR. It has been reported that the male/female ratio is 130/100 among spontaneously aborted, anatomically normal fetuses (Byrne and Warburton, 1987). In the 1960s it was noted that female carriers of the juvenile retinoschisis gene tended to have more sons than daughters. Eriksson et al. (1967) studied 42 sibships and obtained an SSR value of 138. The designation of carrier status was based on information from pedigrees, that is, the carrier had either an affected father or an affected son. To investigate the matter further, Huopaniemi et al. (1999) performed mutation analyses to determine the carrier status of 202 females belonging to families with the Western I mutation (glu72 to lys; 300839.0003), the most common RS founder mutation in Finland, and analyzed the SSR of the offspring of 149 carrier females. The SSR in the offspring of the 149 carriers was 129.8, which differed significantly from that of the Finnish population (SSR = 106) but not from that of 53 noncarrier females belonging to the same pedigree (SSR = 116.7). Since possible causes for the skewed SSR include factors affecting fertilization, implantation, and embryonic deaths, Huopaniemi et al. (1999) searched for expression for the RS1 gene in various placental and uterine cells and found that, in addition to the retina, RS1 is expressed in the uterus. They hypothesized that the RS1 protein has a role in implantation or embryonic survival.
The predicted RS1 protein sequence contains a highly conserved discoidin domain, shared with a number of other proteins (Sauer et al., 1997; Springer et al., 1984). The Retinoschisis Consortium (1998) commented that the discoidin domain is implicated in cell-cell adhesion and phospholipid binding, a function that is in agreement with the observed splitting of the retina in retinoschisis patients, indicating that the RS gene is important during retinal development.
Grayson et al. (2000) generated a polyclonal antibody against a peptide from a unique region within retinoschisin. A screen of human tissues with this antibody revealed retinoschisin to be retina-specific. Using in situ hybridization and immunohistochemistry, they showed that the gene is expressed only in the photoreceptor layer, but the protein product is present both in the photoreceptors and within the inner portions of the retina. Furthermore, differentiated retinoblastoma cells (Weri-Rb1 cells) express RS1 mRNA and release retinoschisin. The authors suggested that retinoschisin is released by photoreceptors, has functions within the inner retinal layers, and that X-linked retinoschisis may be caused by abnormalities in a putative secreted photoreceptor protein.
Sauer et al. (1997) performed mutation analyses of XLRS1 in affected individuals from 9 unrelated X-linked retinoschisis (RS1; 312700) families and identified 1 nonsense, 1 frameshift, 1 splice acceptor, and 6 missense mutations (e.g., 300839.0001) segregating with the disease phenotype in the respective families.
In 60 XLRS patients who shared 27 missense mutations in RS1, Sergeev et al. (2010) evaluated possible correlations of the molecular modeling with retinal function as determined by the electroretinogram (ERG) a- and b-waves. The b/a-wave ratio reflects visual-signal transfer in retina. The majority of RS1 mutations caused minimal structural perturbations and targeted the protein surface. Maximum structural perturbations from either the removal or insertion of cysteine residues or changes in the hydrophobic core were associated with greater difference in the b/a-wave ratio with age, with a significantly smaller ratio at younger ages. The molecular modeling suggested an association between the predicted structural alteration and/or damage to retinoschisin and the severity of XLRS as measured by the ERG analogous to the RS1-knockout mouse.
For a complete discussion of the molecular genetics of this form of retinoschisis, see 312700.
Liu et al. (2019) found that Rs1-knockout mice and 2 mouse models with missense mutations in Rs1 associated with XLRS in humans developed intraretinal schisis and reductions in ERG that were greater for the b-wave than the a-wave, recapitulating key features of human XLRS. However, the severity of the disease phenotype was genotype dependent. All 3 mouse models also had elevated patterns of spontaneous activity, resulting in disrupted detection of visual stimuli. Immunohistochemical analysis showed early abnormalities in all cells of the outer retina in all 3 mouse models.
In affected members of a family with X-linked juvenile retinoschisis (RS1; 312700), Sauer et al. (1997) identified a T-to-C transition that changed codon 96 from TGG (trp) to CGG (arg) (W96R) in the XLRS1 gene. The family contained 6 affected males and 4 heterozygous carriers in 4 generations.
In a family with X-linked juvenile retinoschisis (RS1; 312700), Sauer et al. (1997) identified a C-to-T transition in codon 102 of the XLRS1 gene, changing it from CGG (arg) to TGG (trp) (R102W).
In a mutation screen of the RS gene in 234 familial and sporadic retinoschisis cases, the Retinoschisis Consortium (1998) identified a G-to-A change at nucleotide 214, predicting a glu72-to-lys (E72K) mutation, in 34 cases (RS1; 312700). This mutation was found in patients from all 6 populations studied but not in corresponding controls. Since the mutation occurred on at least 3 different haplotypes in the Dutch population, the authors concluded that it had several independent origins and was very likely to be disease-causing.
In 2 of 234 familial and sporadic retinoschisis cases (RS1; 312700), the Retinoschisis Consortium (1998) identified a G-to-C change at nucleotide 216 of the RS1 gene, predicting a glu72-to-asp mutation (E72D) in the same codon as that involved in the glu72-to-lys mutation (E72K; 300839.0003).
Huopaniemi et al. (1999) found that the founder mutations glu72 to lys (E72K; 300839.0003) and gly74 to val (G74V) in the XLRS1 gene account for RS (RS1; 312700) in western Finland.
Huopaniemi et al. (1999) found that the founder mutation gly109 to arg (G109R) in the XLRS1 gene gives rise to RS (RS1; 312700) in northern Finland.
In a patient with X-linked juvenile retinoschisis (RS1; 312700), Hiriyanna et al. (1999) found a T-to-C transition at nucleotide 38 of the RS1 gene, resulting in a leu13-to-pro (L13P) amino acid change. This missense mutation was in the predicted signal peptide of the protein, encoded by exons 1 and 2, and was expected to disrupt the folding of the signal peptide domain.
In a patient with X-linked juvenile retinoschisis (RS1; 312700), Hiriyanna et al. (1999) found a T-to-C transition at nucleotide 667 of the RS1 gene, resulting in the conversion of cysteine-223, on the C-terminal side of the discoidin domain, to arginine (C223R).
Hiraoka et al. (2000) screened 6 sporadic cases of retinoschisis for mutations in the RS1 gene. They found a mutation in only 1 family (RS1; 312700): a 4-bp insertion at codon 55, resulting in 9 aberrant amino acid residues. The unaffected mother did not carry this mutation.
In a Greek family with retinoschisis (RS1; 312700), Gehrig et al. (1999) reported a C-to-T transition at nucleotide 608 of the RS1 gene resulting in the substitution of a leucine residue for a proline at position 203 (P203L) in the discoidin domain.
In a 5-year-old girl with X-linked retinoschisis (RS1; 312700), Saldana et al. (2007) identified a heterozygous mutation in the RS1 gene, resulting in an arg102-to-gln (R102Q) substitution in the discoidin domain likely to interfere with retinoschisin secretion. She had retinal pigmentary epithelial changes in both maculae and bilateral peripheral schisis associated with bridging vessels and vitreous veils. X-inactivation studies were uninformative. Her father, who also had the mutation, had a longstanding history of poor vision and ocular features consistent with retinoschisis. The same codon is affected in another family with the disorder (R102W; 300839.0002).
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Gehrig, A., Weber, B. H. F., Lorenz, B., Andrassi, M. First molecular evidence for a de novo mutation in RS1 (XLRS1) associated with X-linked juvenile retinoschisis. J. Med. Genet. 36: 932-934, 1999. [PubMed: 10636740]
Grayson, C., Reid, S. N. M., Ellis, J. A., Rutherford, A., Sowden, J. C., Yates, J. R. W., Farber, D. B., Trump, D. Retinoschisin, the X-linked retinoschisis protein, is a secreted photoreceptor protein, and is expressed and released by Weri-Rb1 cells. Hum. Molec. Genet. 9: 1873-1879, 2000. [PubMed: 10915776] [Full Text: https://doi.org/10.1093/hmg/9.12.1873]
Hiraoka, M., Trese, M. T., Shastry, B. S. X-linked juvenile retinoschisis associated with a 4-base pair insertion at codon 55 of the XLRS1 gene. Biochem. Biophys. Res. Commun. 268: 370-372, 2000. [PubMed: 10679210] [Full Text: https://doi.org/10.1006/bbrc.2000.2133]
Hiriyanna, K. T., Bingham, E. L., Yashar, B. M., Ayyagari, R., Fishman, G., Small, K. W., Weinberg, D. V., Weleber, R. G., Lewis, R. A., Andreasson, S., Richards, J. E., Sieving, P. A. Novel mutations in XLRS1 causing retinoschisis, including first evidence of putative leader sequence change. Hum. Mutat. 14: 423-427, 1999. [PubMed: 10533068] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(199911)14:5<423::AID-HUMU8>3.0.CO;2-D]
Huopaniemi, L., Fellman, J., Rantala, A., Eriksson, A., Forsius, H., de la Chapelle, A., Alitalo, T. Skewed secondary sex ratio in the offspring of carriers of the 214G-A mutation of the RS1 gene. Ann. Hum. Genet. 63: 521-533, 1999. [PubMed: 11246454] [Full Text: https://doi.org/10.1017/S0003480099007812]
Huopaniemi, L., Rantala, A., Forsius, H., Somer, M., de la Chapelle, A., Alitalo, T. Three widespread founder mutations contribute to high incidence of X-linked juvenile retinoschisis in Finland. Europ. J. Hum. Genet. 7: 368-376, 1999. [PubMed: 10234514] [Full Text: https://doi.org/10.1038/sj.ejhg.5200300]
Liu, Y., Kinoshita, J., Ivanova, E., Sun, D., Li, H., Liao, T., Cao, J., Bell, B. A., Wang, J. M., Tang, Y., Brydges, S., Peachey, N. S., Sagdullaev, B. T., Romano, C. Mouse models of X-linked juvenile retinoschisis have an early onset phenotype, the severity of which varies with genotype. Hum. Molec. Genet. 28: 3072-3090, 2019. [PubMed: 31174210] [Full Text: https://doi.org/10.1093/hmg/ddz122]
Retinoschisis Consortium. Functional implications of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis (XLRS). Hum. Molec. Genet. 7: 1185-1192, 1998. [PubMed: 9618178] [Full Text: https://doi.org/10.1093/hmg/7.7.1185]
Saldana, M., Thompson, J., Monk, E., Trump, D., Long, V., Sheridan, E. X-linked retinoschisis in a female with a heterozygous RS1 missense mutation. (Letter) Am. J. Med. Genet. 143A: 608-609, 2007. [PubMed: 17304551] [Full Text: https://doi.org/10.1002/ajmg.a.31568]
Sauer, C. G., Gehrig, A., Warneke-Wittstock, R., Marquardt, A., Ewing, C. C., Gibson, A., Lorenz, B., Jurklies, B., Weber, B. H. F. Positional cloning of the gene associated with X-linked juvenile retinoschisis. Nature Genet. 17: 164-170, 1997. [PubMed: 9326935] [Full Text: https://doi.org/10.1038/ng1097-164]
Sergeev, Y. V., Caruso, R. C., Meltzer, M. R., Smaoui, N., MacDonald, I. M., Sieving, P. A. Molecular modeling of retinoschisin with functional analysis of pathogenic mutations from human X-linked retinoschisis. Hum. Molec. Genet. 19: 1302-1313, 2010. [PubMed: 20061330] [Full Text: https://doi.org/10.1093/hmg/ddq006]
Sikkink, S. K., Biswas, S., Parry, N. R. A., Stanga, P. E., Trump, D. X-linked retinoschisis: an update. J. Med. Genet. 44: 225-232, 2007. [PubMed: 17172462] [Full Text: https://doi.org/10.1136/jmg.2006.047340]
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