Alternative titles; symbols
SNOMEDCT: 236531005; ORPHA: 3156; DO: 0050576;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q13 | Senior-Loken syndrome-1 | 266900 | Autosomal recessive | 3 | NPHP1 | 607100 |
A number sign (#) is used with this entry because of evidence that Senior-Loken syndrome-1 (SLSN1) is caused by homozygous mutation in the NPHP1 gene (607100) on chromosome 2q13.
Senior-Loken syndrome is an autosomal recessive disease with the main features of nephronophthisis (NPHP; see 256100) and Leber congenital amaurosis (see 204000). Mutations in some of the same genes that cause nephronophthisis (see 256100) cause Senior-Loken syndrome.
Genetic Heterogeneity of Senior-Loken Syndrome
Other forms of SLSN include SLSN4 (606996), caused by mutation in the NPHP4 gene (607215) on chromosome 1p36; SLSN5 (609254), caused by mutation in the NPHP5 gene (IQCB1; 609237) on chromosome 3q13; SLSN6 (610189), caused by mutation in the NPHP6 gene (CEP290; 610142) on chromosome 12q21; SLSN7 (613615), caused by mutation in the SDCCAG8 gene (613524) on chromosome 1q43; SLSN8 (616307), caused by mutation in the WDR19 gene (608151) on chromosome 4p14; and SLSN9 (616629), caused by mutation in the TRAF3IP1 gene (607380) on chromosome 2q37.
Another form of SLSN, SLSN3 (606995), has been mapped to a locus on chromosome 3q22, overlapping the NPHP3 locus (604387).
The symbols used for the first 3 identified forms of Senior-Loken syndrome were correlated with the original symbols used for proteins mutated in various forms of nephronophthisis (NPHP1-NPHP4). Because no form of SLSN had been found to be associated with the NPHP2 gene (now symbolized INVS, 243305), which is mutant in NPHP2 (602088), the symbol SLSN2 was left out of the series.
Loken et al. (1961) reported brother and sister with the main features of nephronophthisis and Leber congenital amaurosis. In the sister, renal dysplasia was proved at autopsy. Senior et al. (1961) and Fairley et al. (1963) also reported families with an oculorenal syndrome. In the former family the renal changes resembled those in Fanconi familial juvenile nephronophthisis (256100). In the latter family the renal change was similar to that in polycystic kidney.
In an Amish isolate, Schimke (1969) found 2 cousins with vasopressin-resistant diabetes insipidus, progressive azotemia, and retinitis pigmentosa. A more remotely related person may also have been affected. Despite some histologic similarities to juvenile nephronophthisis and to medullary cystic disease, Schimke (1969) concluded that the total clinicogenetic picture supported the view that this is a distinct entity.
Dekaban (1969) described 2 brothers with congenital retinal blindness and a developmental renal abnormality leading to uremia. Autopsy was performed in 1 of the patients who died at age 10 years.
The heterogeneity of the renal-retinal syndrome is indicated by the variable age of onset of the retinal abnormality. In some families it is congenital, whereas in others it behaves like isolated recessive retinitis pigmentosa. In connection with the longstanding association claimed between juvenile nephronophthisis, bone dysplasia, and retinitis pigmentosa, Mendley et al. (1995) expressed doubts concerning the rigor with which the renal diagnoses has been made in some patients.
Hogewind et al. (1977) found asymptomatic electroretinographic changes in some obligatory heterozygotes for renal-retinal dysplasia. Diekmann et al. (1977) described retinitis pigmentosa and nephronophthisis in 2 young sisters, one of whom died at age 7 years. Boichis et al. (1973), Proesmans et al. (1975), and Delaney et al. (1978) described the triad of nephronophthisis, retinal degeneration or hypoplasia, and congenital hepatic fibrosis. Whether this is a separate entity is not clear. Godel et al. (1979) reviewed the retinopathy in 3 families and emphasized its variability: congenital Leber amaurosis, retinitis pigmentosa, and sector retinitis pigmentosa.
Clarke et al. (1992) described a brother and sister, the products of a first-cousin marriage between parents of Asiatic Indian origin, who had nephronophthisis and retinal dystrophy associated with moderately severe sensorineural hearing loss bilaterally. Deafness had not previously been reported with the Senior-Loken syndrome; Clarke et al. (1992) suggested that this 'may represent a genetically linked condition.'
Warady et al. (1994) reported 2 sporadic cases: a girl in whom the diagnosis of Leber amaurosis had been made at 3 months of age, who had polyuria and polydipsia from the age of 4 years and who was found to have end-stage renal disease at age 11; and a 5.5-year-old boy with Dandy-Walker syndrome, Leber amaurosis, and mental retardation as well as longstanding polyuria and polydipsia.
The prevalence of nephronophthisis is estimated to be 1 in 100,000, with 1 in 10 affected individuals having retinal dysfunction, constituting Senior-Loken syndrome (summary by Otto et al., 2005).
Caridi et al. (1998) described Senior-Loken syndrome (SLSN1) in patients with homozygous deletion (607100.0005) of the NPHP1 gene.
Modifier Genes
Khanna et al. (2009) presented evidence that a common allele in the RPGRIP1L gene (A229T; 610937.0013) may be a modifier of retinal degeneration in patients with ciliopathies due to other mutations, including SLSN.
Antignac et al. (1993) demonstrated linkage of nephronophthisis to a region on chromosome 2p (NPHP1; 256100) but excluded linkage of Senior-Loken syndrome from this region. They suggested that there may be genetic heterogeneity between nephronophthisis and Senior-Loken syndrome.
Omran et al. (2002) identified a gene locus for Senior-Loken syndrome on chromosome 3q21-q22 (SLSN3; 606995), in the region of the NPHP3 locus (604387).
Schuermann et al. (2002) identified a Senior-Loken syndrome locus on 1p36.31 (SLSN4; 606996), overlapping the NPHP4 locus (606996). In patients with Senior-Loken syndrome mapping to chromosome 1p36, Otto et al. (2002) identified mutations in the NPHP4 gene (607215).
Otto et al. (2005) refined the critical genetic region for SLSN5 to an 8.7-Mb interval containing the IQCB1 gene on chromosome 3q21.1. They identified 8 different mutations in the IQCB1 gene in patients with SLSN (e.g., 609237.0001). All individuals with IQCB1 mutations had retinitis pigmentosa, and Otto et al. (2005) concluded that mutation in IQCB1 is the most frequent cause of SLSN.
Antignac, C., Arduy, C. H., Beckmann, J. S., Benessy, F., Gros, F., Medhioub, M., Hildebrandt, F., Dufier, J.-L., Kleinknecht, C., Broyer, M., Weissenbach, J., Habib, R., Cohen, D. A gene for familial juvenile nephronophthisis (recessive medullary cystic kidney disease) maps to chromosome 2p. Nature Genet. 3: 342-345, 1993. [PubMed: 7981755] [Full Text: https://doi.org/10.1038/ng0493-342]
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Caridi, G., Murer, L., Bellantuono, R., Sorino, P., Caringella, D. A., Gusmano, R., Ghiggeri, G. M. Renal-retinal syndromes: association of retinal anomalies and recessive nephronophthisis in patients with homozygous deletion of the NPH1 locus. Am. J. Kidney Dis. 32: 1059-1062, 1998. [PubMed: 9856524] [Full Text: https://doi.org/10.1016/s0272-6386(98)70083-6]
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Khanna, H., Davis, E. E., Murga-Zamalloa, C. A., Estrada-Cuzcano, A., Lopez, I., den Hollander, A. I., Zonneveld, M. N., Othman, M. I., Waseem, N., Chakarova, C. F., Maubaret, C., Diaz-Font, A., and 22 others. A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies. (Letter) Nature Genet. 41: 739-745, 2009. [PubMed: 19430481] [Full Text: https://doi.org/10.1038/ng.366]
Loken, A. C., Hanssen, O., Halvorsen, S., Jolster, N. J. Hereditary renal dysplasia and blindness. Acta Paediat. (Stockh.) 50: 177-184, 1961. [PubMed: 13763238] [Full Text: https://doi.org/10.1111/j.1651-2227.1961.tb08037.x]
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Omran, H., Sasmaz, G., Haffner, K., Volz, A., Olbrich, H., Melkaoui, R., Otto, E., Wienker, T. F., Korinthenberg, R., Brandis, M., Antignac, C., Hildebrandt, F. Identification of a gene locus for Senior-Loken syndrome in the region of the nephronophthisis type 3 gene. J. Am. Soc. Nephrol. 13: 75-79, 2002. [PubMed: 11752023] [Full Text: https://doi.org/10.1681/ASN.V13175]
Otto, E. A., Loeys, B., Khanna, H., Hellemans, J., Sudbrak, R., Fan, S., Muerb, U., O'Toole, J. F., Helou, J., Attanasio, M., Utsch, B., Sayer, J. A., and 21 others. Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. Nature Genet. 37: 282-288, 2005. [PubMed: 15723066] [Full Text: https://doi.org/10.1038/ng1520]
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Schuermann, M. J., Otto, E., Becker, A., Saar, K., Ruschendorf, F., Polak, B. C., Ala-Mello, S., Hoefele, J., Wiedensohler, A., Haller, M., Omran, H., Nurnberg, P., Hildebrandt, F. Mapping of gene loci for nephronophthisis type 4 and Senior-Loken syndrome, to chromosome 1p36. Am. J. Hum. Genet. 70: 1240-1246, 2002. [PubMed: 11920287] [Full Text: https://doi.org/10.1086/340317]
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