ORPHA: 3156; DO: 0050576;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q13.33 | Senior-Loken syndrome 5 | 609254 | Autosomal recessive | 3 | IQCB1 | 609237 |
A number sign (#) is used with this entry because Senior-Loken syndrome-5 (SLSN5) is caused by homozygous or compound heterozygous mutation in the IQCB1 gene (609237) on chromosome 3q13.
Senior-Loken syndrome is an autosomal recessive disorder with the main features of nephronophthisis (NPHP; see 256100) and Leber congenital amaurosis (LCA; see 204000).
For a general phenotypic description and a discussion of genetic heterogeneity of Senior-Loken syndrome, see 266900.
Otto et al. (2005) identified a cohort of unrelated individuals with nephronophthisis, 435 with isolated kidney involvement and 92 with SLSN. In this cohort, recessive mutations in NPHP1 (607100), NPHP2 (INVS; 243305), NPHP3 (608002), or NPHP4 (607215) had been detected in 151 of 435 individuals with NPHP (35%) and in 19 of 92 individuals with SLSN (21%). To identify additional genes causing NPHP and SLSN, Otto et al. (2005) carried out a genomewide screen in a consanguineous Turkish kindred in which linkage to known NPHP loci had been excluded. They obtained a significant maximum lod score of 3.458 at marker D3S1267 on chromosome 3q21.1.
By haplotype analysis, Otto et al. (2005) refined the critical genetic region for SLSN5 to an 8.7-Mb interval containing the IQCB1 gene. They identified 8 different mutations in the IQCB1 gene in patients with SLSN, including an arg461-to-ter mutation (R461X; 609237.0001) in the Turkish family in which the SLSN5 locus was mapped. 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.
In a cohort of 276 individuals diagnosed with an early-onset form of retinal dystrophy designated Leber congenital amaurosis (LCA; see 204000) who were negative for mutation in 8 known LCA genes, Stone et al. (2011) identified homozygosity or compound heterozygosity for frameshift or nonsense IQCB1 mutations in 9 patients (see, e.g., 609237.0001 and 609237.0006-609237.0008). None of the patients had overt renal disease in the first decade of life, but 2 of the oldest patients, aged 23 and 14 years, had developed severe renal disease, and another patient had an elevated creatinine level at 19 years of age. Stone et al. (2011) suggested that patients with molecularly uncharacterized LCA should be screened for mutations in the NPHP5 (IQCB1) and NPHP6 (CEP290; 610142) genes, because a subset of patients without current evidence of kidney disease may harbor mutations in these genes and should be followed by nephrologists familiar with inherited renal disease.
In a cohort of more than 150 unrelated LCA patients who were negative for mutation in known LCA-associated genes, Estrada-Cuzcano et al. (2011) identified 3 patients with large homozygous regions encompassing the IQCB1 gene. Direct sequencing of IQCB1 coding exons in these 3 patients revealed homozygosity for a 2-bp deletion (609237.0002) and a 2-bp duplication in 2 of the patients, respectively; both mutations had previously been identified in patients diagnosed with Senior-Loken syndrome (Otto et al., 2005). Analysis of IQCB1 in 222 additional LCA patients revealed frameshift and nonsense mutations in 9 more patients from 7 families (see, e.g., 609237.0001). Reevaluation of renal function in the 11 mutation-positive patients led to the diagnosis of SLSN in 7 of them, in whom nephronophthisis developed between the ages of 3 years and 50 years. The remaining 4 patients, whose mutations had all previously been identified in SLSN patients, retained normal kidney function at ages 3, 8, 15, and 34 years, respectively. Estrada-Cuzcano et al. (2011) concluded that IQCB1 represented a new gene for LCA, but noted that the patients were at high risk for developing renal failure.
In the probands from 2 consanguineous Saudi Arabian families with LCA, who were known to be negative for mutation in known LCA-associated genes, Wang et al. (2011) identified homozygosity for a splice site mutation in the IQCB1 gene. One of the probands also displayed midface hypoplasia and psychomotor delay; in that patient, the authors noted that rare variants were also found in the ACAT1 (607809) and FGFR2 (176943) genes, which had been associated with psychomotor delay and midface hypoplasia, respectively. In addition, homozygosity for a nonsense mutation in IQCB1 was identified in the proband from a third Saudi Arabian LCA family. The mutations segregated with disease in each family and were not found in 200 matching controls or in the dbSNP (build 130) or 1000 Genomes Project databases. Wang et al. (2011) stated that no kidney defects were observed at the time of diagnosis of LCA in these patients.
Estrada-Cuzcano, A., Koenekoop, R. K., Coppieters, F., Kohl, S., Lopez, I., Collin, R. W. J., De Baere, E. B. W., Roeleveld, D., Marek, J., Bernd, A., Rohrschneider, K., van den Born, L. I., Meire, F., Maumenee, I. H., Jacobson, S. G., Hoyng, C. B., Zrenner, E., Cremers, F. P. M., den Hollander, A. I. IQCB1 mutations in patients with Leber congenital amaurosis. Invest. Ophthal. Vis. Sci. 52: 834-839, 2011. [PubMed: 20881296] [Full Text: https://doi.org/10.1167/iovs.10-5221]
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]
Stone, E. M., Cideciyan, A. V., Aleman, T. S., Scheetz, T. E., Sumaroka, A., Ehlinger, M. A., Schwartz, S. B., Fishman, G. A., Traboulsi, E. I., Lam, B. L., Fulton, A. B., Mullins, R. F., Sheffield, V. C., Jacobson, S. G. Variations in NPHP5 in patients with nonsyndromic Leber congenital amaurosis and Senior-Loken syndrome. Arch. Ophthal. 129: 81-87, 2011. [PubMed: 21220633] [Full Text: https://doi.org/10.1001/archophthalmol.2010.330]
Wang, X., Wang, H., Cao, M., Li, Z., Chen, X., Patenia, C., Gore, A., Abboud, E. B., Al-Rajhi, A. A., Lewis, R. A., Lupski, J. R., Mardon, G., Zhang, K., Muzny, D., Gibbs, R. A., Chen, R. Whole-exome sequencing identifies ALMS1, IQCB1, CNGA3, and MYO7A mutations in patients with Leber congenital amaurosis. Hum. Mutat. 32: 1450-1459, 2011. [PubMed: 21901789] [Full Text: https://doi.org/10.1002/humu.21587]