Alternative titles; symbols
HGNC Approved Gene Symbol: IQCB1
Cytogenetic location: 3q13.33 Genomic coordinates (GRCh38) : 3:121,769,761-121,835,060 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q13.33 | Senior-Loken syndrome 5 | 609254 | Autosomal recessive | 3 |
By sequencing clones obtained from an immature myeloid cell line cDNA library, Nomura et al. (1994) cloned IQCB1, which they designated KIAA0036. The deduced 598-amino acid protein contains a tyrosine phosphorylation site. Northern blot analysis detected high IQCB1 expression in lung and testis, intermediate expression in brain, skeletal muscle, and kidney, and low expression in placenta, liver, spleen, thymus, prostate, ovary, small intestine, colon, and peripheral blood leukocytes. No expression was detected in pancreas.
Using RT-PCR, Otto et al. (2005) obtained a full-length cDNA encoding human IQCB1, which they also called NPHP5. The deduced 598-amino acid protein has a calculated molecular mass of 69 kD. It contains a central coiled-coil region and 2 IQ calmodulin (see CALM1; 114180)-binding regions. Northern blot analysis detected a primary IQCB1 transcript of 2.6 kb that was ubiquitously expressed in human tissues. RNA dot blot analysis confirmed ubiquitous expression in human adult and fetal tissues. In situ hybridization showed ubiquitous but weak expression of Iqcb1 during mouse embryonic development. Immunoblot analysis detected a 55-kD protein in extracts of mouse and human retina and mouse kidney.
By subtractive hybridization to identify stress-regulated genes, Luo et al. (2005) cloned 2 PIQ splice variants, PIQ-L and PIQ-S, that encode proteins with calculated molecular masses of 69.0 and 53.8 kD, respectively. PIQ-L uses all 15 exons, whereas PIQ-S lacks exons 8, 9, and 10. PIQ-L transcripts were more abundant than PIQ-S transcripts in placenta and human cancer cell line cDNA libraries. Northern blot analysis detected highest PIQ expression in testis, with lower expression in other tissues examined.
Otto et al. (2005) determined that the IQCB1 gene spans about 65.7 kb and contains 15 exons. Exons 1 and 2 are not translated.
By genomic sequence analysis, Otto et al. (2005) mapped the IQCB1 gene to chromosome 3q21.1.
Gross (2018) mapped the IQCB1 gene to chromosome 3q13.33 based on an alignment of the IQCB1 sequence (GenBank BC005806) with the genomic sequence (GRCh38).
By yeast 2-hybrid analysis, Otto et al. (2005) showed that IQCB1 interacted with calmodulin. Coimmunoprecipitation analysis revealed that IQCB1, retinitis pigmentosa GTPase regulator (RPGR; 312610), and calmodulin were present in a multiprotein complex in bovine retina. Confocal laser microscopy, immunofluorescence, and immunogold labeling localized IQCB1, RPGR, and calmodulin to connecting cilia of photoreceptors and to primary cilia of renal epithelial cells. Because primary cilia of renal epithelial cells and connecting cilia of photoreceptors are homologous subcellular structures, Otto et al. (2005) proposed that IQCB1 and RPGR may participate in a common pathway of ciliary function.
By subtractive hybridization, Luo et al. (2005) found that PIQ expression was downregulated by p53 (TP53; 191170) and genotoxic stress in human cell lines. In a reporter gene assay, p53 downregulated PIQ promoter activity in a dose-dependent manner. PIQ repressed expression of PUMA (BBC3; 605854), a gene regulated by p53 and by calcium-mobilizing agents. Both PIQ-L and PIQ-S interacted with calcium-bound and calcium-free calmodulin. Luo et al. (2005) concluded that PIQ may bridge signaling between p53 and calmodulin-regulated cellular processes.
One in 10 individuals with nephronophthisis (NPHP; 256100) also have retinitis pigmentosa, constituting Senior-Loken syndrome (SLSN; 266900). Otto et al. (2005) identified 8 different mutations in the IQCB1 gene (see, e.g., 609237.0001-609237.0005) in patients with Senior-Loken syndrome mapping to chromosome 3q21.1 (SLSN5; 609254). 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) analyzed the IQCB1 gene and 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, respectively, had developed severe renal disease, and another patient had an elevated creatinine level at 19 years of age.
In 11 patients with LCA, 7 of whom had already developed renal failure, Estrada-Cuzcano et al. (2011) identified homozygosity or compound heterozygosity for mutations in the IQCB1 gene (see, e.g., 609237.0001 and 609237.0002).
Schafer et al. (2008) found that depletion of either Nphp5 or Nphp6 (CEP290; 610142) in zebrafish embryos caused almost identical abnormalities, including hydrocephalus, developmental eye defects, and pronephric cysts. Combined knockdown of Nphp5 and Nphp6 synergistically augmented these phenotypes. Nphp5 directly bound Nphp6 in vitro. Expression of the Nphp5-binding domain of Nphp6 inhibited neural tube closure during early Xenopus embryogenesis, and a similar phenotype was observed after knockdown of Nphp5 in Xenopus oocytes.
In affected members of a consanguineous Turkish family with Senior-Loken syndrome-5 (SLSN5; 609254), Otto et al. (2005) identified a homozygous C-to-T transition at nucleotide 1381 in exon 13 of the IQCB1 gene, resulting in an arg461-to-ter (R461X) substitution.
In 5 patients with early-onset retinal dystrophy diagnosed as Leber congenital amaurosis (LCA; see 204000), 2 of whom also had severe renal disease, Stone et al. (2011) identified 1 patient with homozygosity for the R461X mutation and 4 patients with compound heterozygosity for the R461X mutation and another IQCB1 mutation. A 14-year-old girl who had been diagnosed with LCA but had no manifestations of renal disease was homozygous for the R461X mutation. A 23-year-old woman with LCA who developed severe renal disease by 13 years of age was compound heterozygous for R461X and a 1-bp del (333delT; 609237.0006) in the IQCB1 gene. A 1-year-old girl and a 13-year-old boy were compound heterozygous for R461X and a 2-bp deletion (1516_1517delCA; 609237.0007) in the IQCB1 gene; both had been diagnosed with LCA, but neither had developed signs of renal disease. A 14-year-old boy with LCA who manifested severe renal disease by 13 years of age was compound heterozygous for R461X and a 1465C-T transition in the IQCB1 gene, resulting in an arg489-to-ter (R489X; 609237.0008) substitution.
In a Puerto Rican father and 2 daughters diagnosed with LCA, Estrada-Cuzcano et al. (2011) identified homozygosity for the R461X mutation in the IQCB1 gene. Reevaluation of the patients' renal function revealed that all 3 had nephronophthisis: the 37-year-old father had undergone renal transplantation at age 24, the 16-year-old daughter had been on dialysis since age 13, and the 12-year-old daughter had undergone renal transplantation at 9 years of age.
In affected members of 2 German families and 2 Swiss families with Senior-Loken syndrome-5 (SLSN5; 609254), Otto et al. (2005) identified a homozygous 2-bp deletion (TT) at nucleotide 424 in exon 6 of the IQCB1 gene, resulting in a frameshift and premature termination.
In a woman with Leber congenital amaurosis (LCA), Estrada-Cuzcano et al. (2011) identified homozygosity for the 424delTT mutation in the IQCB1 gene. At 34 years of age, she retained normal kidney function.
In an individual from a German family with Senior-Loken syndrome-5 (SLSN5; 609254), Otto et al. (2005) identified a homozygous 4-bp deletion (CTCT) at nucleotide 445 in exon 6 of the IQCB1 gene, resulting in a frameshift and premature termination. An individual from another German family with SLSN5 was compound heterozygous for this 4-bp deletion and a second IQCB1 mutation, another 4-bp deletion (609237.0004).
In a German family with Senior-Loken syndrome-5 (SLSN5; 609254), Otto et al. (2005) identified a 4-bp deletion (ACAG) at nucleotide 825 in exon 9 of the IQCB1 gene, resulting in a frameshift and premature termination, in compound heterozygous state with a second 4-bp deletion (609237.0003). In another German family with SLSN5 they identified this mutation in compound heterozygous state with a C-to-T transition at nucleotide 1069 in exon 11 of the IQCB1 gene, resulting in a gln357-to-ter mutation (Q357X; 609237.0005).
For discussion of the gln357-to-ter (Q357X) mutation in the IQCB1 gene that was found in compound heterozygous state in patients with Senior-Loken syndrome-5 (SLSN5; 609254) by Otto et al. (2005), see 609237.0004.
For discussion of the 1-bp deletion in the IQCB1 gene (333delT) that was found in compound heterozygous state in a patient diagnosed with Leber congenital amaurosis (LCA; see 204000) by Stone et al. (2011), see 609237.0001.
In 5 patients with early-onset retinal dystrophy diagnosed as Leber congenital amaurosis (LCA; see 204000), 1 of whom had an elevated creatinine level, Stone et al. (2011) identified homozygosity for a 2-bp deletion (1516delCA) in the IQCB1 gene or compound heterozygosity for 1516delCA and another IQCB1 mutation. Two of the patients were compound heterozygous for 1516delCA and the R461X mutation (609237.0001). A 7-year-old boy was homozygous for 1516delCA; he had been diagnosed with LCA but had no manifestations of renal disease. A 5-year-old boy with LCA and no manifestations of renal disease was compound heterozygous for 1516delCA and the R489X mutation (609237.0008) in the IQCB1 gene. A 19-year-old woman with LCA and an elevated creatinine level was compound heterozygous for 1516delCA and a 1036G-T transversion in the IQCB1 gene, resulting in a glu346-to-ter (E346X; 609237.0009) substitution.
For discussion of the arg489-to-ter (R489X) mutation in the IQCB1 gene that was found in compound heterozygous state in patients with Senior-Loken syndrome (SLSN5; 609254) by Stone et al. (2011), see 609237.0001 and 609237.0007.
For discussion of the glu346-to-ter (E346X) mutation in the IQCB1 gene that was found in compound heterozygous state in a patient diagnosed with Leber congenital amaurosis (LCA; see 204000) by Stone et al. (2011), see 609237.0007.
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]
Gross, M. B. Personal Communication. Baltimore, Md. 1/17/2018.
Luo, X., He, Q., Huang, Y., Sheikh, M. S. Cloning and characterization of a p53 and DNA damage down-regulated gene PIQ that codes for a novel calmodulin-binding IQ motif protein and is up-regulated in gastrointestinal cancers. Cancer Res. 65: 10725-10733, 2005. [PubMed: 16322217] [Full Text: https://doi.org/10.1158/0008-5472.CAN-05-1132]
Nomura, N., Miyajima, N., Sazuka, T., Tanaka, A., Kawarabayashi, Y., Sato, S., Nagase, T., Seki, N., Ishikawa, K., Tabata, S. Prediction of the coding sequences of unidentified human genes. I. The coding sequences of 40 new genes (KIAA0001-KIAA0040) deduced by analysis of randomly sampled cDNA clones from human immature myeloid cell line, KG-1. DNA Res. 1: 27-35, 1994. Note: Erratum: DNA Res. 2: 210 only, 1995. [PubMed: 7584026] [Full Text: https://doi.org/10.1093/dnares/1.1.27]
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]
Schafer, T., Putz, M., Lienkamp, S., Ganner, A., Bergbreiter, A., Ramachandran, H., Gieloff, V., Gerner, M., Mattonet, C., Czarnecki, P. G., Sayer, J. A., Otto, E. A., Hildebrandt, F., Kramer-Zucker, A., Walz, G. Genetic and physical interaction between the NPHP5 and NPHP6 gene products. Hum. Molec. Genet. 17: 3655-3662, 2008. Note: Erratum: Hum. Molec. Genet. 18: 4226 only, 2009. [PubMed: 18723859] [Full Text: https://doi.org/10.1093/hmg/ddn260]
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]