HGNC Approved Gene Symbol: AIPL1
Cytogenetic location: 17p13.2 Genomic coordinates (GRCh38) : 17:6,423,738-6,435,121 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17p13.2 | Cone-rod dystrophy | 604393 | Autosomal dominant; Autosomal recessive | 3 |
| Leber congenital amaurosis 4 | 604393 | Autosomal dominant; Autosomal recessive | 3 | |
| Retinitis pigmentosa, juvenile | 604393 | Autosomal dominant; Autosomal recessive | 3 |
Sohocki et al. (1999) mapped sequence tagged sites (STSs) designed to the retinal/pineal-expressed EST clusters to 17p13.3 near a retinitis pigmentosa (RP13; 600059) candidate region. Further testing refined the localization to 17p13.1, within the candidate region for Leber congenital amaurosis-4 (LCA4; 604393) and approximately 2.5 Mb distal to GUCY2D (600179), which is mutant in LCA1 (204000). Sohocki et al. (2000) confirmed this localization by fluorescence in situ hybridization. The results were consistent with the placement of AIPL1 in the Stanford G3 radiation hybrid panel. By cDNA sequencing of the 2 clusters, they determined that the ESTs represented transcripts of 1 gene. The protein encoded by this gene was named 'arylhydrocarbon receptor interacting protein-like 1' because of its similarity to arylhydrocarbon receptor-interacting protein (AIP), a member of the FK506-binding protein (FABP) family. The predicted 384-amino acid protein contains 3 tetratricopeptide motifs and a 56-amino acid proline-rich 'hinge' region near the C terminus that is present only in primate AIPL1. Northern blot hybridization identified mRNA molecules of the predicted size in total retinal RNA. The probe also cross-hybridized to 18s rRNA in the retina. In situ hybridization indicated expression in rat and mouse pineal gland, a high level of expression in adult mouse photoreceptors, and no expression in cornea.
Sohocki et al. (1999) identified the AIPL1 gene on chromosome 17p13.1, within the candidate region for LCA4.
Using a polyclonal antibody directed against AIPL1, van der Spuy et al. (2002) screened human tissues and immortalized cell lines and revealed AIPL1 to be specific to human retina and cell lines of retinal origin (Y79 retinoblastoma cells). Within the retina, AIPL1 was detected only in the rod photoreceptor cells of the peripheral and central human retina. The AIPL1 staining pattern extended within the rod photoreceptor cells from the inner segments, through the rod nuclei to the rod photoreceptor synaptic spherules in the outer plexiform layer. AIPL1 was not detected in the cone photoreceptors of peripheral or central human retina. The authors hypothesized that AIPL1 may perform a function essential to the maintenance of rod photoreceptor function.
Akey et al. (2002) performed a yeast 2-hybrid screen to identify AIPL1-interacting proteins in the retina. One of the identified interacting proteins corresponded to NEDD8 ultimate buster-1 (NUB1; 607981). The AIPL1-NUB1 interaction was verified by coimmunoprecipitation studies in retinoblastoma cells, demonstrating that this interaction occurred within cells that share a number of features with retinal progenitor cells. In situ hybridization studies showed that both AIPL1 and NUB1 are expressed in the developing and adult retina. The authors hypothesized that the early-onset form of retinal degeneration seen in LCA patients with AIPL1 mutations may be due to a defect in NUB1 regulation of cell cycle progression during photoreceptor maturation.
To understand the molecular basis of Leber congenital amaurosis caused by AIPL1 mutations, and to elucidate the normal function of AIPL1, Ramamurthy et al. (2003) performed a yeast 2-hybrid screen using AIPL1 as bait. The screen demonstrated that AIPL1 interacts specifically with farnesylated proteins. Mutations in AIPL1 linked to LCA compromise this activity. The findings suggest that the essential function of AIPL1 within photoreceptors requires interactions with farnesylated proteins. Analysis of isoprenylation in cultured human cells showed that AIPL1 enhances the processing of farnesylated proteins.
In a Pakistani family in which Leber congenital amaurosis associated with anterior keratoconus mapped to 17p13.1 (LCA4; 604393), but in a region distinct from that occupied by GUCY2D, the gene mutant in LCA1, Sohocki et al. (2000) demonstrated homozygosity for a nonsense mutation in the AIPL1 gene (W278X; 604392.0001). In addition, they identified homozygous or compound heterozygous mutations in the AIPL1 gene in 4 of 14 unrelated LCA families (see 604392.0002-604392.0003), and concluded that mutations in this gene may account for approximately 20% of recessive LCA.
To determine more generally the prevalence of AIPL1 mutations in inherited retinal degenerative disease, Sohocki et al. (2000) screened for mutations in 512 unrelated probands with a range of retinal degenerative diseases. They identified 11 Leber congenital amaurosis families whose retinal disorder was caused by homozygosity or compound heterozygosity for AIPL1 mutations. They also identified affected individuals in 2 apparently dominant families, diagnosed with juvenile retinitis pigmentosa (see 604393) or dominant cone-rod dystrophy (see 604393), respectively, who were heterozygous for a 12-bp deletion (604392.0004) in the AIPL1 gene. The results suggested that AIPL1 mutations cause approximately 7% of LCA worldwide and may cause dominant retinopathy.
To investigate the essential role of AIPL1 in the retina, Ramamurthy et al. (2004) generated a mouse model of Leber congenital amaurosis by inactivating the Aipl1 gene. In Aipl1 -/- retinas, the outer nuclear layer developed normally, but rods and cones then quickly degenerated. Aipl1-null mice had highly disorganized, short, fragmented photoreceptor outer segments and lacked both rod and cone electroretinogram responses. Other studies indicated that Aipl1 can enhance protein farnesylation. Their study showed that rod cGMP phosphodiesterase (PDE; see 180071), a farnesylated protein, is absent and that cGMP levels are elevated in Aipl1 -/- retinas before the onset of degeneration. These findings demonstrated that Aipl1 enhances the stability of PDE and is essential for photoreceptor viability.
Liu et al. (2004) showed that knockdown of Aipl1 expression in mice produces a retinopathy similar to that of Leber congenital amaurosis, but over a more extended time course. Before any noticeable pathology, there was a reduction in the level of rod cGMP PDE proportional to the decrease in Aipl1 expression, whereas other photoreceptor proteins were unaffected. Consistent with less PDE in rods, flash responses had a delayed onset, a reduced gain, and a slower recovery of flash responses. Liu et al. (2004) suggested that AIPL1 is a specialized chaperone required for rod PDE biosynthesis. Thus, loss of AIPL1 would result in a condition that mimics retinal degeneration in the rd mouse and in a subgroup of human patients.
Makino et al. (2006) investigated the impact of Aipl1 on photoreception in mouse rods. Reduced Aipl1 delayed the photoresponse, decreased its amplification constant, slowed a rate-limiting step in its recovery, and limited the light-induced decrease in calcium. Not all changes were attributable to decreased PDE or to elevated cGMP and calcium in darkness. Thus, Makino et al. (2006) concluded that AIPL1 directly or indirectly affects more than one component of phototransduction.
Tan et al. (2009) evaluated whether adeno-associated virus (AAV)-mediated gene replacement therapy was able to improve photoreceptor function and survival in retinal degeneration associated with AIPL1 defects. Two mouse models of AIPL1 deficiency were used: the Aipl1-hypomorphic (h/h) mouse (with reduced Aipl1 levels and a relatively slow degeneration), and the Aipl1-null mouse (with no functional Aipl1 and a very rapid retinal degeneration). Two pseudotypes of recombinant AAV exhibiting different transduction kinetics were used for gene transfer. The authors demonstrated restoration of cellular function and preservation of photoreceptor cells and retinal function in Aipl1 h/h mice 28 weeks after subretinal injection of an AAV2/2 vector and in the light-accelerated Aipl1 h/h model and Aipl1-null mice using an AAV2/8 vector. Tan et al. (2009) established the potential of gene replacement therapy in varying rates of degeneration that reflect the clinical spectrum of disease.
Kirschman et al. (2010) transgenically expressed human AIPL1 exclusively in the rod photoreceptors of the Aipl1 -/- mouse. Transgenic expression of AIPL1 restored rod morphology and the rod-derived electroretinogram response, but cone photoreceptors were nonfunctional in the absence of AIPL1. Cone photoreceptors degenerated, but at a slower rate compared with Aipl1 -/- mice. This degeneration was linked to the highly reduced levels of cone PDE6 (180071) observed in the AIPL1 transgenic mice. The authors concluded that AIPL1 is needed for the proper functioning and survival of cone photoreceptors. However, rod photoreceptors may also provide support that partially preserves cone photoreceptors from rapid death in the absence of AIPL1.
Ku et al. (2015) generated transgenic mice in which the endogenous Aipl1 gene was replaced by wildtype human AIPL1 or by human AIPL1 with the 12-bp in-frame deletion leading to deletion of 4 amino acids beginning at pro351 (P351del12; 604392.0004). Homozygous mice from both lines were normal, healthy, and fertile, with no gross morphologic abnormalities. However, P351del12 mice showed slow and progressive degeneration of cone photoreceptors compared with mice homozygous for wildtype human AIPL1. Electroretinography (ERG) analysis of P351del12 mice revealed drastically reduced photopic responses and reduced scotopic responses at an early age that were associated with decreased rod and cone phosphodiesterase-6 (see 180071). These visual defects worsened rapidly and progressively as mice aged. Transgenic mice coexpressing wildtype human AIPL1 and P351del12 exhibited visual defects similar to those of P351del12 mice, indicating that P351del12 acted as dominant for visual deficits over wildtype human AIPL1. However, P351del12 expression did not affect visual responses in mice also expressing endogenous wildtype mouse Aipl1, and AAV-mediated overexpression of wildtype human AIPL1 rescued cone defects and visual function in P351del12 mice, likely due to drastically higher overexpression of AIPL1 via AAV-mediated delivery than in transgenic mice.
In the original Pakistani family identified as LCA4 (604393) and in a second Pakistani family, whose LCA had been mapped to 17p13.1, Sohocki et al. (2000) demonstrated homozygosity for a nonsense mutation (trp278 to ter; W278X), TGG-to-TGA, in the AIPL1 gene. The mutation segregated with disease in both families and was not found in 100 ethnically matched controls. The 2 families differed in haplotype (GCG and GAA, respectively) of the AIPL1 exon 3 polymorphisms, as well as for microsatellite markers tightly linked to AIPL1. These findings suggested that the W278X mutation causing LCA in these 2 families was not derived from a recent, common ancestor. In a European family (RFS127), Sohocki et al. (2000) found homozygosity for the W278X mutation. In this case haplotype analysis of tightly linked microsatellite markers and of the AIPL1 exon 3 polymorphisms suggested that the mutations in the RFS127 family and the second Pakistani family were likely to have descended from a common ancestor; however, there was no indication of Pakistani origin in this family. Noting that AIPL1 is not expressed in the cornea and that affected members of the second Pakistani family and the European family who were homozygous for W278X had LCA without keratoconus, the authors suggested that the keratoconus present in affected members of the original LCA4 family was possibly secondary to eye rubbing due to the LCA.
In a more extensive study, Sohocki et al. (2000) found homozygosity for the W278X mutation in 3 of 13 families and compound heterozygosity in 3 additional families. The mutation was identified in affected individuals from multiple populations, including Pakistani, Spanish, French, and American.
From a study of data on 42 patients from 18 countries with molecularly confirmed LCA4, Aboshiha et al. (2015) found that W278X was the most common mutation, being found on one or more alleles in 26 patients (62%) and on both alleles in 15 patients (36%).
In 2 affected members of a European family with LCA4 (604393), Sohocki et al. (2000) identified compound heterozygosity for the W278X mutation (604392.0001) and a 2-bp deletion in codon 336 in the AIPL1 gene (ala336del2).
In 3 affected members of a European family with LCA4 (604393), Sohocki et al. (2000) found that Leber congenital amaurosis segregated with homozygosity for a T-to-C transition in the AIPL1 gene, predicted to encode a cys239-to-arg (C239R) amino acid substitution.
In affected individuals in 2 unrelated families with an apparently dominant retinal degenerative disorder, diagnosed as juvenile retinitis pigmentosa (see 604393) in one and cone-rod dystrophy (see 604393) in the other, Sohocki et al. (2000) found heterozygosity for a 12-bp AIPL1 deletion, pro351del12, or del1053-1064, in the 'hinge' region of the protein.
Aboshiha, J., Dubis, A. M., van der Spuy, J., Nishiguchi, K. M., Cheeseman, E. W., Ayuso, C., Ehrenberg, M., Simonelli, F., Bainbridge, J. W., Michaelides, M. Preserved outer retina in AIPL1 Leber's congenital amaurosis: implications for gene therapy. Ophthalmology 122: 862-864, 2015. [PubMed: 25596619] [Full Text: https://doi.org/10.1016/j.ophtha.2014.11.019]
Akey, D. T., Zhu, X., Dyer, M., Li, A., Sorensen, A., Blackshaw,S., Fukuda-Kamitani, T., Daiger, S. P., Craft, C. M., Kamitani, T., Sohocki, M. M. The inherited blindness associated protein AIPL1 interacts with the cell cycle regulator protein NUB1. Hum. Molec. Genet. 11: 2723-2733, 2002. Note: Erratum: Hum. Molec. Genet. 12: 451 only, 2003. [PubMed: 12374762] [Full Text: https://doi.org/10.1093/hmg/11.22.2723]
Kirschman, L. T., Kolandaivelu, S., Frederick, J. M., Dang, L., Goldberg, A. F. X., Baehr, W., Ramamurthy, V. The Leber congenital amaurosis protein, AIPL1, is needed for the viability and functioning of cone photoreceptor cells. Hum. Molec. Genet. 19: 1076-1087, 2010. [PubMed: 20042464] [Full Text: https://doi.org/10.1093/hmg/ddp571]
Ku, C. A., Chiodo, V. A., Boye, S. L., Hayes, A., Goldberg, A. F. X., Hauswirth, W. W., Ramamurthy, V. Viral-mediated vision rescue of a novel AIPL1 cone-rod dystrophy model. Hum. Molec. Genet. 24: 670-684, 2015. [PubMed: 25274777] [Full Text: https://doi.org/10.1093/hmg/ddu487]
Liu, X., Bulgakov, O. V., Wen, X.-H., Woodruff, M. L., Pawlyk, B., Yang, J., Fain, G. L., Sandberg, M. A., Makino, C. L., Li, T. AIPL1, the protein that is defective in Leber congenital amaurosis, is essential for the biosynthesis of retinal rod cGMP phosphodiesterase. Proc. Nat. Acad. Sci. 101: 13903-13908, 2004. Note: Erratum: Proc. Nat. Acad. Sci. 102: 515 only, 2005. [PubMed: 15365173] [Full Text: https://doi.org/10.1073/pnas.0405160101]
Makino, C. L., Wen, X.-H., Michaud, N., Peshenko, I. V., Pawlyk, B., Brush, R. S., Soloviev, M., Liu, X., Woodruff, M. L., Calvert, P. D., Savchenko, A. B., Anderson, R. E., Fain, G. L., Li, T., Sandberg, M. A., Dizhoor, A. M. Effects of low AIPL1 expression on phototransduction in rods. Invest. Ophthal. Vis. Sci. 47: 2185-2194, 2006. Note: Erratum: Ophthal. Vis. Sci. 47: 2279 only, 2006. [PubMed: 16639031] [Full Text: https://doi.org/10.1167/iovs.05-1341]
Ramamurthy, V., Niemi, G. A., Reh, T. A., Hurley, J. B. Leber congenital amaurosis linked to AIPL1: a mouse model reveals destabilization of cGMP phosphodiesterase. Proc. Nat. Acad. Sci. 101: 13897-13902, 2004. [PubMed: 15365178] [Full Text: https://doi.org/10.1073/pnas.0404197101]
Ramamurthy, V., Roberts, M., van den Akker, F., Niemi, G., Reh, T. A., Hurley, J. B. AIPL1, a protein implicated in Leber's congenital amaurosis, interacts with and aids in processing of farnesylated proteins. Proc. Nat. Acad. Sci. 100: 12630-12635, 2003. [PubMed: 14555765] [Full Text: https://doi.org/10.1073/pnas.2134194100]
Sohocki, M. M., Bowne, S. J., Sullivan, L. S., Blackshaw, S., Cepko, C. L., Payne, A. M., Bhattacharya, S. S., Khaliq, S., Mehdi, S. Q., Birch, D. G., Harrison, W. R., Elder, F. F. B., Heckenlively, J. R., Daiger, S. P. Mutations in a new photoreceptor-pineal gene on 17p cause Leber congenital amaurosis. Nature Genet. 24: 79-83, 2000. [PubMed: 10615133] [Full Text: https://doi.org/10.1038/71732]
Sohocki, M. M., Malone, K. A., Sullivan, L. S., Diager, S. P. Localization of retina/pineal-expressed sequences: identification of novel candidate genes for inherited retinal disorders. Genomics 58: 29-33, 1999. [PubMed: 10331942] [Full Text: https://doi.org/10.1006/geno.1999.5810]
Sohocki, M. M., Perrault, I., Leroy, B. P., Payne, A. M., Dharmaraj, S., Bhattacharya, S. S., Kaplan, J., Maumenee, I. H., Koenekoop, R., Meire, F. M., Birch, D. G., Heckenlively, J. R., Daiger, S. P. Prevalence of AIPL1 mutations in inherited retinal degenerative disease. Molec. Genet. Metab. 70: 142-150, 2000. [PubMed: 10873396] [Full Text: https://doi.org/10.1006/mgme.2000.3001]
Tan, M. H., Smith, A. J., Pawlyk, B., Xu, X., Liu, X., Bainbridge, J. B., Basche, M., McIntosh, J., Tran, H. V., Nathwani, A., Li, T., Ali, R. R. Gene therapy for retinitis pigmentosa and Leber congenital amaurosis caused by defects in AIPL1: effective rescue of mouse models of partial and complete Aipl1 deficiency using AAV2/2 and AAV2/8 vectors. Hum. Molec. Genet. 18: 2099-2114, 2009. Note: Erratum: Hum. Molec. Genet. 19: 735 only, 2010. Erratum: Hum. Molec. Genet. 32: 3391-3393, 2023; Erratum: Hum. Molec. Genet. 33: 931-933, 2024. [PubMed: 19299492] [Full Text: https://doi.org/10.1093/hmg/ddp133]
van der Spuy, J., Chapple, J. P., Clark, B. J., Luthert, P. J., Sethi, C. S., Cheetham, M. E. The Leber congenital amaurosis gene product AIPL1 is localized exclusively in rod photoreceptors of the adult human retina. Hum. Molec. Genet. 11: 823-831, 2002. [PubMed: 11929855] [Full Text: https://doi.org/10.1093/hmg/11.7.823]