Other entities represented in this entry:
ORPHA: 1872, 65, 791; DO: 0110332;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17p13.2 | Retinitis pigmentosa, juvenile | 604393 | Autosomal dominant; Autosomal recessive | 3 | AIPL1 | 604392 |
| 17p13.2 | Leber congenital amaurosis 4 | 604393 | Autosomal dominant; Autosomal recessive | 3 | AIPL1 | 604392 |
| 17p13.2 | Cone-rod dystrophy | 604393 | Autosomal dominant; Autosomal recessive | 3 | AIPL1 | 604392 |
A number sign (#) is used with this entry because Leber congenital amaurosis-4 (LCA4) is caused by homozygous or compound heterozygous mutation in the gene encoding arylhydrocarbon-interacting protein-like-1 (AIPL1; 604392) on chromosome 17p13.
Heterozygous mutation in the AIPL1 gene can cause juvenile retinitis pigmentosa and a form of cone-rod dystrophy.
Autosomal recessive childhood-onset severe retinal dystrophy is a heterogeneous group of disorders affecting rod and cone photoreceptors simultaneously. The most severe cases are termed Leber congenital amaurosis (LCA), whereas the less aggressive forms are usually considered juvenile retinitis pigmentosa (Gu et al., 1997). Various intermediate phenotypes between LCA and retinitis pigmentosa are known and are sometimes described as 'early-onset severe rod-cone dystrophy' or 'early-onset retinal degeneration' (Booij et al., 2005).
For a general phenotypic description and a discussion of genetic heterogeneity of Leber congenital amaurosis, see LCA1 (204000); for retinitis pigmentosa, see 268000; for cone-rod dystrophy, see 120970.
Hameed et al. (2000) studied a consanguineous Pakistani family in which 3 sibs and their cousin had Leber congenital amaurosis and keratoconus. All affected individuals were blind from birth, with absence of rod and cone function as demonstrated by electroretinography (ERG), and the patients also showed bone spicule pigmentation of the retina. In addition, patients developed bilateral ectasia with central thinning of the cornea before age 20 years. On examination, the central cornea had a pronounced cone shape with severe corneal clouding.
Sohocki et al. (2000) examined affected members of 4 unrelated LCA families in whom mutations in the AIPL1 gene (604392) were found (see MOLECULAR GENETICS). Affected individuals from a Pakistani family were blind from birth with absence of rod and cone function as demonstrated by ERG, but without keratoconus. Fundus examination indicated pigmentary retinopathy, attenuated blood vessels, and macular degeneration. In 3 unrelated European families, patients had poor central vision from birth, severe night blindness, and pendular nystagmus. ERG testing revealed borderline or nondetectable cone and rod responses by the second decade of life. Fundus examination showed widespread retinal pigment epithelium changes with pigment clumping, attenuated retinal vessels, macular atrophy, and a pale optic disc.
Aboshiha et al. (2015) compiled data on 42 patients from 18 countries with molecularly confirmed LCA4. The age of the patients ranged from 0.5 to 43 years (median, 8 years); 24 patients were less than 10 years of age and 10 were less than 5 years of age. The model visual acuity was perception of light, which was found in 21 patients, with a range of visual acuities from no perception of light to a logMAR of 0.90. Posterior pole examination findings, which were available for 39 patients, showed a normal posterior pole appearance in 7 (18%, age range 0.5-5 years), with 18 (46%) having retinal pigmentary changes without macular atrophy, and 13 (33%) exhibiting macular atrophy. The youngest patient with macular atrophy was 6 years old. Of 13 patients in whom good optical coherence tomography (OCT) images could be obtained, 3 (23%; aged 1 year or younger) demonstrated significant outer retinal structure, with relative preservation of the inner segment ellipsoid layer and outer nuclear layer at the fovea, and 1 (aged 3 years) demonstrated qualified evidence of a foveal inner segment ellipsoid layer. Three of the 4 patients were homozygous for the common W278X mutation (604372.0001). Aboshiha et al. (2015) suggested the possibility of gene therapy in young patients with LCA4.
Not all LCA families that showed linkage to 17p13.1 had demonstrable mutations in the GUCY2D gene (600179); Perrault et al. (1996) identified disease-causing GUCY2D mutations in only 8 of 15 families showing mapping to 17p13.1, suggesting that there may be another LCA locus on 17p13.1. Confirming this prediction, Hameed et al. (2000) found that the LCA with keratoconus segregating in an autosomal recessive fashion in a consanguineous Pakistani family mapped to 17p13.1, between D17S849 and D17S960--a region that excluded GUCY2D. They designated the LCA in this family LCA4.
In affected members of a consanguineous Pakistani family with Leber congenital amaurosis and keratoconus mapping to chromosome 17p13.1, originally studied by Hameed et al. (2000) and found to be negative for mutation in the GUC2D gene (600179), Sohocki et al. (2000) demonstrated homozygosity for a nonsense mutation in the AIPL1 gene (W278X; 604392.0001). Analysis of the AIPL1 gene in 14 additional LCA families revealed 4 more families that were homozygous or compound heterozygous for W278X and/or other mutations in AIPL1 (see 604392.0002-604392.0003), and Sohocki et al. (2000) concluded that mutations in the AIPL1 gene might account for approximately 20% of recessive LCA. Noting that AIPL1 is not expressed in the cornea and that affected members of 2 unrelated families who had LCA without keratoconus were homozygous for the W278X mutation, the authors suggested that the keratoconus present in affected members of the original LCA4 family, who were also homozygous for W278X, was possibly secondary to eye rubbing due to the 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 LCA 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 or dominant cone-rod dystrophy, 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.
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.
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]
Booij, J. C., Florijn, R. J., ten Brink, J. B., Loves, W., Meire, F., van Schooneveld, M. J., de Jong, P. T. V. M., Bergen, A. A. B. Identification of mutations in the AIPL1, CRB1, GUCY2D, RPE65, and RPGRIP1 genes in patients with juvenile retinitis pigmentosa. J. Med. Genet. 42: e67, 2005. Note: Electronic Article. [PubMed: 16272259] [Full Text: https://doi.org/10.1136/jmg.2005.035121]
Gu, S., Thompson, D. A., Srikumari, C. R. S., Lorenz, B., Finckh, U., Nicoletti, A., Murthy, K. R., Rathmann, M., Kumaramanickavel, G., Denton, M. J., Gal, A. Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy. Nature Genet. 17: 194-197, 1997. [PubMed: 9326941] [Full Text: https://doi.org/10.1038/ng1097-194]
Hameed, A., Khaliq, S., Ismail, M., Anwar, K., Ebenezer, N. D., Jordan, T., Mehdi, S. Q., Payne, A. M., Bhattacharya, S. S. A novel locus for Leber congenital amaurosis (LCA4) with anterior keratoconus mapping to chromosome 17p13. Invest. Ophthal. Vis. Sci. 41: 629-633, 2000. [PubMed: 10711674]
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]
Perrault, I., Rozet, J. M., Calvas, P., Gerber, S., Camuzat, A., Dollfus, H., Chatelin, S., Souied, E., Ghazi, I., Leowski, C., Bonnemaison, M., Le Paslier, D., Frezal, J., Dufier, J.-L., Pittler, S., Munnich, A., Kaplan, J. Retinal-specific guanylate cyclase gene mutations in Leber's congenital amaurosis. Nature Genet. 14: 461-464, 1996. [PubMed: 8944027] [Full Text: https://doi.org/10.1038/ng1296-461]
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., 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]