Other entities represented in this entry:
ORPHA: 65; DO: 0110189;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6p21.31 | Leber congenital amaurosis 15 | 613843 | Autosomal recessive | 3 | TULP1 | 602280 |
A number sign (#) is used with this entry because Leber congenital amaurosis-15 and juvenile retinitis pigmentosa are caused by homozygous or compound heterozygous mutation in the TULP1 gene (602280) on chromosome 6p21.3.
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, whereas the less aggressive forms are usually considered juvenile retinitis pigmentosa (summary by Gu et al., 1997).
Mutation in TULP1 can also cause a form of autosomal recessive retinitis pigmentosa (RP14; 600132).
For a general phenotypic description and a discussion of the genetic heterogeneity of Leber congenital amaurosis, see LCA1 (204000); for retinitis pigmentosa, see 268000.
Hanein et al. (2004) studied 179 unrelated patients fulfilling strict inclusion criteria for diagnosis of LCA, including congenital nystagmus, no or very poor ocular pursuit, oculodigital sign of Franceschetti (repetitive eye-rubbing in infancy, attesting to profoundly impaired vision), and no recordable ERGs since birth or the first months of life. Among these probands, 3 were found to have homozygous or compound heterozygous mutations in the TULP1 gene (see MOLECULAR GENETICS).
Mataftsi et al. (2007) reported a large consanguineous Algerian family in which 7 individuals from 3 sibships were affected with Leber congenital amaurosis or early-onset retinal degeneration. Symptoms started at birth in 2 patients and during infancy in 5 patients, with age at diagnosis ranging from 3 years to 12 years of age. All patients had night blindness and nystagmus, but none had photophobia. Six patients had myopia, and 1 had mild hyperopia; visual acuity ranged from perception of light to 20/100. Visual fields were moderately to severely restricted in patients who were tested, and color vision was severe disturbed without a specific axis of confusion. The pupillary reflex was extremely sluggish in most of the patients. None presented signs of keratoconus. Funduscopic findings varied significantly across and within the sibships, primarily in an age-dependent manner: the youngest patient had no detectable maculopathy, 3 patients of intermediate age had an indistinct foveolar reflex, and the 3 oldest affected individuals had pronounced maculopathy. In addition, the optic disc appeared healthy in the younger patients, whereas moderate to waxy disc pallor was evident in the 3 oldest; the latter patients also displayed an annulus of peripapillary retinal pigment epithelium (RPE) atrophy in both eyes. Pigment retinopathy and retinal vessel attenuation were present in all but the youngest subject, with some patients having severely sclerosed arteries and multiple occluded or ghost vessels in the periphery. Fluorescein angiography confirmed the presence of peripapillary RPE atrophy and absence of macular edema. The proband was examined on 2 occasions 8 months apart, and during that interval his visual acuity declined from 20/100 to 20/250 in the better eye. Full-field ERGs in the proband showed completely extinguished rod- and cone-driven responses, and macular optical coherence tomography scans showed an abnormal lamination due to the underlying degenerative disease. The nerve fiber layer and inner plexiform layer seemed to be preserved, but the structures of the outer retina were nondetectable, and retinal thickness was significantly reduced.
In a large consanguineous Algerian pedigree in which 7 individuals from 3 sibships were affected with Leber congenital amaurosis or early-onset retinal degeneration, Mataftsi et al. (2007) performed homozygosity mapping which excluded all the tested loci except TULP1 (602280) at chromosome 6p21.3.
In 179 unrelated patients diagnosed with Leber congenital amaurosis (LCA), Hanein et al. (2004) analyzed 7 known LCA genes and identified homozygous or compound heterozygous mutations in the TULP1 gene in 3 probands (602280.0004 and 602280.0010-602280.0012, respectively).
In 7 affected individuals from 3 sibships of a large consanguineous Algerian pedigree with Leber congenital amaurosis or early-onset retinal degeneration, Mataftsi et al. (2007) identified homozygosity for a 6-bp duplication in the TULP1 gene (602280.0013). The unaffected parents were heterozygous for the mutation, as were 15 other family members. Examination of the 17 asymptomatic carriers of the duplication revealed that 15 had an unremarkable fundus appearance, whereas 2 individuals, aged 64 years and 66 years, had drusen-like macular deposits; 1 also had age-related pigmentary macular changes.
In 4 unrelated patients diagnosed with juvenile retinitis pigmentosa, 2 from Afghanistan, 1 from Turkey, and 1 from Mexico, den Hollander et al. (2007) identified homozygosity for mutations in the TULP1 gene (see, e.g., 602280.0009).
den Hollander, A. I., Lopez, I., Yzer, S., Zonneveld, M. N., Janssen, I. M., Strom, T. M., Hehir-Kwa, J. Y., Veltman, J. A., Arends, M. L., Meitinger, T., Musarella, M. A., van den Born, L. I., Fishman, G. A., Maumenee, I. H., Rohrschneider, K., Cremers, F. P., Koenekoop, R. K. Identification of novel mutations in patients with Leber congenital amaurosis and juvenile RP by genome-wide homozygosity mapping with SNP microarrays. Invest. Ophthal. Vis. Sci. 48: 5690-5698, 2007. [PubMed: 18055821] [Full Text: https://doi.org/10.1167/iovs.07-0610]
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]
Hanein, S., Perrault, I., Gerber, S., Tanguy, G., Barbet, F., Ducroq, D., Calvas, P., Dollfus, H., Hamel, C., Lopponen, T., Munier, F., Santos, L., Shalev, S., Zafeiriou, D., Dufier, J.-L., Munnich, A., Rozet, J.-M., Kaplan, J. Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis. Hum. Mutat. 23: 306-317, 2004. [PubMed: 15024725] [Full Text: https://doi.org/10.1002/humu.20010]
Mataftsi, A., Schorderet, D. F., Chachoua, L., Boussalah, M., Nouri, M. T., Barthelmes, D., Borruat, F.-X., Munier, F. L. Novel TULP1 mutation causing Leber congenital amaurosis or early onset retinal degeneration. Invest. Ophthal. Vis. Sci. 48: 5160-5167, 2007. [PubMed: 17962469] [Full Text: https://doi.org/10.1167/iovs.06-1013]