ORPHA: 65; DO: 0110215;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 6q14.1 | Leber congenital amaurosis 5 | 604537 | Autosomal recessive | 3 | LCA5 | 611408 |
A number sign (#) is used with this entry because Leber congenital amaurosis-5 (LCA5) is caused by homozygous mutation in the gene encoding lebercilin (LCA5; 611408) on chromosome 6q14.
For a general phenotypic description and a discussion of genetic heterogeneity of LCA, see LCA1 (204000).
Dharmaraj et al. (2000) described a multigenerational kindred of Old Order River Brethren, a religious isolate descended from Swiss immigrants to America in the 1750s (Brechbill, 1972), segregating Leber congenital amaurosis. LCA in this kindred was not associated with multisystem abnormalities. Renal function remained normal. Neurologic and hepatic function were within normal limits. The patients were of normal stature and intelligence. Visual dysfunction, nystagmus, and the digitoocular phenomenon of Franceschetti-Bamatter (Franceschetti and Dieterle, 1954), namely pressing on the globes, were noticed in early infancy. A high hyperopic refractive correction was noted in all the patients. In infancy the fundi had a normal appearance, but in childhood attenuated retinal vasculature with varying degrees of pigmentary changes developed. Electroretinography showed a markedly reduced response in the affected individuals.
Mohamed et al. (2003) identified 3 brothers in a consanguineous Pakistani family with Leber congenital amaurosis. Progression of macular abnormalities resulted in a colobomatous appearance in the eldest compared to only mild atrophy in the youngest. This phenotypic pattern was considered to be different from that in the Old Order River Brethren kindred reported by Dharmaraj et al. (2000).
By linkage studies in the multigenerational kindred of Old Order River Brethren with LCA, Dharmaraj et al. (2000) mapped the disorder, which they designated LCA5, to chromosome 6q11-q16.
In a consanguineous Pakistani family in which 3 brothers had Leber congenital amaurosis, Mohamed et al. (2003) mapped the disorder to 6q11-q16.
By genomewide homozygosity mapping in 10 consanguineous Pakistani LCA families, and in 33 consanguineous and 60 nonconsanguineous affected individuals of various ethnic origins and geographic regions, den Hollander et al. (2007) found that 3 of the Pakistani families, including the family reported by Mohamed et al. (2003), shared an identical homozygous 780-kb haplotype on chromosome 6q14. Two other unrelated individuals were homozygous for marker alleles at the LCA5 locus.
The transmission pattern of LCA5 in the families reported by den Hollander et al. (2007) was consistent with autosomal recessive inheritance.
In affected members of 3 Pakistani families segregating for LCA5, including the family reported by Mohamed et al. (2003), den Hollander et al. (2007) identified a homozygous frameshift mutation in the LCA5 gene (611408.0001). They identified 3 additional mutations in several other affected individuals, including those in the Old Order River Brethren originally reported by Dharmaraj et al. (2000) (see 611408.0002-611408.0004).
Modifier Genes
In the Old Order River Brethren pedigree originally reported by Dharmaraj et al. (2000), in which a homozygous mutation in the LCA5 gene (611408.0004) was identified in affected individuals, Zernant et al. (2005) identified an additional missense mutation (P701S) in the LCA-associated GUCY2D gene (600179) in the more severely affected of 2 sibs. When compared at the same age, the sib with 3 variant alleles presented with a more severe ocular phenotype and experienced greater difficulty with decreased visual function; retinal examination revealed higher hyperopia and more extensive peripheral pigmentary mottling. Zernant et al. (2005) suggested that the variant GUCY2D allele had a modifier effect on the phenotype.
Brechbill, L. T. History of the Old Order River Brethren. Lancaster, Pa.: Brechbill and Strickler 1972.
den Hollander, A. I., Koenekoop, R. K., Mohamed, M. D., Arts, H. H., Boldt, K., Towns, K. V., Sedmak, T., Beer, M., Nagel-Wolfrum, K., McKibbin, M., Dharmaraj, S., Lopez, I., and 21 others. Mutations in LCA5, encoding the ciliary protein lebercilin, cause Leber congenital amaurosis. Nature Genet. 39: 889-895, 2007. [PubMed: 17546029] [Full Text: https://doi.org/10.1038/ng2066]
Dharmaraj, S., Li, Y., Robitaille, J. M., Silva, E., Zhu, D., Mitchell, T. N., Maltby, L. P., Baffoe-Bonnie, A. B., Maumenee, I. H. A novel locus for Leber congenital amaurosis maps to chromosome 6q. (Letter) Am. J. Hum. Genet. 66: 319-326, 2000. [PubMed: 10631161] [Full Text: https://doi.org/10.1086/302719]
Franceschetti, A., Dieterle, P. Importance diagnostique et pronostique de l'electroretinogramme (ERG) dans les degenerescences tapeto-retiniennes avec retrecissement du champ visuel et hemeralopie. Confin. Neurol. 14: 184-186, 1954. [PubMed: 13190865]
Mohamed, M. D., Topping, N. C., Jafri, H., Raashed, Y., McKibbon, M. A., Inglehearn, C. F. Progression of phenotype in Leber's congenital amaurosis with a mutation at the LCA5 locus. Brit. J. Ophthal. 87: 473-475, 2003. [PubMed: 12642313] [Full Text: https://doi.org/10.1136/bjo.87.4.473]
Zernant, J., Kulm, M., Dharmaraj, S., den Hollander, A. I., Perrault, I., Preising, M. N., Lorenz, B., Kaplan, J., Cremers, F. P. M., Maumenee, I., Koenekoop, R. K., Allikmets, R. Genotyping microarray (disease chip) for Leber congenital amaurosis: detection of modifier alleles. Invest. Ophthal. Vis. Sci. 46: 3052-3059, 2005. [PubMed: 16123401] [Full Text: https://doi.org/10.1167/iovs.05-0111]