Alternative titles; symbols
HGNC Approved Gene Symbol: LCA5
Cytogenetic location: 6q14.1 Genomic coordinates (GRCh38) : 6:79,484,991-79,538,782 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q14.1 | Leber congenital amaurosis 5 | 604537 | Autosomal recessive | 3 |
Using homozygosity mapping in the Leber congenital amaurosis-5 (LCA5; 604537) critical region on chromosome 6q, followed by PCR of an available clone, den Hollander et al. (2007) obtained a full-length cDNA encoding lebercilin. The deduced 697-amino acid protein contains 4 coiled-coil domains. RT-PCR detected high expression in adult retina, testis, kidney, and heart, and in fetal eye, cochlea, and brain. Little to no expression was detected in adult brain, lung, and skeletal muscle. In situ hybridization of mouse embryos at day 12.5 postcoitum detected almost ubiquitous, low level staining. At later stages, staining of the eye, inner ear, kidney, regions of the central and peripheral neural system, the gut, and the ciliated epithelium of the nasopharynx, trachea, and lungs was more pronounced. In adult eye, expression was limited to the photoreceptor cell layer. In ciliated cell lines, lebercilin localized to the ciliary axoneme, and in mouse and rat retina, it localized between the outer and inner segments of the photoreceptor layer. Retinal epithelial cells overexpressing fluorescence-tagged lebercilin showed staining of the basal body, transition zone of the cilium, and microtubules.
Den Hollander et al. (2007) determined that the LCA5 gene contains 9 exons.
The C6ORF152 gene maps to chromosome 16q14.1 based on an alignment of the C6ORF152 sequence (AL391840) with the genomic sequence (build 36.2).
Den Hollander et al. (2007) showed that overexpression of lebercilin in a human retinal pigment epithelium cell line disturbed microtubule dynamics. In human embryonic kidney cells, tagged lebercilin interacted with 24 proteins, many of which are associated with centrosomal or ciliary functions, including cytoplasmic dynein (see 600112), nucleophosmin (see 164040), nucleolin (164035), 14-3-3-epsilon (605066), and HSP70 (see 140550).
Using yeast 2-hybrid analysis and coimmunoprecipitation assays, Coene et al. (2009) identified lebercilin as an interacting partner of CXORF5 (300170). The first 2 coiled-coil domains of lebercilin interacted with 5 of the 6 predicted coiled-coil regions of CXORF5. Both proteins were found to localize to the pericentriolar region in human and rat retinal cell lines. Mutations in the CXORF5 gene were found to weaken the interaction with LCA5 to varying degrees.
By yeast 2-hybrid analysis using deletion constructs of lebercilin and the intracellular region of USH2A (608400) isoform B, van Wijk et al. (2009) showed that the intermediate filament region of NLP(isoB) (NINL; 609580) interacts with lebercilin and USH2A(isoB), whereas no interaction was detected for NLP(isoA). Coimmunoprecipitation and GST pull-down assays confirmed interaction between NLP(isoB) and lebercilin and USH2A. Recombinant NLP(isoB), lebercilin, and USH2A(isoB) were all found to colocalize at the centrosomes in human retinal pigment epithelial (ARPE-19) cells. Staining of adult rat retinal sections with specific antibodies against all 3 proteins revealed their colocalization at the basal bodies of the photoreceptor-connecting cilia. A truncation mutation (611408.0003) in lebercilin reduced interaction and colocalization with NLP(isoB); however, RNAi knockdown of both endogenous NLP and lebercilin in ciliated ARPE-19 cells did not result in altered protein localization of NLP or lebercilin.
Den Hollander et al. (2007) found that all members with Leber congenital amaurosis-5 (LCA5; 604537) from 3 Pakistani families that shared an identical homozygous 780-kb haplotype on 6q14, including the family reported by Mohamed et al. (2003), carried a homozygous frameshift mutation in exon 6 of the LCA5 gene (611408.0001). By sequence analysis of the LCA5 gene in other affected individuals, they identified 3 additional mutations (611408.0002-611408.0004).
In affected members of 3 Pakistani families segregating Leber congenital amaurosis-5 (LCA5; 604537), including the family reported by Mohamed et al. (2003), den Hollander et al. (2007) identified homozygosity for deletion of a cytosine at position 1151 in exon 6 of the LCA5 gene, resulting in a frameshift mutation (Pro384GlnfsTer17). The mutation was not found in 180 control individuals.
In a patient with Leber congenital amaurosis-5 (LCA5; 604537) from a consanguineous family in Morocco, den Hollander et al. (2007) identified homozygosity for a 1-bp duplication (1476A) in exon 9 of the LCA5 gene, resulting in a frameshift mutation (Pro493ThrfsTer1). The mutation was not found in 180 control individuals.
In a patient with Leber congenital amaurosis-5 (LCA5; 604537) from a nonconsanguineous family of Ashkenazi Jewish descent, den Hollander et al. (2007) identified homozygosity for an 835C-T transition in exon 5 of the LCA5 gene, resulting in a gln279-to-ter (Q279X) substitution. The mutation was not found in 180 control individuals.
In affected members of the Old Order River Brethren with Leber congenital amaurosis-5 (LCA5; 604537) originally reported by Dharmaraj et al. (2000), den Hollander et al. (2007) identified a 1,598-bp deletion in the LCA5 gene that encompassed 1,077 bp of the promoter region and noncoding exon 1 (g.(-19612)-(-18015)del1598). The mutation was not found in 180 control individuals.
Zernant et al. (2005) studied 2 affected sibs from the Old Order River Brethren pedigree originally reported by Dharmaraj et al. (2000) and identified an additional missense mutation in the GUCY2D gene (600179) in the more severely affected of the 2 sibs. Zernant et al. (2005) suggested that the variant GUCY2D allele had a modifier effect on the phenotype.
Coene, K. L. M., Roepman, R., Doherty, D., Afroze, B., Kroes, H. Y., Letteboer, S. J. F., Ngu, L. H., Budny, B., van Wijk, E., Gorden, N. T., Azhimi, M., Thauvin-Robinet, C., Veltman, J. A., Boink, M., Kleefstra, T., Cremers, F. P. M., van Bokhoven, H., de Brouwer, A. P. M. OFD1 is mutated in X-linked Joubert syndrome and interacts with LCA5-encoded lebercilin. Am. J. Hum. Genet. 85: 465-481, 2009. [PubMed: 19800048] [Full Text: https://doi.org/10.1016/j.ajhg.2009.09.002]
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]
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]
van Wijk, E., Kersten, F. F. J., Kartono, A., Mans, D. A., Brandwijk, K., Letteboer, S. J. F., Peters, T. A., Marker, T., Yan, X., Cremers, C. W. R. J., Cremers, F. P. M., Wolfrum, U., Roepman, R., Kremer, H. Usher syndrome and Leber congenital amaurosis are molecularly linked via a novel isoform of the centrosomal ninein-like protein. Hum. Molec. Genet. 18: 51-64, 2009. [PubMed: 18826961] [Full Text: https://doi.org/10.1093/hmg/ddn312]
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]