Leber Congenital Amaurosis: Ciliary Proteins on the Move

Leber congenital amaurosis (LCA) displays a high degree of clinical and genetic heterogeneity. Up to 2005, mutations in 8 genes (AIPL1, CRB1, CRX, GUCY2D, IMPDH1, RDH12, RPGRIP1, RPE65) accounted for ∼40% of LCA cases. In the last two years, three new LCA genes were identified (CEP290, RD3, LCA5) bringing the new total of LCA genes to 11. Mutations in the CEP290 gene were found to be the most frequent cause of LCA identified thus far, accounting for ∼ 20% of LCA patients

Together with the previously known genes, the genetic causes have been solved for ∼ 70% of LCA cases, which now allows the identification of pathologic variants in the majority of new cases using the arrayed primer extension microarray (Asper Ophthalmics: http://www.asperophthalmics.com/LeberCongenitalAmaurosisDNAtest.htm). Gene-specific disease burdens range from < 1 to 20% (RD3 to CEP290), and the three major genes that account for up to 55% of the LCA mutations are CRB1, GUCY2D and CEP290 (Table 1). LCA genes in the intervals of LCA3 on 14q23 and LCA9 on 1p36 still need to be determined. LCA constitutes the first highly heterogeneous Mendelian disease for which mutations can now be identified in the majority of cases, facilitating accurate clinical diagnosis, prognosis, and family counseling. Moreover, the molecular diagnosis opens up the possibility for patients to enroll in novel therapeutic trials.

TABLE 1 Overview of all currently known LCA genes, with the year of discovery, chromosomal locations, re-interpreted OMIM designations and estimated relative disease burden.

LCA genes	Year of discovery	Locus	OMIM	Frequency estimates (%) with refs.
1. GUCY2D	1996	17p13.1	LCA1	6–20^2, ^3
2. RPE65	1997	1p31	LCA2	3–16^4, ^5
3. CRX	1998	19q13.3	LCA4	∼2^2
4. LCA5	2007	6q11–q16	LCA5	∼2^1
5. AIPL1	2000	17p13.1	LCA6	3–7^6, ^7
6. CRB1	2001	1q31–1q32.1	LCA7	9–13^8, ^9
7. RPGRIP1	2001	14q11	LCA8	4–6^10, ^11
8. RDH12	2004	14q23.3	LCA10	4^12, ^13
9. IMPDH1	2006	7q31.3–q32	LCA11	< 1^14
10. CEP290	2006	12q21.3	LCA12	∼20^15, ^16
11. RD3	2006	1q32.3	LCA13	< 1^17

The most recently identified gene, LCA5, encoding the lebercilin protein, was found to reside in an interval on chromosome 6 that was previously found to be linked to LCA in a family of the “Old Order River Brethren,” a religious isolate originating from Switzerland.¹ The critical interval was refined by homozygosity mapping in additional consanguineous and non-consanguineous families, and was analyzed for candidate genes. Mutations were detected in a putative ciliary protein containing coiled-coil regions, which exhibited a weak protein sequence homology with CEP290. In the original LCA5 family we identified a homozygous deletion in the LCA5 promoter, leading to absence of the LCA5 mRNA transcript in the affected individuals. We also detected families from various origins to carry nonsense and frameshift mutations in the LCA5 gene. The phenotype and the probable clinical evolution of the visual and retinal phenotype of LCA5 still needs to be determined, but we already see that some LCA patients with LCA5 mutations develop enlarging macular colobomas, while others do not.

Interestingly, the proteins encoded by CEP290, LCA5, and RPGRIP1, localize to the connecting cilium and/or the basal bodies of photoreceptor cells. Here, they likely play a role in the transport machinery or processes of photoreceptor cells, either in retina development, circadian-regulated processes, or homeostasis. Mutations in CEP290 have been shown to be associated with extra-ocular features in Joubert and Meckel-Gruber syndrome, linking key ciliary processes across different human organs. These findings add to the growing list of proteins involved in “ciliary diseases,” which also include Bardet-Biedl syndrome and nephronophthisis. It can be predicted that additional ciliary proteins serve important roles in inherited retinal dystrophies.