Review and update on the molecular basis of Leber congenital amaurosis

Table 1 Leber congenital amaurosis genes and phenotype-genotype correlations

Locusname	Genesymbol	Chromosomal locus	Protein name	Protein function	% ofLCA	LCA phenotype	Other retinal dystrophies	Mutations number
LCA1	GUCY2D	17p13.1	Retinal guanylyl ciclase 1	Hydrolysis cGMP	6-21	Marked poor vision, photophobia, hyperopia, nystagmus. Normal appearing fundus or mild granular pigmentary changes in periphery. OCT with significant thinning perifoveal	dCRD, dCD	155
LCA2	RPE65	1p31.3-p31.2	Retinal pigment epithelium protein 65	Isomerohydrolase in vitamin A visual cycle	3-16	Night blindness, nystagmus, poor vision on the first year, transient vision improvement and later deterioration in their third to fifth decades. OCT: thinner retina in both central and perifoveolar areas	rRP, dRP, RPci	138
LCA3	SPATA7	14q31.3	Spermatogenesis-associated protein 7	Possible vesicular transport	Appro- ximately 3	Transient photophobia on the first year, but at three years old all patients had night blindness. Visual acuity at the end of the first decade remained stable. After, only hand motion and 20/200 can be seen. Fundus with typical appearance of RP rapidly progressive	rRP	18
LCA4	AIPL1	17p13.1	Aryl hydrocarbon interacting protein	Rod PDE chaperone	5-10	Keratoconus, cataract, and hyperopia. Variable night blindness or light sensibility. Poor vision. Fundus with bone spicules pigmentation and variable degree of maculopathy. OCT with reduced macular thickness	dCRD, rRP	52
LCA5	LCA5	6q14	Lebercilin	Ciliary functions	1-2	Severe reduced vision at, or near birth. Nystagmus and high hypermetropia. Visual acuity range between 0.20 to light perception. Extensible peripheral field loss. Fundus examination with widespread atrophy of the retina and RPE. Scattered white dots at RPE. Macula is normal most time, but in few patients may be seen macular coloboma. OCT: macular atrophy, disruption of retinal lamination and presence of hyporeflective well-circumscribed area in the outer nuclear layer, with a hyperreflective border (rossettes). Fundus autofluorescence shows hypofluorescence in the macula	No	35
LCA6	RPGRIP1	14q11	RP GTPase regulator-interacting protein 1	Connecting cilium, disc morphogenesis	4-6	Severe loss of vision early in life. Acuity visual worse than 20/200. At the beggining normal retina is seen, then it progress to pigmentary retinopathy. OCT shows remaining photoreceptor in the fovea	rCRD	82
LCA7	CRX	19q13.3	Cone-rod homeobox	Elongation of photoreceptor outer segment, photoreceptor development, phototransduction	1%-3%	Severe vision impairment is expected early in life. Nystagmus and high hyperopia. Fundus grayish with clumping or dot-pigment deposits and macular coloboma-like defect. OCT shows macular atrophy without noticeable signal of the junction between inner segments and outer segments	dCRD, dRP dLCA and rLCA	58
LCA 8	CRB1	1q 31-32.1	Crumbs homologue	Determining ad maintaining photoreceptor architectura	9-13	Nictalopia, nystagmus, keratoconus, corioretinal atrophy and nanophthalmos. Fundus with numular pigment clump, bone spicules and para-arteriolar preservation. Coloboma-like lesions and Coast like lesions	RPpa, rRP
LCA9	NMNAT1	1p36.22	Nicotinamide nucleotide adenylyltransferase 1	Rate-limiting enzyme NAD (+) biosynthesis	----	Severe form of retinal hereditary degeneration, mainly atrophic macular lesion. Macular pseudocoloboma. Retina´s remainder with pigmentary changes. Nistagmus and severe loss of vision (only light or hand movements perception)	----	44
LCA 10	CEP290	12q21.32	Centrosomal protein Cep290	Ciliary function	20	Nystagmus, hyperopia, keratoconus and cataract. Photophobia. Light perception or no vision. Atrophic spot (dot-like) in RPE, intraretinal bone spicules in most patients. A striking tapetal reflex (specific intraretinal greyish and white marbled areas). Perifoveal thinning by OCT	Syndromes (Senior-Loken, Joubert, Meckel)	187
LCA 11	IMPDH1	7q32.1	Inosine 5´- monophosphate dehydrogensase 1	De novo synthesis de guanine nucleotide	8	Nystagmus with no fixation to light. Retina showing diffuse RPE mottling. No pigmentary deposits	dRP	18
LCA12	RD3	1q32.3	Protein RD3	Transcription and splicing. Suppress retinal membrane guanylate cyclase activity. Role in retinal maturation	< 1	Night blindness, severe nystagmus. Initial refraction was hypermetropic and changed to myopic in the disease´s course. Severe impaired visual acuity. Attenuated vessels, salt and pepper aspect, and bone spicules are seen on fundus. Macular changes as hammer beaten appearance were note on the third decade of live. OCT reveal disorganization of all retinal layers	----	9
LCA13	RDH12	14q23.3	Retinol dehydrogensase 12	Unusual dual specificity for all-trans-retinol and cis-retinols	4-5	Poor vision. Night blindness. Chorioretinopathy (reticular or fishnet pattern) with dense hyperpigmentation and bone spicules. There is little or no autofluorescence on the macula. SDOCT: severe macular thinning and loss of the foveal laminar architecture	dRP	76
LCA 14	LRAT	4q31.3	Lecithinretinol acyltransferase	Esterification essential in vitamin A visual cycle	< 1	Poor vision, nyctalopia, and visual field constriction since childhood. Peripheral RPE atrophy with little pigment migration into retina. Asteroid hyalosis occurs more frequently than RP (37% vs 3%). Reduced AF signal	rRP, EORD	13
LCA 15	TULP1	6p21.3	Tubby-like protein	Protein transport from the photoreceptor inner segment to the outer segment	----	Night blindness, nystagmus, moderately to severely limited visual field. Severely disturbed color vision. Fundoscopic findings are variable; pronounced maculopathy in older patients, pigmentary retinopathy in all patients. Pigmentary spicules also are variable affected	rRP	47
LCA 16	KCNJ13	2q37	Inwardly-rectifying potassium cannel subfamily J members	Maintaining resting membrane potential	----	Poor night vision, nystagmus. Cataract. Fundoscopy reveals considerable levels of pigments at RPE and a different configuration that the one seen on typical RP	dVRD	6
LCA 17	GDF6	8q22.1	Grow differentiation factor 6	Codes for a widely expressed growth factor in the TGF-b pathway specifying the dorsal-ventral retinal axis	----	Ocular and skeletal features. Limited vision to detect hand motions	Klippel Feil syndrome, dominant microphthalmia	15
	CABP4	11q13.1	Calcium binding protein 4	Modulate voltage dependent calcium channel	----	Poor vision, nystagmus, photophobia, poor visual acuity	rCSNB, rCRSD	6
	CNGA3	2q11.2	Cone photoreceptor cGMP-gated cation channel alpha subunit	Important for normal vision and olphatory signaling transduction	----	LCA phenotype is not described	Colour blindness total, achromatopsia, cone dystrophy	82
	ALMS1	2p13.1	ALMS1	ALMS protein	----	LCA phenotype is not described	Alstrom syndrome	129
	IQCB1	3q21.1			----	LCA phenotype is not described	Recessive Senior Loken syndrome
	MYO7A	11q13.5			----	LCA phenotype is not described	Usher syndrome, congenital deafness without RP	304

dLCA: Dominant Leber congenital amaurosis; rLCA: Recessive Leber congenital amaurosis; dCRD: Dominant cone-rod dystrophy; dCD: Dominant con dystrophy; rRP: Recessive retinitis pigmentosa; dRP: Dominant retinitis pigmentosa; Rpci: Retinitis pigmentosa with choroidal involvement; PDE: Phosphodiesterase; recessive retinitis pigmentosa with para arteriolar preservation (rRPpa); EORD: Early onset retina dystrophies; AF: Autofluorescence; dVRD: Dominant viteroretinal degeneration; rCSNB: Recessive congenital stationary night blindness; CRSD: Recessive cod-rod synaptic disorder.