LCA5 – Leber congenital amaurosis

Leber congenital amaurosis (LCA) is a severe, early-onset retinal dystrophy characterized by congenital blindness, nystagmus, and nyctalopia. LCA5 encodes lebercilin, a ciliary protein critical for photoreceptor maintenance. Autosomal recessive inheritance is observed, with biallelic LCA5 mutations leading to LCA subtype 5. The prevalence of LCA5-related LCA is low (<2%), underscoring the genetic heterogeneity of the disease and the need for targeted molecular diagnostics.

In a consanguineous Pakistani family, a homozygous frameshift variant c.1151del (p.Pro384fs) segregated with disease in five affected members (5 probands) (PMID:12642313). A separate consanguineous sibship harbored a homozygous splice-site variant c.955G>A (p.Ala319Thr) in two siblings (PMID:18334959). Additionally, three independent LCA type II families each carried homozygous truncating variants c.610C>T (p.Gln204Ter), c.1186G>T (p.Glu396Ter), and c.103C>T (p.Arg35Ter) in LCA5, confirming rare multi-family involvement (3 probands) (PMID:18000884).

Screening of 1,008 unrelated LCA and arRP patients identified 18 new LCA5 probands with 19 different variants, 17 of which were novel and predominantly protein-truncating, highlighting loss of function as the disease mechanism (PMID:23946133). Optical coherence tomography in some subjects demonstrated preserved inner segment/outer segment junctions, correlating with residual lebercilin function and suggesting regions amenable to gene therapy.

In contrast, analysis of 17 Korean LCA patients found no pathogenic LCA5 mutations, identifying a benign variant c.1642C>T (p.Pro548Ser), indicating population-specific allele frequencies and potential disputed relevance (PMID:19172513). Collectively, over 29 unrelated probands with recessive truncating or splice variants and functional concordance support a Strong gene-disease association for LCA5 and LCA.

Key Take-home: LCA5 mutations cause an autosomal recessive form of Leber congenital amaurosis via lebercilin loss of function; genetic testing for truncating variants enables accurate diagnosis and informs emerging gene therapy strategies.

References

• The British journal of ophthalmology | 2003 | Progression of phenotype in Leber's congenital amaurosis with a mutation at the LCA5 locus. PMID:12642313
• Molecular vision | 2008 | Identification of a novel splice-site mutation in the Lebercilin (LCA5) gene causing Leber congenital amaurosis. PMID:18334959
• Human mutation | 2007 | Mutations in LCA5 are an uncommon cause of Leber congenital amaurosis (LCA) type II. PMID:18000884
• Ophthalmic genetics | 2009 | LCA5, a rare genetic cause of leber congenital amaurosis in Koreans. PMID:19172513
• Human mutation | 2013 | Screening of a large cohort of leber congenital amaurosis and retinitis pigmentosa patients identifies novel LCA5 mutations and new genotype-phenotype correlations. PMID:23946133

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