AIPL1 – Leber congenital amaurosis

Autosomal recessive Leber congenital amaurosis (LCA) is caused by biallelic pathogenic variants in the photoreceptor-specific gene AIPL1, originally mapped to 17p13.1 in a consanguineous Pakistani family. A nonsense mutation (c.325C>T (p.Gln109Ter)) segregated with disease in all affected members, designating it LCA4, and excluding other known LCA loci ([PMID:10615133]). Subsequent studies across diverse populations have confirmed a definitive gene–disease relationship.

Genetic evidence includes compound heterozygous or homozygous AIPL1 variants in over 40 unrelated probands from more than 20 families. In a cohort of 303 LCA patients, 17 homozygotes and 9 compound heterozygotes were identified, with p.Trp278Ter the most frequent allele ([PMID:15249368]). A global screening of 512 probands uncovered 11 LCA families with AIPL1 mutations, indicating a 7% contribution worldwide ([PMID:10873396]). Segregation in multiple pedigrees and a consistent autosomal recessive inheritance pattern support a Strong level of genetic evidence.

The spectrum of pathogenic variants is broad: missense (e.g., c.244C>T (p.His82Tyr)), nonsense, splice-site, frameshift and deep-intronic alleles have been described. Recurrent variants such as c.905G>T (p.Arg302Leu) and c.778dup (p.His260fs) occur in multiple ethnic groups, while hypomorphic alleles like c.364G>C (p.Gly122Arg) are linked to milder retinitis pigmentosa phenotypes in adults ([PMID:33067476]).

Functional studies demonstrate that AIPL1 is an HSP90-dependent co-chaperone essential for the stability and assembly of rod and cone phosphodiesterase 6 (PDE6). Aipl1−/− mice exhibit rapid degeneration of both photoreceptor classes due to PDE6 destabilization, recapitulating human LCA ([PMID:20042464]). Transgenic expression of human AIPL1 in rods restores PDE6 levels and electroretinogram responses but does not fully rescue cones, highlighting a direct role in cone survival.

Biochemical assays confirm that pathogenic missense and nonsense variants in the FKBP-like and TPR domains abolish AIPL1 interaction with HSP90 and prevent PDE6 holoenzyme maturation. In vitro, AIPL1 enhances processing of farnesylated proteins and modulates NUB1 localization; LCA-linked mutations disrupt these activities ([PMID:14555765]; [PMID:28973376]). Rescue of cone function in a novel P351_Pro355del mouse model via AAV-mediated wild-type AIPL1 delivery underscores therapeutic potential ([PMID:25274777]).

No significant conflicting evidence has been reported. The convergence of robust segregation data, extensive mutational spectrum, animal models, and diverse functional assays establishes AIPL1 as Definitive for autosomal recessive LCA. Clinical genetic testing for AIPL1 variants informs early diagnosis, genetic counseling, and patient selection for emerging gene therapy.

Key Take-home: Biallelic loss-of-function AIPL1 variants cause severe early-onset photoreceptor degeneration by impairing HSP90-mediated PDE6 assembly, making AIPL1 a critical target for molecular diagnosis and gene replacement strategies.

References

• Nature genetics • 2000 • Mutations in a new photoreceptor-pineal gene on 17p cause Leber congenital amaurosis PMID:10615133
• Molecular genetics and metabolism • 2000 • Prevalence of AIPL1 mutations in inherited retinal degenerative disease PMID:10873396
• Archives of ophthalmology • 2004 • The phenotype of Leber congenital amaurosis in patients with AIPL1 mutations PMID:15249368
• Human molecular genetics • 2010 • The Leber congenital amaurosis protein, AIPL1, is needed for the viability and functioning of cone photoreceptor cells PMID:20042464
• Proceedings of the National Academy of Sciences • 2003 • AIPL1, a protein implicated in Leber's congenital amaurosis, interacts with and aids in processing of farnesylated proteins PMID:14555765
• Human molecular genetics • 2017 • The integrity and organization of the human AIPL1 functional domains is critical for its role as a HSP90-dependent co-chaperone for rod PDE6 PMID:28973376
• PLoS one • 2015 • Viral-mediated vision rescue of a novel AIPL1 cone-rod dystrophy model PMID:25274777

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