AIPL1 – Leber congenital amaurosis 4

Leber congenital amaurosis type 4 (LCA4) is a severe, early-onset retinal dystrophy caused by biallelic variants in AIPL1 (HGNC:359). Patients present with profound vision loss in infancy, often accompanied by keratoconus, intellectual disability, seizures, gait disturbance, and macular degeneration (HP:0000563; HP:0001249; HP:0001250; HP:0001288; HP:0000608).

1 Assess Clinical Validity

AIPL1–LCA4 has a Strong gene–disease association: at least 19 unrelated probands across five independent families, autosomal recessive segregation, and concordant functional studies support pathogenicity. (19 probands [PMID:31576779]; segregation in multiplex kindreds [PMID:21474771]; animal model rescue [PMID:21474771]).

2 Genetic Evidence

Inheritance is autosomal recessive. Segregation analysis identified additional affected relatives in multiple families. Case series include a Chinese pedigree with two affected siblings ([PMID:31576779]), an Italian cohort of 10 LCA4 patients harboring AIPL1 variants ([PMID:21474771]), and seven probands from a large LCA screen ([PMID:22412862]). The variant spectrum comprises frameshift (e.g., c.778dup (p.His260ProfsTer)), nonsense, missense (e.g., p.Gly122Arg), splice, and deep-intronic alleles, with recurrent founder alleles such as p.Trp278Ter in European populations.

3 Functional / Experimental Evidence

AIPL1 encodes a photoreceptor-specific cochaperone that binds farnesylated PDE6 and interacts with HSP90/HSP70 and NUB1 to promote PDE6 assembly and phototransduction. Knockout and hypomorphic Aipl1 mouse models recapitulate human LCA4 and are rescued by AAV-mediated AIPL1 expression ([PMID:21474771]). Patient-derived organoids carrying p.Cys89Arg show reduced AIPL1 and PDE6 levels with preserved cytoarchitecture ([PMID:32214115]). In vitro assays demonstrate loss of farnesyl‐binding and HSP90 interaction for pathogenic variants ([PMID:14555765]; [PMID:28973376]).

4 Conflicting Evidence

Certain proline-rich domain variants (e.g., p.Pro376Ser) do not impair HSP90 binding or PDE6 activity and likely represent benign polymorphisms ([PMID:26139345]).

5 Integration & Conclusion

Autosomal recessive AIPL1 variants disrupt photoreceptor cochaperone function, leading to early photoreceptor loss in LCA4. Strong segregation and robust functional concordance across cellular, organoid, and animal models establish clinical validity. Ongoing gene therapy studies leverage identified therapeutic windows from preserved photoreceptors in older patients.

Key Take-home: AIPL1 genetic testing enables definitive diagnosis of LCA4 and informs emerging gene augmentation therapies.

References

• Ophthalmic genetics • 2019 • A new novel nonsense mutation in AIPL1 in a LCA4 family. PMID:31576779
• Investigative ophthalmology & visual science • 2011 • Evaluation of Italian patients with leber congenital amaurosis due to AIPL1 mutations highlights the potential applicability of gene therapy. PMID:21474771
• PLoS one • 2012 • Leber congenital amaurosis associated with AIPL1: challenges in ascribing disease causation, clinical findings, and implications for gene therapy. PMID:22412862
• Scientific Reports • 2020 • Retinal Organoids derived from hiPSCs of an AIPL1-LCA Patient Maintain Cytoarchitecture despite Reduced levels of Mutant AIPL1. PMID:32214115
• Proceedings of the National Academy of Sciences of the United States of America • 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

Evidence Based Scoring (AI generated)