ABCA4 – Retinitis Pigmentosa

ABCA4 is a photoreceptor-specific ATP-binding cassette transporter whose biallelic deleterious variants cause a spectrum of autosomal recessive retinal dystrophies, including retinitis pigmentosa (RP) (Retinitis Pigmentosa, ABCA4). RP is characterized by progressive rod-cone degeneration, nyctalopia, peripheral field loss and eventual central vision impairment. Inheritance is autosomal recessive with compound heterozygous or homozygous ABCA4 variants leading to disease.

1 Assess Clinical Validity

ABCA4–RP association meets a Definitive ClinGen category based on: at least 12 unrelated probands across multiple populations ([PMID:15017103]) with ABCA4 variants presenting RP; segregation in four consanguineous or familial cases ([PMID:9466990]); and concordant in vitro and in vivo functional data demonstrating loss of ABCA4 activity ([PMID:11017087], [PMID:11123914]).

2 Genetic Evidence

Inheritance is autosomal recessive. Segregation studies in a consanguineous family showed four RP-affected members homozygous for IVS30+1G>T, consistent with pseudodominant inheritance ([PMID:9466990]; affected_relatives = 3). Case reports include a Chinese family with homozygous frameshift c.4845delT (p.Lys1616ArgfsTer46) presenting arRP ([PMID:29437900]) and an Italian pedigree with c.2971G>T (p.Gly991Ter) initially diagnosed as Stargardt but reclassified as RP ([PMID:15017103]). Multi-patient cohorts identified ABCA4 mutations in ~5.6% of RP cases by microarray screening ([PMID:15494742]). Spectrum comprises protein-truncating (nonsense, frameshift, splice) and missense alleles; recurrent variants include c.2971G>T (p.Gly991Ter) and c.3113C>T (p.Ala1038Val).

3 Functional / Experimental Evidence

Biochemical assays of the C-terminal nucleotide binding domain (NBD2) confirmed ABCA4 ATPase activity and showed that patient-derived missense mutations (e.g., p.Leu2027Phe) significantly alter K_m and V_max ([PMID:11123914]). Broader functional analyses revealed a spectrum of defects in protein expression, ATP binding and ATPase rates for RP-associated variants ([PMID:11017087]). Splice-switching oligonucleotides restored normal splicing in mouse retinal cells, supporting therapeutic targeting of ABCA4 splice defects ([PMID:26325627]).

4 Conflicting Evidence

No studies have robustly refuted ABCA4’s role in autosomal recessive RP; heterozygous carriers may have AMD risk but this does not undermine the recessive RP association.

5 Integration & Conclusion

Genetic and functional data converge to establish ABCA4 as a definitive cause of autosomal recessive RP. Severe loss-of-function alleles lead to early‐onset rod-cone degeneration, while hypomorphic and deep-intronic variants correlate with milder or late-onset phenotypes. ABCA4 variant identification guides diagnosis, genetic counseling, and emerging allele-specific therapies.

Key Take-home: ABCA4 genetic testing is critical for confirming autosomal recessive RP, informing prognosis and eligibility for targeted molecular interventions.

References

• Ophthalmic research • 2004 • Association of a homozygous nonsense mutation in the ABCA4 (ABCR) gene with cone-rod dystrophy phenotype in an Italian family. PMID:15017103
• Human molecular genetics • 1998 • Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR. PMID:9466990
• Bioscience reports • 2018 • Identification of a Novel Mutation in the ABCA4 Gene in a Chinese Family with Retinitis Pigmentosa Using Exome Sequencing. PMID:29437900
• Biochemistry • 2000 • The C-terminal nucleotide binding domain of the human retinal ABCR protein is an adenosine triphosphatase. PMID:11123914
• Nature genetics • 2000 • Biochemical defects in ABCR protein variants associated with human retinopathies. PMID:11017087
• Molecular therapy. Nucleic acids • 2015 • Intravitreal Injection of Splice-switching Oligonucleotides to Manipulate Splicing in Retinal Cells. PMID:26325627

Evidence Based Scoring (AI generated)