ABCA4 – Stargardt Disease

ABCA4 encodes a photoreceptor-specific ATP-binding cassette transporter critical for all-trans-retinal clearance in rod and cone outer segments. Mutations in ABCA4 underlie Stargardt disease (STGD1; MONDO:0019353), the most common autosomal recessive macular dystrophy characterized by childhood central vision loss and progressive macular atrophy. Inheritance is autosomal recessive, with pseudodominant patterns arising from the high carrier frequency of pathogenic alleles.

Genetic evidence supporting a definitive association includes segregation of biallelic ABCA4 variants in large multicase families, compound heterozygosity in unrelated probands, and pseudodominant transmission in populations with high allele frequencies. Over 800 distinct ABCA4 mutations have been reported worldwide, with >1,000 probands studied[PMID:9973280]. Founder effects, such as the c.2588G>C (p.Gly863Ala) allele in Western Europeans, account for ~37.5 % of disease alleles in some cohorts[PMID:10090887].

The variant spectrum spans missense, nonsense, frameshift, canonical splice-site, deep-intronic and copy-number variants. Two prevalent missense mutations, c.5882G>A (p.Gly1961Glu) and c.3113C>T (p.Ala1038Val), each comprise ~9 % of STGD1 alleles[PMID:9973280]. Hypomorphic alleles such as c.5603A>T (p.Asn1868Ile; MAF ~7 %) modulate disease penetrance and onset, often presenting as late-onset foveal sparing disease when in trans with severe variants[PMID:29971439].

Functional studies demonstrate that the C-terminal nucleotide binding domain 2 of ABCA4 is an active ATPase, with patient-derived mutants showing altered ATP affinity (e.g., p.Leu2027Phe, K m shift 631 μM → 46 μM and V max reduction) and mislocalization in photoreceptors[PMID:11123914]. In vitro splice assays and patient-derived photoreceptor progenitor cells confirm that the intronic c.5461-10T>C variant causes exon 39 skipping and protein truncation[PMID:26976702]. Expression and ATPase assays of >20 ABCA4 missense variants correlate residual activity with clinical severity[PMID:29847635].

No significant conflicting evidence has refuted the role of ABCA4 in STGD1. Common ABCA4 variants have also been ruled out as major contributors to age-related macular degeneration, distinguishing STGD1 from complex late-onset retinal disorders.

In summary, ABCA4 has a definitive ClinGen gene-disease association with autosomal recessive Stargardt disease, supported by extensive genetic segregation, diverse variant spectrum, and concordant functional data. Comprehensive ABCA4 sequencing and copy-number analysis are essential for accurate diagnosis, genetic counseling, and eligibility for emerging variant-specific therapies.

References

• American Journal of Human Genetics • 1999 • Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease PMID:9973280
• American Journal of Human Genetics • 1999 • The 2588G-->C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease PMID:10090887
• Biochemistry • 2000 • The C-terminal nucleotide binding domain of the human retinal ABCR protein is an adenosine triphosphatase PMID:11123914
• Ophthalmology • 2016 • Photoreceptor Progenitor mRNA Analysis Reveals Exon Skipping Resulting from the ABCA4 c.5461-10T>C Mutation in Stargardt Disease PMID:26976702
• Investigative Ophthalmology & Visual Science • 2018 • The Common ABCA4 Variant p.Asn1868Ile Shows Nonpenetrance and Variable Expression of Stargardt Disease When Present in trans With Severe Variants PMID:29971439
• Investigative Ophthalmology & Visual Science • 2018 • Correlating the Expression and Functional Activity of ABCA4 Disease Variants With the Phenotype of Patients With Stargardt Disease PMID:29847635

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