ABCA4 – Cone-Rod Dystrophy

ABCA4 encodes a photoreceptor-specific ATP-binding cassette transporter essential for clearing all-trans-retinal derivatives from outer segments. Germline biallelic ABCA4 mutations cause autosomal recessive cone-rod dystrophy (CRD), characterised by early cone dysfunction with subsequent rod involvement, leading to progressive central and peripheral vision loss. Abca4 dysfunction spans a clinical continuum from Stargardt disease to CRD and retinitis pigmentosa, reflecting mutation severity.

Genetic evidence for ABCA4 in CRD is strong: in AR-CRD cohorts, ABCA4 variants were detected in 13 of 20 probands (65%) (PMID:10958761), 11 of 30 (37%) (PMID:11846518), 18 of 54 (33%) (PMID:15494742), 17 of 65 (26%) (PMID:22264887), and biallelic variants in 16 of 64 (25%) (PMID:18285826). These findings across independent populations support a reproducible autosomal recessive inheritance pattern.

Segregation analyses in a consanguineous pedigree demonstrated five affected relatives with compound heterozygous splice site mutations and a null allele, confirming AR transmission ([PMID:9466990]). Additional pedigree studies report pseudo-dominant clusters attributable to the high carrier frequency of ABCA4 alleles.

Variant spectrum in CRD includes protein-truncating alleles (nonsense, frameshift, splice), missense substitutions, and rare deep-intronic changes. A representative null mutation, c.2971G>T (p.Gly991Ter), was identified homozygously in an Italian family with early-onset CRD (PMID:15017103). Recurrent and population-specific alleles, such as p.Leu541Pro;Ala1038Val, further underscore allelic heterogeneity.

Functional assays demonstrate that missense and splice variants impair ABCA4 folding, ATPase activity, and proper trafficking. The C-terminal nucleotide-binding domain exhibits altered kinetics for p.Leu2027Phe (PMID:11123914), and severe protein defects in p.Gly1961Glu and p.Arg2107His correlate with null function (PMID:11017087). Splice-switching oligonucleotides can rescue aberrant CEP290 and ABCA4 splicing in retinal cells, highlighting potential therapeutic avenues (PMID:26325627).

Genotype–phenotype correlations reveal that biallelic truncating variants lead to severe early-onset CRD, whereas hypomorphic alleles (e.g., p.Asn1868Ile) confer late-onset foveal-sparing phenotypes. Comprehensive ABCA4 testing, including coding, splice, and CNV analysis, is critical for accurate diagnosis, prognosis, and patient selection for emerging therapies.

Key Take-home: ABCA4 is a definitive autosomal recessive CRD gene; full locus screening informs clinical management and therapeutic stratification.

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
• American Journal of Human Genetics • 2000 • Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy. PMID:10958761
• Experimental Eye Research • 2001 • Visual function in patients with cone-rod dystrophy (CRD) associated with mutations in the ABCA4(ABCR) gene. PMID:11846518
• European Journal of Human Genetics • 2004 • Microarray-based mutation analysis of the ABCA4 (ABCR) gene in autosomal recessive cone-rod dystrophy and retinitis pigmentosa. PMID:15494742
• Ophthalmology • 2012 • Clinical course, genetic etiology, and visual outcome in cone and cone-rod dystrophy. PMID:22264887
• European Journal of Human Genetics • 2008 • ABCA4 gene analysis in patients with autosomal recessive cone and cone rod dystrophies. PMID:18285826
• 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
• 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

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