ELOVL4 – Stargardt Disease

ELOVL4 variants have been reported in a total of 12 unrelated patients with clinically diagnosed Stargardt disease (MONDO:0019353): two probands in a Turkish cohort (PMID:27813578), one patient carrying two promoter variants (PMID:29417145), a single sporadic missense c.59A>G (p.Asn20Ser) case (PMID:32534057), and eight Swiss patients sharing a founder truncating allele c.810C>G (p.Tyr270Ter) (PMID:34073554). These reports lack informative pedigree segregation and in most families the inheritance pattern and phase are unresolved.

Functional studies demonstrate that truncating ELOVL4 alleles mislocalize from the endoplasmic reticulum and form cytoplasmic aggregates, sequestering wild-type protein and inducing cellular stress (PMID:15557430; PMID:15028284; PMID:16036915). Enzymatic assays and knock-in mouse models further support a dominant-negative mechanism with loss of very-long-chain polyunsaturated fatty acid synthesis (PMID:23509295; PMID:16877435).

Overall, the clinical validity of ELOVL4 for generic Stargardt disease (MONDO:0019353) is Limited given the small number of unrelated probands, absence of segregation data, and overlap with ABCA4-mediated AR STGD1. Functional evidence is concordant with a dominant-negative mechanism but derives primarily from STGD3 models. Additional segregation studies and natural history data are needed before ELOVL4 testing can be routinely applied for MONDO:0019353.

Key take-home: Limited genetic evidence links ELOVL4 to Stargardt disease, though robust functional data support dominant-negative pathogenicity of truncating alleles; further familial studies are required to establish diagnostic utility.

References

• Genetics and Molecular Research • 2016 • Analysis of ELOVL4 and PRPH2 genes in Turkish Stargardt disease patients. PMID:27813578
• Investigative Ophthalmology & Visual Science • 2018 • Stargardt Phenotype Associated With Two ELOVL4 Promoter Variants and ELOVL4 Downregulation: New Possible Perspective to Etiopathogenesis? PMID:29417145
• Genes • 2021 • Absence of Genotype/Phenotype Correlations Requires Molecular Diagnostic to Ascertain Stargardt and Stargardt-Like Swiss Patients. PMID:34073554
• Investigative Ophthalmology & Visual Science • 2004 • A novel mutation in the ELOVL4 gene causes autosomal dominant Stargardt-like macular dystrophy. PMID:15557430
• Genomics • 2004 • Atrophic macular degeneration mutations in ELOVL4 result in the intracellular misrouting of the protein. PMID:15028284
• The Journal of Biological Chemistry • 2005 • Dominant negative mechanism underlies autosomal dominant Stargardt-like macular dystrophy linked to mutations in ELOVL4. PMID:16036915
• Proceedings of the National Academy of Sciences • 2013 • Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy. PMID:23509295
• Investigative Ophthalmology & Visual Science • 2006 • Haploinsufficiency is not the key mechanism of pathogenesis in a heterozygous Elovl4 knockout mouse model of STGD3 disease. PMID:16877435

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