ELOVL4 – Stargardt Disease 3

Stargardt disease 3 (STGD3) is an autosomal dominant juvenile-onset macular dystrophy characterized by progressive loss of central visual acuity and macular atrophy. The disease is caused by heterozygous mutations in ELOVL4, which encodes a very long-chain fatty acid elongase localized to the endoplasmic reticulum (PMID:15557430). Truncating and frameshift variants cluster in exon 6, abolishing the C-terminal dilysine ER-retention motif and leading to pathological mislocalization and aggregation.

Inheritance is autosomal dominant, with at least 6 probands across three unrelated pedigrees (PMID:15557430, PMID:15028284, PMID:23509295) and segregation in 8 affected relatives (PMID:15557430). Reported variant classes include frameshift indels (c.790_794del (p.Asn264fs)), nonsense mutations (c.810C>G (p.Tyr270Ter), c.646C>T (p.Arg216Ter)), and missense alleles (c.59A>G (p.Asn20Ser)). Recurrent hotspots at the 5-bp deletion and c.810C>G sites underscore mutational clustering.

Functional assays demonstrate that C-terminal truncation mutants mislocalize from the ER to aggresomes, sequester wild-type ELOVL4 via dominant-negative interaction, and trigger the unfolded protein response and apoptosis in cell culture (PMID:16036915, PMID:15073583). In vivo, STGD3 knock-in mice recapitulate lipofuscin accumulation and reduced electroretinogram amplitudes, confirming the pathogenic mechanism (PMID:17356513).

Overall, the genetic and experimental evidence support a Strong clinical validity classification for the ELOVL4–STGD3 association. Additional large-scale cohorts and long-term follow-up could elevate this to a Definitive designation.

Key take-home: ELOVL4 sequencing is critical for diagnosing autosomal dominant STGD3 and guiding genetic counseling.

References

• 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
• Proceedings of the National Academy of Sciences of the United States of America • 2013 • Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy. PMID:23509295
• The Journal of biological chemistry • 2005 • Dominant negative mechanism underlies autosomal dominant Stargardt-like macular dystrophy linked to mutations in ELOVL4. PMID:16036915
• Molecular vision • 2004 • Expression of wild type and mutant ELOVL4 in cell culture: subcellular localization and cell viability. PMID:15073583
• Molecular vision • 2007 • Retinal pathology and skin barrier defect in mice carrying a Stargardt disease-3 mutation in elongase of very long chain fatty acids-4. PMID:17356513

Evidence Based Scoring (AI generated)