A novel mutation in the ELOVL4 gene causes autosomal dominant Stargardt-like macular dystrophy.
OBJECTIVE
To conduct clinical and genetic studies in a European family with autosomal dominant Stargardt-like macular dystrophy (adSTGD-like MD) and to investigate the functional consequences of a novel ELOVL4 mutation.


METHODS
Ophthalmic examination and mutation screening by direct sequencing of the ELOVL4 gene was performed in two affected individuals. Wild-type and mutant ELOVL4 genes were expressed as enhanced green fluorescent protein (EGFP) fusion proteins in transient transfection in NIH-3T3 and HEK293 cells. To determine the subcellular localization of ELOVL4, an endoplasmic-reticulum (ER)-specific marker for pDsRed2-ER was cotransfected with ELOVL4 constructs. Transfected cells were viewed by confocal microscopy. Western blot analysis was performed to assess protein expression using an anti-GFP antibody.


RESULTS
Affected patients exhibited macular atrophy with surrounding flecks characteristic of adSTGD-like MD. A novel ELOVL4 p.Tyr270X mutation was detected in affected individuals. In cell-transfection studies, wild-type ELOVL4 localized preferentially to the ER. In contrast, the mutant protein appeared to be mislocalized within transfected cells.


CONCLUSIONS
In a European family with adSTGD-like MD, a novel ELOVL4 mutation was found to underlie the disorder. Transfection studies indicated that, unlike wild-type ELOVL4, the mutant protein does not localize to the ER but rather appears to be sequestered elsewhere in an aggregated pattern in the cytoplasm. Further analysis of the function of normal and mutant ELOVL4 will provide insight into the mechanism of macular degeneration.
Maugeri
Alessandra
A
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10, PO Box 9101, 6500 HB Nijmegen, The Netherlands. a.maugeri@antrg.umcn.nl
Meire
Francoise
F
Hoyng
Carel B
CB
Vink
Carolien
C
Van Regemorter
Nicole
N
Karan
Goutam
G
Yang
Zhenglin
Z
Cremers
Frans P M
FP
Zhang
Kang
K
D000293:Adolescent; D000328:Adult; D001284:Atrophy; D015153:Blotting, Western; D002460:Cell Line; D018388:Codon, Terminator; D003593:Cytoplasm / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005799:Genes, Dominant; D049452:Green Fluorescent Proteins; D006801:Humans; D008164:Luminescent Proteins; D008266:Macula Lutea / Q000473:pathology; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D018613:Microscopy, Confocal; D009154:Mutation; D010375:Pedigree; D014018:Tissue Distribution; D014162:Transfection; D014443:Tyrosine; D014792:Visual Acuity
D018388:Codon, Terminator; C418975:ELOVL4 protein, human; D005136:Eye Proteins; D008164:Luminescent Proteins; D008565:Membrane Proteins; D049452:Green Fluorescent Proteins; D014443:Tyrosine