Stargardt macular dystrophies are a collection of
early-onset disorders characterized by macular atrophy surrounded by
lipofuscin-containing orange-yellow fundus flecks. Stargardt disease
(STGD; Mendelian Inheritance in Man [MIM] 248200) can be inherited as
an autosomal recessive (ar) trait (MIM 248200) or an autosomal dominant
(ad) trait (MIM 600110; 603786). All recessive forms of STGD have been
linked to a locus on 1p32, containing the
ABCR (
ABCA4) gene.
1 Mutations in
ABCR, a
photoreceptor-specific adenosine triphosphate (ATP)-binding cassette
(ABC) transporter, are causal in arSTGD
2 and in a
number of other retinal diseases, such as recessive cone–rod dystrophy
(CRD),
3 and some forms of autosomal recessive retinitis
pigmentosa (RP19).
4 5 Heterozygous carriers of
ABCR variant alleles are more susceptible to age-related
macular degeneration (AMD), a late-onset complex trait.
6 7 Rare autosomal dominant forms of STGD-like phenotypes have been mapped
to several loci on the human genome, including those on chromosome 6q14
(STGD3)
8 and 4p (STGD4).
9 Recently, we cloned
and characterized the gene responsible for STGD-like macular dystrophy
(STGD3) on 6q14.
10 The protein, encoded by this
photoreceptor-specific gene, elongation factor of very-long-chain fatty
acids (ELOVL4), probably performs an important function in the
biosynthesis of photoreceptor outer segment membrane components.
Affected members in all five families segregating the STGD3 or other
macular dystrophy phenotypes harbored the same presumed founder
mutation, 797-801delAACTT.
10 This 5-bp deletion causes a
frameshift and premature termination of the protein, strongly
suggesting the pathogenic nature of this sequence change. Until now,
screening of patients with AMD or additional families with autosomal
dominant macular dystrophy phenotypes has not revealed any other
disease-associated
ELOVL4 sequence variants
11 to directly support the previous conclusion. In the current study, we
investigated the potential involvement of
ELOVL4 gene
variation in adSTGD-like and other macular dystrophy phenotypes
segregating in a large pedigree from Utah.