# Stargardt disease with low lipofuscin

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $508,519

## Abstract

Autosomal recessive macular dystrophies caused by mutations in the ABCA4 gene, STGD1, CRD, RP,
etc., are together the most prevalent Mendelian inherited cause of vision loss in both children and adults.
Importantly, 5% (1:20) of the general population carry a disease-associated ABCA4 allele although not all
combinations of variants are fully penetrant. Despite extensive genetic variability, several mutations account for
large fractions of the disease and often result in specific, discernable sub-phenotypes. The most frequent
disease-associated ABCA4 allele, p.G1961E, is a causal mutation in 20% to 50% of patients amongst
ethnically different populations. When present in either compound heterozygous or homozygous state it results
in a very consistent phenotype characterized by early ablation of foveal cones, but otherwise slow progression
and the absence or moderate expression of the major consequence of ABCA4 protein dysfunction, lipofuscin
accumulation. Another recently identified common disease allele, p.N1868I, is present in ~7% in the general
population and represents an ‘extremely’ hypomorphic allele, which is causal only when in trans with a
deleterious allele. Patients harboring p.N1968I also exhibit no significant lipofuscin accumulation, slow disease
progression and disease changes similar to p.G1961E. However, in contrast to p.G1961E patients, p.N1868I is
highly associated with the “foveal sparing” phenotype, i.e., preservation of foveal cones during the course of
the disease. Since lipofuscin accumulation, and consequent RPE toxicity, is the common therapeutic target for
ABCA4 disease, existing data suggest that such interventions may have no applicability for patients harboring
p.G1961E and p.N1861I as causal variants. Elucidating the functional consequences of these two variants
would direct treatment options for up to half of affected individuals with ABCA4 disease.
 The proposed research strategy utilizes complementary clinical and functional methodology and is
organized into two Specific Aims. In the first Aim, we propose using our existing genetic and clinical databases,
accumulated knowledge, and a combination of advanced imaging methods and functional testing to determine
precise, quantifiable differences between patients with hypomorphic alleles and other deleterious alleles. In the
second Aim we will determine the functional consequences of the hypomorphic ABCA4 mutations on protein
function by a combination of studies, which determine the mutant protein structure, localization, transport and
ATPase activity, in iPSC-derived patient cell cultures and mouse models. The outcome of these studies will
substantially aid in disease diagnosis, prognosis and will serve as a platform for designing clinical trials for a
significant fraction of ABCA4 disease.

## Key facts

- **NIH application ID:** 10085237
- **Project number:** 5R01EY028954-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** RANDO L ALLIKMETS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $508,519
- **Award type:** 5
- **Project period:** 2019-03-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10085237

## Citation

> US National Institutes of Health, RePORTER application 10085237, Stargardt disease with low lipofuscin (5R01EY028954-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10085237. Licensed CC0.

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