An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease.

Autosomal recessive retinal degenerative diseases cause visual impairment and blindness in both humans and dogs. Currently, no standard treatment is available, but pioneering gene therapy-based canine models have been instrumental for clinical trials in humans. To study a novel form of retinal degeneration in Labrador retriever dogs with clinical signs indicating cone and rod degeneration, we used whole-genome sequencing of an affected sib-pair and their unaffected parents. A frameshift insertion in the ATP binding cassette subfamily A member 4 (ABCA4) gene (c.4176insC), leading to a premature stop codon in exon 28 (p.F1393Lfs*1395), was identified. In contrast to unaffected dogs, no full-length ABCA4 protein was detected in the retina of an affected dog. The ABCA4 gene encodes a membrane transporter protein localized in the outer segments of rod and cone photoreceptors. In humans, the ABCA4 gene is associated with Stargardt disease (STGD), an autosomal recessive retinal degeneration leading to central visual impairment. A hallmark of STGD is the accumulation of lipofuscin deposits in the retinal pigment epithelium (RPE). The discovery of a canine homozygous ABCA4 loss-of-function mutation may advance the development of dog as a large animal model for human STGD.

Characterization of the ABCA4 gene in Stargardt's Disease in Trinidad and Tobago

Objectives: Stargardt's disease is an autosomal recessive macular dystrophy caused by mutations in the photoreceptor cell-specific ATP-binding cassette sub-family A member 4, transporter (ABCA4) gene. We studied (i) the predicted effects of mutations on the function of the ABCA4 transporter and (ii) the existence of four common mutations in local Stargardt patients. Design and Methodology: (i) The freeware PROVEAN (Protein VariationEffect Analyzer; J. Craig Venter Institute, CA,USA) was used to predict the deleterious effect257 mutations in the ABCA4 gene. PROVEANscores below -2.5 were considered deleterious.One-way ANOVAs were used to detect anysignificant differences in mean (±SE) PROVEANscores among mutation types or protein domains I,II, III or IV. (ii) Using saliva, DNA was isolated from three Stargardt patients. Chromosomal regions were amplified by PCR, sequenced (Macrogen Inc., Seoul, Korea) and sequence alignment (NCBI, MD, USA) used to detect the presence of four mutations; c.768G>T (p.Val256=), c.4469G>A (p.Cys1490Tyr), c.6079C>T (p.Leu2027Phe) and c.1804C>T (p.Arg602Trp). Results: (i) Sixty-three percent of mutations predicted deleterious effects. There were no significant (p<0.05) differences between mean PROVEAN scores among mutation types (substitutions, - 4.49±0.20; deletions/insertions, -6.35±0.67) or protein domains (domain I, -4.79 ± 0.39; domain II, -4.65 ± 0.36; domain III, -5.48 ± 0.51; domain IV, -4.39 ± 0.34). (ii) These mutations were not detected in Stargardt's patients. Conclusion: (i) Functionality of the ABCA4 protein is affected by multiple mutations. (ii) Novel mutations are present in local patients. Currently, we seek to profile novel mutations in six families using molecular inversion probes.

Enfermedad de stargardt o degeneración macular de stargardt / Stargardt disease or stargardt macular degeneration

La degeneración macular de Stargardt es considerada una enfermedad rara pues se presenta un caso por cada 10.000 personas (1).Es de transmisión hereditaria de un patrón autosómico recesivo. Está provocada por una mutación del gen ABCA4, que tiene una función transportadora a través de la membrana de las células fotorreceptoras. Hay 558 mutaciones diferentes que pue-den originar el mal (2).La enfermedad Stargardt y Fundusflavima-culatus son la misma enfermedad, siendo el segundo, un estado más avanzado de almacenamiento de lipofucsina (3).CASO CLINÍCOPaciente de 16 años de edad acude a consulta de medicina preventiva refiriendo presentar disminución de agudeza visual, antecedentes de miopía y astigmatismo con debida corrección de error refracta-rio. Actualmente presenta disminución de agudeza visual más notoria en zona central, usando así su visión periférica. Agudeza visual: 20/100. Campimetría: hay es-cotomas. Angiofluorgrafía: muestra una coroides oscura por depósitos de lipofuscina del epitelio pigmentario de la retina dando como resultado la enfermedad de Stargardt.

The Stargardt Macular degeneration is con-sidered a rare disease; one case per 10,000 people is presented. (1)It is Inheritance and it is given an autoso-mal recessive pattern. It is caused by a mu-tation of ABCA4 gene, which has a trans-port function through the membrane of the photoreceptor cells. There are 558 different mutations that can cause it. (2)The Stargardt disease and fundusflavima-culatus are the same disease, the second is a more advanced state of lipofuscin sto-rage. (3)CASE REPORTA 16 years old patient attends to the pre-ventive health referring to have a decrea-sed visual acuity, history of myopia and as-tigmatism with refractive error correction. Currently has more noticeable decrease in central visual acuity, so using your periphe-ral vision. Visual acuity 20/100 Campimetry: there is noscotoma, angiofluorgrafia: it dis-plays a dark choroid by deposits of lipofus-cin of the pigment epithelium of the retina which results the Stargardt disease.