Meta-Biol

• Pathways

ATP-binding cassette protein A4 (ABCA4, ABCR), expressed exclusively in retinal photoreceptors, is thought to be involved in the clearance of toxic by-products of the retinoid cycle. Defects in ABCA4 cause a diverse range of human diseases. One such disease is Stargardt's disease type 1 (STGD1, MIM:248200) (Allikmets et al. 1997), an autosomal recessive form of juvenile macular degeneration leading to progressive irreversible loss of central vision and delayed dark adaptation. STGD1 was first identified by Stargardt in 1909 (Stargardt, Arch. Klin. Exp. Ophthal. 71: 534-549, 1909), has an approximate prevalence of 1 in 10,000 (see reviews Paskowitz et al. 2006, Walia & Fishman 2009) and is usually diagnosed within the first two decades of life.

The cause of retinal cell death is believed to be due to the accumulation of an age-related pigment called lipofuscin, which contains toxic by-products of the visual cycle (see review Sparrow et al. 2009). One prevelant toxic by-product, diretinoid-pyridinium-ethanolamine (A2E), is formed from condensation of two molecules of all-trans-retinal and one molecule of phosphatidylethanolamine (PE). Its precursors (atRAL and N-retinyl-phosphatidylethanolamine (NRPE)) are found in ocular tissues from Stargardt patients (Rozet et al. 1998). Another toxic intermediate is atRAL itself, the precursor to A2E. Studies in Abca4- and Rdh-deficient mice reveal atRAL's involvement in acute light-induced retinopathy (Maeda et al. 2009a, b).

Common mutations leading to STGD1 are A1038V, G1961E (Lewis et al. 1999), G863A (or delG863, not described here; Maugeri et al. 1999), R943Q (Allikmets et al. 1997) and T1428M (thought to be prevelant in 8% of the Japanese population; Kuroiwa et al. 1999).