ABCA4 mutations causing mislocalization are found frequently in patients with severe retinal dystrophies

The Clinical Effect of Homozygous ABCA4 Alleles in 18 Patients

“…Patient 3, homozygous for p.Leu541Pro and p.Ala1038Val, had a very early onset associated with severe disease. These findings are similar to genetically identical patients reported by Wiszniewski et al 22 A very severe phenotype also was observed in patient 8 (p.Arg1640Trp), in keeping with the severe findings of genetically identical subjects, homozygous for p.Arg1640Trp, in a previous report by Briggs et al 10 In contrast, patients with homozygous null variants consistently showed a very severe phenotype: 6 of 7 had early-onset disease (<10 years), and all 7 had electrophysiologic evidence of generalized rod and cone system dysfunction. These findings support previous familial reports 6,10,27 and highlight the fact that generalized functional loss (ERG) precedes fundus or AF abnormalities, as observed in 5 pediatric patients.…”

“…2,13 In only a few studies is it possible to evaluate the effects of specific variants. 12,14,20,22,23,25 Individuals who have homozygous variants in ABCA4 offer a valuable opportunity to investigate the phenotype associated with specific single variants. There are a number of reports of families or small case series describing the phenotypic features of homozygous patients, 6,10,11,22,25e28 and 1 report features homozygous patients with 1 specific common allele (p.Gly1961Glu).…”

Pediatric Hereditary Macular Degenerations

“…That the spectrum of disease is likely to represent a continuum is suggested by the identification of pedigrees with STGD1 and CORD or RP in different individuals [53]. Truncation mutants of ABCR (hypomorphic mutants) commonly lead to the development of STGD1, missense mutations not involving charged residues commonly promote FFM, and mutations promoting mislocalization of the protein cause RP [151][152][153][154], (Wiszniewski et al, 2005). These studies suggest a plethora of functional and structural impairments of the ABCR protein proper that manifest a range of clinical outcomes at the level of photoreceptor metabolism and survivability.…”

Protein Misfolding and Retinal Degeneration

“…These mutations cause retention of ABCA4 in the photoreceptor inner segment, likely by impairing correct folding, resulting in the total absence of physiologic protein function (Wiszniewski et al 2005). …”