Disease relevance of ABCA4

• Heterozygosity for ABCA4 mutations may also represent a risk factor for age-related macular degeneration (AMD), although this idea is controversial [1].
• Sequence variants in a gene coding for a retina-specific ATP-binding cassette (ABCA4) transporter protein, which is responsible for a phenotypically similar Mendelian form of retinal disease, were proposed to increase the risk of ARM [2].
• These two ABCA4 alleles were slightly more frequent in patients with AMD with choroidal neovascularization (2.7%) than those without this complication (2.5%) [3].
• Cellular mechanisms of retinal degenerations: RPE65, ABCA4, RDS, and bicarbonate transporter genes as examples [4].
• Two other genes from ABCA subfamily are associated with human inherited diseases, ABCA1 with the cholesterol transport disorders Tangier disease and familial hypoalphalipoproteinemia, and ABCA4 with several retinal degeneration disorders [5].

Psychiatry related information on ABCA4

• These findings imply that the FFM deficits are not caused by impairment of basic visual motion or form perception but are the consequence of damage to a parietal brain structure involved in the combined analysis of visual motion and form information [6].
• The simple model was described by V(O2) peak = M(b) (or FFM(b)) exp(c SR-PA) exp(a + d age) epsilon (where M is body mass in kg; FFM is fat-free mass in kg; SR-PA is self-reported physical activity; epsilon is a multiplicative error term; and exp indicates natural antilogarithms) [7].
• The NEO-FFI is a brief personality inventory measuring each of the key dimensions of the five-factor model of personality (FFMP), a comprehensive, empirically-derived model of personality structure [8].
• Children with eating disorders of normal weight, such as bulimia nervosa and selective eating, did not differ significantly from reference children in their relative FM and FFM [9].
• The Chinese FFM and MFM are valid and reliable measures of family and marital functioning in Chinese-speaking SLE patients, with psychometric properties very similar to the source English version [10].

High impact information on ABCA4

• An ongoing challenge in the analysis of ABCA4-based retinopathies arises from the observation that most of the ABCA4 sequence variants identified so far are missense mutations that are rare in both patient and control populations [1].
• Here we show by immunofluorescence microscopy and western-blot analysis that ABCR is present in foveal and peripheral cone, as well as rod, photoreceptors [11].
• ABCR expression in foveal cone photoreceptors and its role in Stargardt macular dystrophy [11].
• Here, we characterize the ocular phenotype in abcr knockout mice [12].
• Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR [13].

Chemical compound and disease context of ABCA4

• CONCLUSIONS: Some individuals who have ABCR mutations may be predisposed to develop retinal toxicity when exposed to chloroquine/hydroxychloroquine [14].
• Analysis of the ABCR (ABCA4) gene in 4-aminoquinoline retinopathy: is retinal toxicity by chloroquine and hydroxychloroquine related to Stargardt disease [14]?
• Evaluation of the ABCR and glutathione peroxidase-3 genes in familial and sporadic cases of exudative age-related macular degeneration [15].
• CONCLUSIONS: Turner's syndrome is associated with glucose intolerance, diminished first-phase insulin response, elevated blood pressure, reduced FFM, and physical fitness [16].
• The increased weight loss in the sibutramine group was associated with an increase in the FFM adjusted REE (2.2+/-16.1%) unlike the expected decrease (5.8+/-9.5%) in the placebo group (P=0.11) [17].

Biological context of ABCA4

• The missense mutations were analyzed functionally in the photoreceptors of Xenopus laevis tadpoles, which revealed mislocalization of ABCA4 protein [18].
• Overall, there were 2480 instances of 213 different variants in the ABCA4 gene, including 589 instances of 97 amino acid substitutions, and 45 instances of 33 truncating variants [19].
• No evidence was found of significantly different allele frequencies of ABCA4 sequence variants in patients compared with control subjects, and no evidence for association or cosegregation with disease in family-based analyses [2].
• Haplotype analysis in 16 families segregating the 2588G>C mutation showed four intragenic polymorphisms invariably present in all 16 disease chromosomes and sharing of the same allele for several markers flanking the ABCA4 locus in most of the disease chromosomes [20].
• Here we describe ABCA4-associated phenotypes, including a proband with a homozygous nonsense mutation in a family from Southern Italy [21].

Anatomical context of ABCA4

• 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 [18].
• Both ABCA1 and ABCA4 have been shown to transport lipids across cellular membranes, and ABCA3 may play a similar role in transporting pulmonary surfactant [22].
• These results suggest that glycosylated ABCA4 protein is expressed in rat choroid plexus epithelial cells [23].
• RT-PCR analysis detected ABCA4 mRNA in isolated rat choroid plexus and conditionally immortalized rat choroid plexus epithelial cells (TR-CSFB) [23].
• In situ hybridization analysis revealed that ABCA4 mRNA was localized in the lateral ventricles [23].

Associations of ABCA4 with chemical compounds

• Mutations in ABCA4 result in accumulation of lipofuscin before slowing of the retinoid cycle: a reappraisal of the human disease sequence [24].
• Chimeric transporters, generated by substituting the C termini of either ABCA4 or ABCA7 for the endogenous terminus, demonstrated that ABCA1 could stimulate cholesterol efflux without its PDZ-binding motif but not without the VFVNFA motif [25].
• Moreover, the transporter ABCA4 (ABCR) plays a pivotal role in retinaldehyde processing, and ABCA3 has recently implicated in lung surfactant processing [26].
• We have previously described a general ribonucleotidase activity of the first nucleotide binding domain (NBD1) of human ABCR (Biswas, E. E. (2001) Biochemistry 40, 8181-8187) [27].
• Homozygous Null Mutations in the ABCA4 Gene in Two Families With Autosomal Recessive Retinal Dystrophy [28].

Other interactions of ABCA4

• In particular, the expression of ABCA4 and ABCC3 was increased by 132- and 459-fold, respectively, whereas ABCG2 was increased by approximately 3000-fold [29].
• The nucleotide diversity of the ABCA4 coding region, a collective measure of the number and prevalence of polymorphic sites in a region of DNA, was found to be 1.28, a value that is 9 to 400 times greater than that of two other macular disease genes that were examined in a similar fashion (VMD2 and EFEMP1) [19].
• Here, we identify a new kindred with dominant STGD and demonstrate genetic linkage to the STGD3 locus [30].
• The expanding roles of ABCA4 and CRB1 in inherited blindness [31].
• No disease causative mutations have been identified in MYOC or ABCA4 [32].

Analytical, diagnostic and therapeutic context of ABCA4

• A combination of denaturing high-performance liquid chromatography (DHPLC) and bidirectional sequencing was used to detect ABCA4 sequence variants [2].
• Furthermore, ABCA4 protein was also detected in the isolated rat choroid plexus at about 250 kDa by western blot analysis, and its apparent molecular size was reduced by N-glycosidase F treatment [23].
• METHODS: Two pairs of siblings with STGD1, for whom diagnosis had been confirmed by genetic linkage to the ABCA4 gene region, were examined regarding visual acuity, kinetic perimetry, fundus photography, full-field ERG and multifocal ERG (MERG) [33].
• Animal models created by removing the normal genes, similar to what was performed with ABCA4, can assist in the development of therapeutic interventions [34].
• Using trypsin digestion, site-directed mutagenesis, concanavalin A binding, and endoglycosidase digestion, we show that ABCR contains eight glycosylation sites [35].

References