ABCMdb

PMID: 24713488

Bertelsen M, Zernant J, Larsen M, Duno M, Allikmets R, Rosenberg T
Generalized choriocapillaris dystrophy, a distinct phenotype in the spectrum of ABCA4-associated retinopathies.
Invest Ophthalmol Vis Sci. 2014 Apr 29;55(4):2766-76. doi: 10.1167/iovs.13-13391., [PubMed]

Sentences

No. Mutations Sentence Comment

13 ABCA4 p.Asn965Ser Most patients harbored at least one mutation classified as ''severe,`` the most common of which was the p.N965S variant that had been found previously at a high frequency among patients with ABCA4-associated retinal dystrophies in Denmark. Login to comment 81 ABCA4 p.Tyr1723* The remaining mutations were 4 nonsense mutations (found in 15% of the patients), 6 deletions (found in 23% of the patients), 6 splice-site mutations (found in 23% of the patients), and 2 other intron mutations. Most of the variants were already known pathogenic mutations; however, the c.5169C>G; p.Y1723* variant found by NGS is a novel and likely deleterious mutation, since it generates a stop codon that terminates translation at codon 1723 of ABCA4. Login to comment 82 ABCA4 p.Asn965Ser The most frequent mutations in the cohort were the p.N965S Danish founder TABLE 1. Login to comment 89 ABCA4 p.Ala1038Val ABCA4 p.Gly863Ala ABCA4 p.Leu541Pro mutation (21%), p.G863A, c.2408delG, and p.L541P/A1038V. Login to comment 114 ABCA4 p.Asn965Ser ABCA4 p.Gln1412* Two ABCA4 mutations were detected in patient D109 from generation III; a common Danish missense mutation p.N965S and a nonsense mutation p.Q1412*. Login to comment 115 ABCA4 p.Gln1412* In the fourth generation, the array screening identified only the p.Q1412* mutation, which was presumably inherited from the unaffected father. Login to comment 123 ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro ABCA4 p.Leu541Pro ABCA4 p.Cys1488Arg ABCA4 p.Cys1490Tyr ABCA4 p.Asn965Ser ABCA4 p.Asn965Ser ABCA4 p.Asn965Ser ABCA4 p.Asn965Ser ABCA4 p.Asn965Ser ABCA4 p.Asn965Ser ABCA4 p.Asn965Ser ABCA4 p.Asn965Ser ABCA4 p.Asn965Ser ABCA4 p.Asn965Ser ABCA4 p.Asn965Ser ABCA4 p.Leu2027Phe ABCA4 p.Val767Asp ABCA4 p.Arg1108Cys ABCA4 p.Arg1108Cys ABCA4 p.Arg2030Gln ABCA4 p.Thr972Asn ABCA4 p.Leu510Arg ABCA4 p.Arg1368Cys ABCA4 p.Arg1368Cys ABCA4 p.Gly550Arg ABCA4 p.Ser1642Arg ABCA4 p.Arg2077Trp ABCA4 p.Arg2077Trp ABCA4 p.Pro68Leu ABCA4 p.Pro68Leu ABCA4 p.Gln1412* ABCA4 p.Gln1412* ABCA4 p.Tyr1723* ABCA4 p.Arg681* Summary of Detected Potential Pathogenic Variants (Known and Novel [in Bold Face]) Found in the ABCA4 Gene of Patients With Generalized Choriocapillaris Dystrophy Patient Method Mutation 1 Mutation 2 Nucleotide Protein Nucleotide Protein D513 NGS c.203C>T p.P68L c.2894A>G p.N965S D514 Microarray, NGS c.2894A>G p.N965S c.5461-10T>C - D516 NGS c.4926C>G p.S1642R c.5041_5055del p.V1681_C1685del D517 NGS c.5169C>G p.Y1723* c.6079C>T p.L2027F D137 Microarray, NGS c.2894A>G p.N965S c.2894A>G p.N965S D801 Microarray, NGS c.6386&#fe;1G>A Aberrant splicing c.4234C>T p.Q1412* D109 Microarray c.2894A>G p.N965S c.4234C>T p.Q1412* D040 Microarray c.6229C>T p.R2077W c.6229C>T p.R2077W D159 Microarray c.3113C>T p.L541P/A1038V c.3113C>T p.L541P/A1038V D129 Microarray c.2894A>G p.N965S c.3322C>T p.R1108C D115 Microarray c.2894A>G p.N965S c.3113C>T p.L541P/A1038V D033 Microarray c.2894A>G p.N965S c.2041C>T p.R681* D023 Microarray c.203C>T p.P68L c.3329-2A>G Aberrant splicing D001 Microarray c.666_678del p.K223_R226delfs c.4667&#fe;2T>C Aberrant splicing D147 Microarray, HRM c.2894A>G p.N965S c.2408delG p.G803fs D162 Microarray c.3329-2A>G Aberrant splicing c.6089G>A p.R2030Q D022 Microarray, HRM c.4462T>C p.C1488R c.4102C>T p.R1368C D112 Microarray, HRM c.2894A>G p.N965S c.1529T>G p.L510R D108 Microarray, HRM c.1648G>A p.G550R c.4102C>T p.R1368C D107 Microarray c.666_678del p.K223_R226delfs c.2588G>C p.G863A D070 Microarray c.2588G>C p.G863A c.2588G>C p.G863A D116 Microarray c.2300T>A p.V767D c.5461-10T>C - D135 Microarray, HRM c.2894A>G p.N965S c.2408delG p.G803fs D117 Microarray, HRM c.3191-2A>G Aberrant splicing c.2408delG p.G803fs D186 Microarray, HRM c.3322C>T p.R1108C c.6386&#fe;1G>A Aberrant splicing D173 Microarray, HRM c.4469G>A p.C1490Y c.2915C>A p.T972N TABLE 3. Login to comment 124 ABCA4 p.Ala1038Val ABCA4 p.Gly863Ala ABCA4 p.Leu541Pro ABCA4 p.Cys1488Arg ABCA4 p.Cys1490Tyr ABCA4 p.Asn965Ser ABCA4 p.Leu2027Phe ABCA4 p.Val767Asp ABCA4 p.Arg1108Cys ABCA4 p.Arg2030Gln ABCA4 p.Thr972Asn ABCA4 p.Leu510Arg ABCA4 p.Arg1368Cys ABCA4 p.Gly550Arg ABCA4 p.Ser1642Arg ABCA4 p.Arg2077Trp ABCA4 p.Pro68Leu ABCA4 p.Gln1412* ABCA4 p.Tyr1723* ABCA4 p.Arg681* In Silico Analysis of ABCA4 Variants Detected in This Study Using Alamut 2.2 Software cDNA Variant Protein Variant Effect on Protein Function AGVGD Class SIFT Prediction Effect on Protein PPH2 Prediction Effect on Protein TASTER Prediction Effect on Splicing Missense variants c.203C>T p.P68L C65 Deleterious Probably damaging Disease causing c.1529T>G p.L510R C65 Deleterious Benign Polymorphism c.1622T>C p.L541P Reduced ATP binding mislocali- zation26,27 C65 Deleterious Probably damaging Disease causing c.1648G>A p.G550R C65 Deleterious Possibly damaging Disease causing New acceptor site c.2300T>A p.V767D Reduced protein28 C65 Deleterious Benign Disease causing c.2588G>C p.G863A Reduced protein level, reduced ATP binding, reduced ATPase activity26 C55 Deleterious Possibly damaging Disease causing Predicted change at acceptor site 1 bp upstream: 11.1%, creating a new stronger acceptor 3 bp downstream c.2894A>G p.N965S Reduced ATP binding26 C45 Deleterious Probably damaging Disease causing New acceptor site c.2915C>A p.T972N C55 Deleterious Probably damaging Disease causing c.3113C>T p.A1038V Reduced ATP binding, reduced ATP hydrolysis26 C65 Deleterious Benign Disease causing c.3322C>T p.R1108C Reduced ATP binding26 C65 Deleterious Probably damaging Disease causing c.4102C>T p.R1368C C65 Deleterious Probably damaging Disease causing c.4462T>C p.C1488R C65 Deleterious Possibly damaging Disease causing c.4469G>A p.C1490Y Misfolding, mislocali- zation27 C65 Deleterious Probably damaging Disease causing Cryptic donor strongly activated c.4926C>G p.S1642R C25 Deleterious Benign Disease causing c.6079C>T p.L2027F Reduced ATP binding26,29 C15 Deleterious Probably damaging Disease causing c.6089G>A p.R2030Q C35 Deleterious Probably damaging Disease causing c.6229C>T p.R2077W Reduced ATP binding26 C65 Deleterious Probably damaging Disease causing Deletion/frame-shift/stop variants c.666_678del p.K223_ R226delfs c.2041C>T p.R681* c.2408delG p.G803fs c.4234C>T p.Q1412* c.5041_5055del p.V1681_ C1685del c.5169C>G p.Y1723* Splicing affecting variants c.3191-2A>G Predicted change at acceptor site 2 bps downstream: 100% c.3329-2A>G Predicted change at acceptor site 2 bps downstream: 100% c.4667&#fe;2T>C Predicted change at donor site 2 bps upstream: 100% generalized choriocapillaris dystrophy have the occasional hallmarks of early Stargardt disease, such as vermillion fundus, fundus hyperautofluorescence, and a dark choroid on fluorescein angiograms. Login to comment 127 ABCA4 p.Asn965Ser The Danish p.N965S founder mutation was among the most frequent mutations found in our patients, and this mutation is believed to lead to moderate-to-severe retinal phenotypes, because ABCA4 protein dysfunction results in impaired ATP hydrolysis. Login to comment 129 ABCA4 p.Gly863Ala In addition, most other, missense, mutations are deemed severe either by in silico or indirect functional analyses (Table 3), or from data presented in previous studies even if the exact effect of the variant on the protein is unknown (e.g., the c.5461-10T>C variant).26-29 The p.G863A mutation found in some of our patients is a common mutation in Stargardt disease patients of mainly Dutch descent,30 and it also has been observed in patients with CRD.31 This mutation is considered to be relatively mild and claimed not to be disease-causing in a homozygous state32 ; however, the patient D070 (Table 2) who is homozygous for this mutation, is one of a few examples of two mild mutations leading to generalized choriocapillaris dystrophy. Login to comment