ABCMdb

PMID: 19074458

Cideciyan AV, Swider M, Aleman TS, Tsybovsky Y, Schwartz SB, Windsor EA, Roman AJ, Sumaroka A, Steinberg JD, Jacobson SG, Stone EM, Palczewski K
ABCA4 disease progression and a proposed strategy for gene therapy.
Hum Mol Genet. 2009 Mar 1;18(5):931-41. Epub 2008 Dec 12., [PubMed]

Sentences

No. Mutations Sentence Comment

31 ABCA4 p.Val935Ala Mild macular disease could include minor lipofuscin disturbance limited to the foveal and/or parafoveal region such as P32 (patient 32) carrying V935A and IVS40þ5G.A alleles (Fig. 1A). Login to comment 33 ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Cys54Tyr ABCA4 p.Asn1799Asp Intermediate stages of macular disease showing different extents of macular atrophy surrounded by flecks or speckled regions are exemplified by individuals such as P31 carrying G863A and N1799D alleles (Fig. 1B) and P4 with C54Y and G863A alleles (Fig. 1C). Login to comment 36 ABCA4 p.Arg1640Gln ABCA4 p.Ala1598Asp ABCA4 p.Leu244Pro More severe macular disease consisted of a near-complete loss of the lipofuscin signal and atrophy of the macular RPE surrounded by additional smaller patches of atrophy as illustrated by P56, a compound heterozygote for A1598D and R1640Q alleles (Fig. 1D) or by P16, a homozygote for the L244P allele (Fig. 1E). Login to comment 47 ABCA4 p.Ala1038Val ABCA4 p.Asn965Ser At age 11, P36 (A1038V;L541P/ N965S) had a sensitivity loss of 5.3 dB which was within normal limits; 8 years later at age 19 there was no significant change in sensitivity loss (5.6 dB). Login to comment 48 ABCA4 p.Gly1961Glu ABCA4 p.Pro1380Leu Similarly, P47 (P1380L/ G1961E) had a sensitivity loss (2.3 dB) that was within normal limits at age 45, and this increased, but not significantly, to 3.6 dB over an 8-year period. Login to comment 50 ABCA4 p.Arg1098Cys ABCA4 p.Trp41* P3 (W41X/R1098C) progressed from normal sensitivity (3.1 dB loss) at age 19 to a loss of 12.5 dB at age 27. Login to comment 51 ABCA4 p.Thr1526Met ABCA4 p.Arg2030Gln P54 (T1526M/R2030Q) progressed from a mildly abnormal loss of 7.6 dB at age 47 to a greater loss of 14.4 dB at age 54. Login to comment 53 ABCA4 p.Arg152* For example, P10 (R152X/IVS38-10T.C) progressed from normal sensitivity (5.5 dB loss) at age 11 to a dramatically abnormal sensitivity (30.9 dB loss) at age 29. Login to comment 54 ABCA4 p.Leu1940Pro P61 (L1940P/ IVS40þ5G.A) progressed from normal sensitivity (6.1 dB loss) at age 34 to an abnormal sensitivity (23.8 dB loss) at age 54. Login to comment 118 ABCA4 p.Tyr245* Next, we defined a standard ADI resulting from two truncating mutation alleles as 10.6 years based on the average value of the ADIs estimated for siblings (P19, P20) homozygous for the Y245X truncation. Login to comment 119 ABCA4 p.Arg1098Cys Then, we calculated a severity value for six alleles (D654N, R1098C, Figure 4. Login to comment 125 ABCA4 p.Gly1961Glu ABCA4 p.Cys2150Tyr ABCA4 p.Gly1961Arg IVS38-10T.C, G1961R, G1961E and C2150Y) occurring in trans to the truncation and frame shift mutations by subtracting the standard ADI from the ADI of each individual; if there were several individuals with the same genotype, their ADIs were averaged. Login to comment 126 ABCA4 p.Asn965Ser ABCA4 p.Pro1380Leu ABCA4 p.Leu244Pro ABCA4 p.Arg220Cys For four missense mutations occurring homozygously (L244P, R220C, N965S and P1380L), we assumed that each allele contributed equally to disease severity. Login to comment 127 ABCA4 p.Ala1038Val ABCA4 p.Glu1087Asp ABCA4 p.Arg1108Cys ABCA4 p.Glu1122Lys ABCA4 p.Lys2172Arg ABCA4 p.Lys2172Arg ABCA4 p.Leu1940Pro ABCA4 p.Leu1940Pro ABCA4 p.Gly818Glu And for an additional eight mutations (G818E, A1038V;L541P, E1087D, R1108C, E1122K, IVS40þ5G.A, L1940P and K2172R), we performed severity estimates recursively by using estimates established above. Login to comment 134 ABCA4 p.Gly1961Glu ABCA4 p.Arg152* Unrelated individuals P11 and P12 had the same pair of mutant alleles, R152X and G1961E. Login to comment 136 ABCA4 p.Gly1961Glu ABCA4 p.Cys54Tyr P7 with C54Y and G1961E alleles had normal extramacular vision at age 40 consistent with a predicted ADI of 46.4 years (¼10.6 - 2.1 þ 37.9 years, Table 1). Login to comment 151 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Arg18Trp ABCA4 p.Arg18Trp ABCA4 p.Leu11Pro ABCA4 p.Leu11Pro ABCA4 p.Cys54Tyr ABCA4 p.Ser100Pro ABCA4 p.Ser100Pro ABCA4 p.Arg602Trp ABCA4 p.Arg602Trp ABCA4 p.Asn965Ser ABCA4 p.Asn965Ser ABCA4 p.Arg1098Cys ABCA4 p.Arg1098Cys ABCA4 p.Arg1640Gln ABCA4 p.Arg1640Gln ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Ala1598Asp ABCA4 p.Ala1598Asp ABCA4 p.Glu1087Asp ABCA4 p.Glu1087Asp ABCA4 p.Thr1526Met ABCA4 p.Thr1526Met ABCA4 p.Arg1108Cys ABCA4 p.Arg1108Cys ABCA4 p.Arg2030Gln ABCA4 p.Arg2030Gln ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Asp600Glu ABCA4 p.Asp600Glu ABCA4 p.Cys2150Tyr ABCA4 p.Leu1201Arg ABCA4 p.Leu1201Arg ABCA4 p.Glu1122Lys ABCA4 p.Val1433Ile ABCA4 p.Val1433Ile ABCA4 p.Lys2172Arg ABCA4 p.Lys2172Arg ABCA4 p.Leu244Pro ABCA4 p.Leu1940Pro ABCA4 p.Leu1940Pro ABCA4 p.Gly1961Arg ABCA4 p.Gly1961Arg ABCA4 p.Arg220Cys ABCA4 p.Arg220Cys ABCA4 p.Gly818Glu ABCA4 p.Gly818Glu ABCA4 p.Val1896Asp ABCA4 p.Val1896Asp Estimated severity of ABCA4 alleles and their properties ABCA4 allele Delay of retina-wide disease initiation (years)a In vitro or in vivo studiesb Molecular structural localizationc C2150Y 225.8 NBD-2 A1038V;L541P 214.0 35, 38 ECD-1/NBD-1 IVS38-10 T.C 211.1 L244P 25.7 ECD-1 E1122K 23.5 NBD-1 C54Y 22.1 35 ECD-1 IVS35þ2 T.C 22.1 R602W 21.8 38 ECD-1 V1896D 21.8 TM12 L1940P 21.4 NBD-2 Truncation mutationsd 0.0 E1087D 2.8 NBD-1 R220C 3.9 ECD-1 A1598D 3.9 ECD-2 R1640Q 3.9 ECD-2 R1098C 4.9 NBD-1 P1380L 7.4 35 TM7 N965S 7.6 35 NBD-1 V1433I 8.6 ECD-2 R1108C 10.4 35 NBD-1 T1526M 14.5 35 ECD-2 R2030Q 14.5 NBD-2 L2027F 15.1 35,37 NBD-2 G818E 17.3 35 TM5/TM6 S100P 18.2 ECD-1 L1201R 18.2 NBD-1 R18W 18.5 Nt D600E 18.5 ECD-1 L11P 21.7 Nt D654N 25.3 36 ECD-1 K2172R 27.9 NBD-2 IVS40þ5 G.A 28.1 G1961E 37.9 35 NBD-2 G1961R 44.0 NBD-2 a Delay of retina-wide disease initiation relative to the standard of age 10.6 years. Login to comment 153 ABCA4 p.Tyr362* ABCA4 p.Arg681* ABCA4 p.Arg152* ABCA4 p.Trp663* ABCA4 p.Trp41* ABCA4 p.Tyr245* c Nt, amino-terminal domain; ECD-1 and ECD-2, exocytoplasmic domains 1 and 2; NBD-1 and NBD-2, nucleotide binding domains 1 and 2; TM5, TM6, TM7, TM12, within, near or between transmembrane helices 5, 6, 7 and 12. d W41X, R152X, Y245X, Y362X, W663X, M669del2tccAT, R681X and A1739 del11gcTGGGCTGGTGG. retina-wide blindness, the quality of life deteriorates dramatically with loss of mobility and independence. Login to comment 180 ABCA4 p.Tyr245* Consistent with this hypothesis were siblings in the current study (P19, P20) homozygous for Y245X truncation showing retina-wide disease within the first decade. Login to comment