ABCMdb

PMID: 11726554

Shroyer NF, Lewis RA, Yatsenko AN, Wensel TG, Lupski JR
Cosegregation and functional analysis of mutant ABCR (ABCA4) alleles in families that manifest both Stargardt disease and age-related macular degeneration.
Hum Mol Genet. 2001 Nov 1;10(23):2671-8., [PubMed]

Sentences

No. Mutations Sentence Comment

22 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn A subsequent multicenter international study confirmed this initial association for two specific disease-associated variants (G1961E and D2177N) and estimated a 3-5-fold increased risk for development of AMD among carriers of these two ABCR mutations (20). Login to comment 43 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Thr1253Met ABCA4 p.Thr1253Met ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu Of note, AR468-8 was heterozygous for three mutations: the transitions 3758C→T (encoding the missense mutation T1253M), 4139C→T (encoding the missense mutation P1380L) and 5882G→A (encoding the missense mutation G1961E). Login to comment 44 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Thr1253Met ABCA4 p.Thr1253Met ABCA4 p.Pro1380Leu Segregation analysis in this family revealed that two alterations (T1253M and G1961E) were on the same chromosome; thus AR468-8 is compound heterozygous for a novel complex allele [T1253M; G1961E] and the missense mutation P1380L (Fig. 1). Login to comment 45 ABCA4 p.Arg1640Trp ABCA4 p.Trp1408Arg AR33 and AR215 segregate complex alleles as well: the mutant allele [W1408R; R1640W] was observed in all affected siblings of the proband AR33-1 and also both the AMD-affected mother and AMD-affected maternal aunt (Fig. 1). Login to comment 46 ABCA4 p.Val2050Leu ABCA4 p.His1406Tyr The complex allele [H1406Y; V2050L] was identified in STGD-affected AR215-4 (Fig. 1). Login to comment 47 ABCA4 p.Gly1961Glu ABCA4 p.Thr1253Met ABCA4 p.Thr1253Met ABCA4 p.Gly550Arg ABCA4 p.Gly550Arg Two novel mutations were identified in this cohort: the missense mutation T1253M was identified as part of the complex allele [T1253M; G1961E] and the transition 1648G→A (encoding the missense mutation G550R) was identified in STGD-affected AR484-4. Login to comment 50 ABCA4 p.Arg1640Trp ABCA4 p.Trp1408Arg The complex allele [W1408R; R1640W] was reported recently in an unrelated family segregating both STGD and retinitis pigmentosa (9). Login to comment 84 ABCA4 p.Asp645Asn The seventh mutation, D645N, had an increased affinity for ATP determined by these ATP-labeling experiments. Login to comment 97 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Arg212Cys ABCA4 p.Arg212Cys ABCA4 p.Arg212Cys ABCA4 p.Arg212Cys ABCA4 p.Arg2107His ABCA4 p.Arg2107His ABCA4 p.Arg2107His ABCA4 p.Arg2107His ABCA4 p.Arg1640Trp ABCA4 p.Gly1977Ser ABCA4 p.Gly1977Ser ABCA4 p.Cys1488Arg ABCA4 p.Cys1488Arg ABCA4 p.Cys54Tyr ABCA4 p.Cys54Tyr ABCA4 p.Val2050Leu ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Leu2027Phe ABCA4 p.Pro68Arg ABCA4 p.Pro68Arg ABCA4 p.Thr1526Met ABCA4 p.Thr1526Met ABCA4 p.Arg1108Cys ABCA4 p.Arg1108Cys ABCA4 p.Arg1108Cys ABCA4 p.Arg1108Cys ABCA4 p.Trp821Arg ABCA4 p.Trp821Arg ABCA4 p.Trp821Arg ABCA4 p.Trp821Arg ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Gly550Arg ABCA4 p.Gly550Arg ABCA4 p.Glu1087Lys ABCA4 p.Glu1087Lys ABCA4 p.Trp1408Arg ABCA4 p.Glu2096Lys ABCA4 p.Glu2096Lys ABCA4 p.Asp1532Asn ABCA4 p.Asp645Asn ABCA4 p.Asp645Asn ABCA4 p.His1406Tyr ABCA4 p.Arg24His ABCA4 p.Ile2113Met ABCA4 p.Ile2113Met Pedigree Maternal allele Paternal allele AMD relative A priori Cosegregation AR19 pGM, -6 0.5 - AR33 [W1408R; R1640W] R24H and D1532N mA, -16 0.5 Yes AR59 4232insTATG C1488R pGM, -6 0.5 No AR80 T1526M pGF, -5 0.5 - AR80 T1526M mGF, -7 0.5 Yes AR125 4947delC C1488R pGM, -7 0.5 Yes AR215 [H1406Y; V2050L] pGM, -5 0.5 - AR218 2160+1G→C G1961E mA, -8 0.5 No AR262 W821R pGGF, -7 0.25 No AR271 P68R E1087K mGA, -6 0.25 No AR335 D645N F608I mGM, -9 0.5 Yes AR382 R1108C mGM, -6 0.5 Yes AR389 E2096K 5714+5G→A pGM, -8 0.5 Yes AR397 5196+1G→A 5585-1G→A mA, -5 0.5 No AR410 A1038V 768G→T pC, -5 0.25 Yes AR422 pGM, -6 0.5 - AR423 P1380L D1532N pGF, -4 0.5 No AR468 P1380L P1380L mU, -9 0.5 Yes AR484 L2027F G550R mGU, -5 0.25 Yes AR562 R2107H 3050+5G→A pGU, -5 0.25 No AR643 5196+2T→C L2027F mU, -4 0.5 Yes AR661 P1380L C54Y mGF, -6 0.5 Yes AR669 664del13 pGF, -4 0.5 No AR534 W821R P1380L pGM, -7 0.5 Yes (17) Family 1 R212C I2113M mGM, I-2 0.5 Yes (27) Family 2 R1108C R2107H mGM, I-2 0.5 Yes (27) Family 3 R212C G1977S mGF, I-1 0.5 Yes (27) 10.25 15 unlikely to account for many of the remaining alleles (our unpublished observations). Login to comment 99 ABCA4 p.Arg1640Trp ABCA4 p.Trp1408Arg Alternatively, presumed benign alterations may be pathogenic when combined with other alterations in a complex allele; evidence for a synergistic effect of two mutations in a complex allele has been reported recently for the [W1408R; R1640W] allele (9). Login to comment 108 ABCA4 p.Pro1380Leu For example, the mutation P1380L was identified in 3/3 AMD-affected relatives of STGD patients (AR468-9, AR534-7, AR661-6). Login to comment 109 ABCA4 p.Pro1380Leu Although not significant (P = 0.083) by itself, analysis of additional STGD families who share the P1380L allele may reveal a selective association with AMD and thus allow calculation of the risk for this allele. Login to comment 114 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn ABCA4 p.Ala1038Val ABCA4 p.Gly863Ala ABCA4 p.Arg212Cys ABCA4 p.Cys1488Arg ABCA4 p.Leu2027Phe ABCA4 p.Thr1526Met ABCA4 p.Arg1108Cys ABCA4 p.Pro1380Leu ABCA4 p.Arg1898His ABCA4 p.Arg1129Leu ABCA4 p.Glu471Lys Sun et al. (28) reported substantial defects in protein expression or ATP binding of eight AMD-associated mutations (R212C, G863A, A1038V, R1108C, R1129L, P1380L, G1961E and L2027F) and an abnormal increase in the ATPase activity of the D2177N mutation, and they reported mild defects or wild-type activity within the sensitivity of the assay in four other AMD-associated variants (E471K, C1488R, T1526M and R1898H). Login to comment 115 ABCA4 p.Arg1640Trp ABCA4 p.Trp1408Arg Furthermore, the AMD-associated complex allele [W1408R; R1640W] has been reported to cause a severe defect in protein expression and ATP binding (9). Login to comment 116 ABCA4 p.Leu1970Phe ABCA4 p.Ile1562Thr ABCA4 p.Thr901Ala ABCA4 p.Asp645Asn ABCA4 p.Thr1428Met ABCA4 p.Arg1517Ser ABCA4 p.Gly1578Arg To analyze the function of AMD-associated ABCR mutations, we characterized the effects of seven different missense mutations (D645N, T901A, T1428M, R1517S, I1562T, G1578R and L1970F) on protein expression and ATP binding. Login to comment 117 ABCA4 p.Asp645Asn We found that six of these mutations substantially reduced the ATP-binding ability of the mutant protein, whereas the mutation D645N showed no apparent defect compared to wild-type and actually had an increased affinity for ATP (Fig. 2). Login to comment 118 ABCA4 p.Leu1970Phe These results are intriguing because none of the tested mutations is within either the Walker A or B nucleotide-binding domains (the alteration L1970F is adjacent to the second Walker A motif). Login to comment 120 ABCA4 p.Arg1640Trp ABCA4 p.Trp1408Arg Our data, taken with those of Sun et al. (28) and with the results on the [W1408R; R1640W] allele (9), demonstrate that 16/21 AMD-associated missense ABCR mutations manifest an abnormal effect on either protein expression, ATP-binding or ATPase activity. Login to comment