ABCMdb

PMID: 11379881

Yatsenko AN, Shroyer NF, Lewis RA, Lupski JR
Late-onset Stargardt disease is associated with missense mutations that map outside known functional regions of ABCR (ABCA4).
Hum Genet. 2001 Apr;108(4):346-55., [PubMed]

Sentences

No. Mutations Sentence Comment

61 ABCA4 p.Ala1038Val ABCA4 p.Leu541Pro Overall, these 33 mutant alleles represent 24 different ABCR alterations; 22 of 33 (66%) mutant alleles represent 15 different missense amino acid changes (one complex allele consisted of two missense mutations [L541P; A1038V]; Table 1, Fig.2). Login to comment 62 ABCA4 p.Ile1562Thr ABCA4 p.Gly991Arg ABCA4 p.Trp339Gly Five of these ABCR mutations (1025-1038del14 bp, W339G, G991R, W1100X, and 6238-6239del2 bp) are novel, and the sixth mutation, I1562T, had been described previously only in AMD patients (Table 1; Allikmets et al. 1997a). Login to comment 65 ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Ala1038Val ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Gly863Ala ABCA4 p.Leu541Pro ABCA4 p.Cys1488Arg ABCA4 p.Arg2106Cys ABCA4 p.Arg1640Gln ABCA4 p.Leu2027Phe ABCA4 p.Ile1562Thr ABCA4 p.Arg1108Cys ABCA4 p.Arg1108Cys ABCA4 p.Arg1108Cys ABCA4 p.Arg1108Cys ABCA4 p.Arg2030Gln ABCA4 p.Arg2030Gln ABCA4 p.Arg152* ABCA4 p.Leu1201Arg ABCA4 p.Gly991Arg ABCA4 p.Arg1129Leu ABCA4 p.Arg943Trp ABCA4 p.Trp339Gly ABCA4 p.Trp1101* Allele 1 nucleotide Amino acid Allele 2 Amino acid Age of change nucleotide change onset (years) AR129-08 37 AR140-01 6079C→T L2027F 3322C→T R1108C 36 AR204-04 35 AR280-03 6316C→T R2106C 6710insA T2237fs 35 AR311-04 4462T→C C1488R 35 AR336-03 2588G→C G863A 5898+1G→A E1966splice 39 AR343-06 2588G→C G863A 3322C→T R1108C 43 AR387-03 4919G→A R1640Q 2971G→C G991R 40 AR410-04 768G→T V256splice 3113C→T A1038V 38 AR440-03 6238-6239del2 bp S2080fs 44 AR448-01a 454C→T R152X 6089G→A R2030Q 52 AR452-04 2005-2006del2 bp M669fs 6089G→A R2030Q 40 AR455-05 [1622T→C;3113C→T] [L541P;A1038V] 43 AR474-02 36 AR516-01a 5196+1G→A I1732splice 3113C→T A1038V 47 AR518-03 3322C→T R1108C 35 AR540-01a 4685T→C I1562T 51 AR594-02a 5196+1G→A I1732splice 36 AR606-04 3322C→T R1108C 2588G→C G863A 39 AR608-02 1025-1038del14 bp D342fs 40 AR617-03 2827C→T R943W 39 AR632-02a 3386G→T R1129L 50 AR649-03 3303G→A W1101X 3113C→T A1038V 36 AR662-02a 1015T→G W339G 50 AR723-01a 3602T→G L1201R 65 Fig.1 Pedigrees of late-onset Stargardt disease families (filled symbols STGD1-affected individuals). Login to comment 70 ABCA4 p.Ile1562Thr ABCA4 p.Gly991Arg ABCA4 p.Trp339Gly ABCA4 p.Trp1101* Furthermore, three of these alterations (W339G, G991R, and 6238-6239del2 bp) segregated with multiple STGD1 affecteds within the family; families with the alterations 1025-1038del14 bp, W1101X, and I1562T had only single affecteds and were uninformative for segregation. Login to comment 71 ABCA4 p.Ala1038Val ABCA4 p.Arg1108Cys Each of the two more common mutations, A1038V and R1108C, was identified in four disease chromosomes and together comprised 24% (8/33) of identified mutant alleles. Login to comment 74 ABCA4 p.His423Arg Exon 10 is highly polymorphic and contains at least four polymorphic alterations: IVS9-14C→T, H423R (1268C→T), H423H (1269C→T), and IVS10+11delG. Login to comment 79 ABCA4 p.Arg2030Gln ABCA4 p.Arg152* Of note, subject AR448-01 with onset of STGD1 at 52 years was a compound heterozygote for the nonsense allele R152X and missense allele R2030Q. Login to comment 80 ABCA4 p.Arg152* The truncated R152X (454C→T) allele has been reported previously in the heterozygous state in one AMD patient (Zhang et al. 1999), one dominant STGD family (Zhang et al. 1999), and one late-onset STGD1/FFM patient (Souied et al. 1999b). Login to comment 87 ABCA4 p.Leu2027Phe ABCA4 p.Arg1108Cys Proband AR140-01 is a father with onset of STGD at 36 years and who carries two missense mutant alleles (L2027F, R1108C; Fig.1). Login to comment 88 ABCA4 p.Gln285* His asymptomatic wife carries a single novel nonsense ABCR allele, Q285X. Login to comment 89 ABCA4 p.Gln285* Their children have inherited several combinations of alleles; siblings who inherited the maternal mutant allele Q285X have been affected at an early age (onset at 11, 8, and 9 years). Login to comment 90 ABCA4 p.Arg1129Leu ABCA4 p.Lys1148Thr In family AR632, individuals -04 and -05 have two ABCR alterations in exon 23 (R1129L and a novel mutation K1148T, 3443A→C) located between the first Walker B motif and a second transmembrane region of ABCR (Fig.2). Login to comment 93 ABCA4 p.Arg1129Leu ABCA4 p.Lys1148Thr N, C Amino or carboxy termini, asterisk novel missense ABCR mutation, bold numbers beginning and end of predicted functional motifs K1148T and the affected mother (onset at 49 years) carries the mutation R1129L. Login to comment 94 ABCA4 p.Arg1129Leu ABCA4 p.Lys1148Thr Affected siblings (onset at 11 and 32 years) are compound heterozygotes for mutations K1148T and R1129L. Login to comment 96 ABCA4 p.Trp339Gly In family AR662, the asymptomatic father has a K1108T allele, and the STGD1-affected mother (onset at 50 years) has a single identified mutation, W339G. Login to comment 97 ABCA4 p.Trp339Gly All their children have inherited the paternal mutation but only the STGD1 affected siblings with an age-of-onset at 7 and 13 years have the maternal mutation W339G. Login to comment 103 ABCA4 p.Arg2030Gln In family AR452, three asymptomatic siblings AR452-03, -06, and -09 carry one mutant allele; however, the unaffected individual AR452-05 (age 43 years) has inherited two mutant alleles, 2005-2006del2 bp and R2030Q, identical to his STGD1-affected siblings AR452-04 and AR452-08 (onset at 40 and 29 years). Login to comment 106 ABCA4 p.Arg212His ABCA4 p.Asn1868Ile ABCA4 p.Arg943Gln ABCA4 p.His423Arg ABCA4 p.Ser2255Ile 351 Table 2 Novel and previously reported polymorphic sites identified in the ABCR gene in late-onset STGD subjects and controls (bold novel polymorphic sites) Exon Nucleotide alteration Predicted AA change STGD1 chromosomes Control chromosomes P value Reference 6 635 GÆA R212H 1/50 Simonelli et al. (2000) 7 IVS6-32 TÆC 4/48 N. F. Shroyer et al. (in preparation) 10 IVS9-14CÆÆÆÆT 22/50 (44%) 18/166 (10.8%) P<0.001 Present study 10 1268AÆG H423R 10/50 (20%) 46/170 (27%) P<0.4 Rivera et al. (2000) 10 1269CÆT H423H 4/50 (8%) 7/170 (4%) P<0.2 Rivera et al. (2000) 10 IVS10+11delG 16/50 (32%) 57/170 (33.5%) P>0.5 Papaioannou et al. (2000) 19 2828 GÆA R943Q 4/50 Allikmets et al. (1997b) 28 4203 CÆA P1401P 7/50 Maugeri et al. (1999) 33 IVS33+48TÆÆÆÆC 22/50 (44%) 48/114 (42%) P<0.5 Present study 39 IVS38-10CÆT 1/48 Maugeri et al. (1999) 40 5603AÆT N1868I 8/48 Stone et al. (1998) 41 5814AÆG L1938L 3/50 N. F. Shroyer et al. (in preparation) 42 IVS41-44CÆA 3/48 N. F. Shroyer et al. (in preparation) 42 IVS41-11GÆA 3/48 Maugeri et al. (1999) 42 5844AÆG P1948P 2/48 Maugeri et al. (1999) 44 IVS43-16GÆA 1/48 N. F. Shroyer et al. (in preparation) 44 6069CÆT I2023I 4/50 Allikmets et al. (1997b) 45 6249CÆT I2083I 4/50 Maugeri et al. (1999) 45 IVS45+7GÆA 5/50 (10%) 9/160 (5.6%) P>0.1 Papaioannou et al. (2000) 49 IVS48-3TÆC 3/50 (6%) 10/170 (5.9%) P>0.9 Maugeri et al. (1999) 49 6764GÆT S2255I 3/50 Allikmets et al. (1997b) 49 IVS49+27GÆC 2/48 Papaioannou et al. (2000) All missense mutations in late-onset STGD1 occur outside known functional regions of ABCR The positions of late-onset associated ABCR missense mutations were placed on the predicted ABCR structure that includes four regions of known function (transmembrane and ATP-binding domains in each of two symmetric halves of the protein). Login to comment 111 ABCA4 p.Ala1038Val ABCA4 p.Val2050Leu ABCA4 p.Arg2038Trp ABCA4 p.Leu2027Phe ABCA4 p.Arg2030Gln To compare this observation directly with our previous report (Lewis et al. 1999), we replaced five mutations (A1038V, L2027F, R2030Q, R2038W, V2050L) to linker regions. Login to comment 134 ABCA4 p.Ala1038Val ABCA4 p.Gly863Ala ABCA4 p.Leu541Pro ABCA4 p.Cys1488Arg ABCA4 p.Arg2106Cys ABCA4 p.Arg1108Cys ABCA4 p.Arg1129Leu Conversely, missense mutations located in other regions (e.g., missense mutations in late-onset STGD1) might retain some ABCR activity. This hypothesis is supported by the observations of Sun et al. (2000) that ABCR missense mutations located outside the known functional domains (L541P, G863A, A1038V, R1108C, R1129L, C1488R, R2106C) have a milder functional effect on expression and ATP-binding activity (1/3-2/3 activity of wild-type). Login to comment 143 ABCA4 p.Arg152* In addition, evidence for modifier gene effects on ABCR has been suggested recently in a family with dominant STGD1 linked to chromosome 6q and in which some members are reported to carry an ABCR nonsense mutation, R152X (Zhang et al. 1999). Login to comment