ABCMdb

PMID: 23419329

Chacon-Camacho OF, Granillo-Alvarez M, Ayala-Ramirez R, Zenteno JC
ABCA4 mutational spectrum in Mexican patients with Stargardt disease: Identification of 12 novel mutations and evidence of a founder effect for the common p.A1773V mutation.
Exp Eye Res. 2013 Apr;109:77-82. doi: 10.1016/j.exer.2013.02.006. Epub 2013 Feb 16., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCA4 p.Ala1773Val ABCA4 mutational spectrum in Mexican patients with Stargardt disease: Identification of 12 novel mutations and evidence of a founder effect for the common p.A1773V mutation Oscar F. Chac&#f3;n-Camacho a , Mariella Granillo-Alvarez b , Raul Ayala-Ram&#ed;rez a , Juan C. Zenteno a,c,* a Department of Genetics-Research Unit, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico b Gynecology and Obstetrics Service, Hospital General de Zona No. Login to comment 10 ABCA4 p.Gly818Glu ABCA4 p.Ala1773Val The two most common mutations in our study were the missense changes p.A1773V and p.G818E, which were identified in eight (17%) and seven (15%) of the total 46 disease-associated alleles, respectively. Login to comment 11 ABCA4 p.Ala1773Val Haplotype analyses of intragenic SNPs in four subjects carrying the p.A1773V mutation supported a common origin for this mutation. Login to comment 12 ABCA4 p.Ala1773Val In conclusion, this is the first report of ABCA4 molecular screening in Latin American Stargardt disease patients. Our results expand the mutational spectrum of the disease by adding 12 novel ABCA4 pathogenic variants and support the occurrence of a founder effect for the p.A1773V mutation in the Mexican population. Login to comment 79 ABCA4 p.Gly818Glu ABCA4 p.Ala1773Val The two most common mutations in our study were the missense changes p.A1773V and p.G818E, which were identified in eight (17%) and seven (15%) of the total 46 disease-associated alleles, respectively (Table 2 and Supplementary Fig. 4). Login to comment 80 ABCA4 p.Ala1773Val ABCA4 p.Tyr1779His ABCA4 p.Ile1775Asn The most commonly mutated exon was number 38, as 12 out of 46 pathogenic alleles (26%) carried mutations in that segment, including eight alleles that harbored the recurrent p.A1773V change, two that carried the p. I1775N substitution, and two that carried the p.Y1779H replacement (Table 2). Login to comment 82 ABCA4 p.Asn1868Ile ABCA4 p.Pro1380Leu ABCA4 p.Arg1705Gln ABCA4 p.Gly818Glu ABCA4 p.Ala1773Val ABCA4 p.Tyr1779His ABCA4 p.Ile1775Asn ABCA4 p.Arg24Trp These mutations were p.R24W, p.G818E, p.P1380L, p.V1682_V1686del, p.R1705Q, p.A1773V, p.I1775N, p.Y1779H, and p.N1868I. Login to comment 84 ABCA4 p.Ala1773Val Remarkably, the p.A1773V mutation was observed in four patients originating from the same geographical area, suggesting a founder effect. Login to comment 85 ABCA4 p.Ala1773Val Analysis of intragenic SNPs haplotypes linked to the ABCA4 p.A1773V substitution in DNA from these subjects showed concordance for a same haplotype of SNPs rs4847281, rs3112831, rs4147831, rs 1801666, rs 1801574, and c.6543C>T (novel SNP), supporting a founder effect for this particular mutation in our population (Table 3). Login to comment 86 ABCA4 p.Ala1773Val The haplotype linked to the p.A1773V mutationwas observed only in 2 of the 27 (7%) remaining STGD patients in this cohort. Login to comment 89 ABCA4 p.Tyr1779His ABCA4 p.Ile1775Asn ABCA4 p.Glu241Asp ABCA4 p.Arg1556Thr ABCA4 p.Gly2074Val Six changes were missense mutations, including p.E241D, p.R1556T, p.I1775N, p.Y1779H, p.P1942Q, and p.G2074V, and were not identified in a group of 150 control alleles or in public databases as 1000 Genomes or Exome Variant Sever (Table 2). Login to comment 100 ABCA4 p.Arg212Cys ABCA4 p.Arg18Trp ABCA4 p.Arg602Trp ABCA4 p.Asn965Ser ABCA4 p.Asn965Ser ABCA4 p.Arg1443His ABCA4 p.Asn1868Ile ABCA4 p.Pro1380Leu ABCA4 p.Arg1705Gln ABCA4 p.Arg943Gln ABCA4 p.Arg943Gln ABCA4 p.Arg1129Leu ABCA4 p.Arg1129Leu ABCA4 p.Ser2255Ile ABCA4 p.Ser2255Ile ABCA4 p.Ser2255Ile ABCA4 p.Ser2255Ile ABCA4 p.Gly818Glu ABCA4 p.Gly818Glu ABCA4 p.Gly818Glu ABCA4 p.Gly818Glu ABCA4 p.Gly818Glu ABCA4 p.Gly818Glu ABCA4 p.Gly818Glu ABCA4 p.Arg290Trp ABCA4 p.Leu1014Arg ABCA4 p.Arg24His ABCA4 p.His2128Arg ABCA4 p.Ala1773Val ABCA4 p.Ala1773Val ABCA4 p.Ala1773Val ABCA4 p.Ala1773Val ABCA4 p.Ala1773Val ABCA4 p.Ala1773Val ABCA4 p.Ala1773Val ABCA4 p.Ala1773Val ABCA4 p.Tyr1779His ABCA4 p.Tyr1779His ABCA4 p.Ile1775Asn ABCA4 p.Ile1775Asn ABCA4 p.Glu241Asp ABCA4 p.Arg1556Thr ABCA4 p.Arg1556Thr ABCA4 p.Gly2074Val ABCA4 p.Glu1942Gln ABCA4 p.Glu89* Allele 1 Allele 2 Genotype Exon Nucleotide change Polypeptide change Exon Nucleotide change Polypeptide change Familial case # 1 38 c.5318C>T p.A1773V (D) 38 c.5318C>T p.A1773V (D) Homozygous 2 e NI e e NI e e 3 6 c.634C>T p.R212C (D) 38 c.5318C>T p.A1773V (D) Compound heterozygous 4 23 c.3386G>T p.R1129L (D) 28 c.4139C>T p.P1380L (D) Compound heterozygous 5 e NI e e NI e e 6 38 c.5318C>T p.A1773V (D) 38 c.5318C>T p.A1773V (D) Homozygous 7 e NI e e NI e e 8 16 c.2453G>A p.G818E (D) 28 c.4249_4251 delTTC p.F1417del (D; N) Compound heterozygous 9 38 c.5318C>T p.A1773V (D) 38 c.5318C>T p.A1773V (D) Homozygous Sporadic case # 1 8 c.868C>T p.R290W (D) e IVS8&#fe;1G>A Splicing (D; N) Compound heterozygous 2 38 c.5318C>T p.A1773V (D) - NI - Heterozygous 3 20 c.3041T>G p.L1014R (D) 1; 49 c.52C>T; c.6764G>T p.R18W (D); p.S2255I (B) Compound heterozygous 4 13; 19 c.1804C>T; c.2828G>A p.R602W (D); p.R943Q (U) 16 c.2453G>A p.G818E (D) Compound heterozygous 5 38 c.5324T>A p. I1775N (D; N) 38 c.5324T>A p.I1775N (D; N) Homozygous 6 e NI e e NI e e 7 49 c.6764G>T p.S2255I (B) 49 c.6764 G>T p.S2255I (B) Homozygous 8 19; 40 c.2828 G>A; c.5503A>T p.R943Q (U); p.N1868I (U) 3 c.265G>T p.E89* (D; N) Compound heterozygous 9 38 c.5335T>C p.Y1779H (D;N) 38 c.5335T>C p.Y1779H (D;N) Homozygous 10 16 c.2453G>A p.G818E (D) 16 c.2453G>A p.G818E (D) Homozygous 11 6 c.723A>T p.E241D (D;N) 36 c.5114G>A p.R1705Q (D) Compound heterozygous 12 2 c.71G>A (D) p.R24H e NI e Heterozygous 13 30 c.4537_4538insC p.Q1513Pfs*41 (D; N) e NI e Heterozygous 14 32 c.4667G>C p.R1556T (D; N) 32 c.4667G>C p.R1556T (D; N) Homozygous 15 45 c.6221G>T p.G2074V (D; N) 16 c.2453G>A p.G818E (D) Compound heterozygous 16 16; 41 c.2453G>A; c.5824G>C p. G818E (D); p. E1942Q (B;N) 46 c.6384A>G p.H2128R (D) Compound heterozygous 17 16 c.2453G>A p. G818E (D) e NI e Heterozygous 18 32 c.4653G>A p. W1551* (D; N) e NI e Heterozygous 19 23 c.3386G>T p. R1129L (D) e NI e Heterozygous 20 36 c.5045_5059del GTTGCCATCTGCGTG p.V1682_ V1686del (D; N) 29; 49 c.4328G>A; c.6764G>T p.R1443H (D); p.S2255I (B) Compound heterozygous 21 19 c.2894A>G p.N965S (D) 19 c.2894A>G p.N965S (D) Homozygous 22 e NI e e NI e e STGD accounts for approximately 7% of all retinal dystrophies; it is one of the most common genetic forms of juvenile or early adult onset macular degeneration. Login to comment 108 ABCA4 p.Ala1773Val Prior to the present study, ABCA4 molecular analysis had not been performed in Latin American STGD patients. Our results expand the disease mutational spectrum by reporting 12 novel ABCA4 mutations, and they also suggest a possible founder effect for the recurrent p.A1773V mutation. Login to comment 110 ABCA4 p.Ala1773Val Despite the use of a variety of mutation detection techniques such as SSCP (single-strand conformation polymorphism), heteroduplex analysis, high resolution melting, and ABCA4 microarray, which in conjunction or in different combinations detect approximately 65e 75% of disease-associated alleles (Jaakson et al., 2003; Zernant et al., 2011), direct Sanger sequencing is currently considered the Table 3 Intragenic SNPs haplotype analysis in four patients carrying the ABCA4 p.A1773V mutation. Login to comment 119 ABCA4 p.Arg212Cys ABCA4 p.Arg18Trp ABCA4 p.Arg602Trp ABCA4 p.Asn965Ser ABCA4 p.Arg1443His ABCA4 p.Asn1868Ile ABCA4 p.Pro1380Leu ABCA4 p.Arg1705Gln ABCA4 p.Arg943Gln ABCA4 p.Arg1129Leu ABCA4 p.Ser2255Ile ABCA4 p.Gly818Glu ABCA4 p.Arg290Trp ABCA4 p.Leu1014Arg ABCA4 p.Arg24His ABCA4 p.His2128Arg ABCA4 p.Ala1773Val ABCA4 p.Tyr1779His ABCA4 p.Ile1775Asn ABCA4 p.Glu241Asp ABCA4 p.Arg1556Thr ABCA4 p.Gly2074Val ABCA4 p.Glu1942Gln ABCA4 p.Glu89* ABCA4 p.Trp1551* ABCA4 Exon # Nucleotide change Predicted protein effect Number of alleles Population genotypic frequency in EVS Population allelic frequency in EVS (%) 1 c.52C>T p.R18W 1 TT &#bc; 0/TC &#bc; 2/CC &#bc; 6501 T &#bc; 0.015/C &#bc; 99.985 2 c.71G>A p.R24H 1 AA &#bc; 0/AG &#bc; 1/GG &#bc; 6502 A &#bc; 0.008/G &#bc; 99.992 3 c.265G>T p.E89* (N) 1 NR NR 6 c.634C>T p.R212C 1 TT &#bc; 0/TC &#bc; 2/CC &#bc; 6501 T &#bc; 0.015/C &#bc; 99.985 6 c.723A>T p.E241D (N) 1 NR NR 8 c.868C>T p.R290W 1 NR NR IVS8 IVS8 &#fe; 1G>A Splicing mutation (N) 1 NR NR 13 c.1804C>T p.R602W 1 NR NR 16 c.2453G>A p.G818E 7 NR NR 19 c.2828G>A p.R943Q 2 AA &#bc; 8/AG &#bc; 400/GG &#bc; 6095 A &#bc; 3.199/G &#bc; 96.801 19 c.2894A>G p.N965S 2 GG &#bc; 0/GA &#bc; 1/AA &#bc; 6502 G &#bc; 0.008/A &#bc; 99.992 20 c.3041T>G p.L1014R 1 NR NR 23 c.3386G>T p.R1129L 2 NR NR 28 c.4139C>T p.P1380L 1 TT &#bc; 0/TC &#bc; 2/CC &#bc; 6501 T &#bc; 0.015/C &#bc; 99.985 28 c.4249_4251del TTC p.F1417del (N) 1 NR NR 29 c.4328G>A p.R1443H 1 AA &#bc; 0/AG &#bc; 1/GG &#bc; 6502 A &#bc; 0.008/G &#bc; 99.992 30 c.4537_4538insC p.Q1513Pfs*41 (N) 1 NR NR 32 c.4653G>A p.W1551* (N) 1 NR NR 32 c.4667G>C p.R1556T (N) 2 NR NR 36 c.5044_5058del GTTGCCATCTGCGTG p.V1682_V1686del (N) 1 NR NR 36 c.5114G>A p.R1705Q 1 AA &#bc; 0/AG &#bc; 1/GG &#bc; 6502 A &#bc; 0.008/G &#bc; 99.992 38 c.5318C>T p.A1773V 8 NR NR 38 c.5324T>A p.I1775N (N) 2 NR NR 38 c.5335T>C p.Y1779H (N) 2 NR NR 40 c.5503A>T p.N1868I 1 TT &#bc; 16/TA &#bc; 589/AA &#bc; 5898 T &#bc; 4.775/A &#bc; 95.225 41 c.5824G>C p.E1942Q (N) 1 NR NR 45 c.6221G>T p.G2074V (N) 1 NR NR 46 c.6384A>G p.H2128R 1 NR NR 49 c.6764G>T p.S2255I 4 TT &#bc; 516/TG &#bc; 1473/GG &#bc; 4514 T &#bc; 19.26/G &#bc; 80.74 gold standard for ABCA4 mutational screening. Login to comment 122 ABCA4 p.Tyr1779His ABCA4 p.Tyr1779His ABCA4 p.Ile1775Asn ABCA4 p.Ile1775Asn ABCA4 p.Glu241Asp ABCA4 p.Arg1556Thr ABCA4 p.Arg1556Thr ABCA4 p.Gly2074Val Here, six novel misssense mutations were identified: p.E241D, p.R1556T, p.I1775N, p.Y1779H, p.P1942Q, and p.G2074V; only p.I1775N, p.Y1779H, and p.R1556T were observed in a homozygous state. Login to comment 123 ABCA4 p.Glu1942Gln Each of these novel missense mutations occurred once, and in silico pathogenicity prediction analyses using PolyPhen2 indicated that these changes (with the exception of p.E1942Q) were damaging with scores close to 1.0. Login to comment 124 ABCA4 p.Gly818Glu ABCA4 p.His2128Arg ABCA4 p.Glu1942Gln The novel p.E1942Q mutation was detected in a heterozygous state and was predict to be a benign variant by PolyPhen2; however, it occurred as a complex allele together with p.G818E and coexisting with p.H2128R in the other allele. Login to comment 126 ABCA4 p.Arg18Trp ABCA4 p.Arg602Trp ABCA4 p.Arg1443His ABCA4 p.Asn1868Ile ABCA4 p.Ser2255Ile ABCA4 p.Ser2255Ile ABCA4 p.Gly818Glu ABCA4 p.Arg943Trp ABCA4 p.Arg943Trp ABCA4 p.Glu1942Gln Interestingly, five out of 46 mutant alleles (11%) were complex alleles (p.R18W &#fe; p.S2255I; p.R602W &#fe; p.R943W; p.R943W &#fe; p.N1868I; p.G818E &#fe; p.E1942Q; and p.R1443H &#fe; p.S2255I), a frequency that is in agreement with previous reports (Lewis et al., 1999; Shroyer et al., 2001; Zernant et al., 2011). Login to comment 127 ABCA4 p.Ala1773Val The most common ABCA4 mutation in our study was c.5318C>T, located in exon 38 and predicting a p.A1773V missense change. Login to comment 130 ABCA4 p.Ala1773Val Haplotype analyses of SNPs linked to the p.A1773V mutation were concordant in DNA from all four subjects, supporting the idea that this mutation has a common origin. Login to comment 131 ABCA4 p.Ala1773Val To the best of our knowledge, the p.A1773V mutation has been identified in only three ABCA4 alleles from STGD patients (Stenirri et al., 2008; Burke et al., 2010) and in our study it was absent in a panel of 250 control alleles screened either by PCR-RFLP (100 alleles) or direct sequencing (150 alleles). Login to comment 132 ABCA4 p.Gly818Glu The second most common ABCA4 mutation in the present study was c.2453G>A, which is located in exon 16, predicts the missense p.G818E change, and was detected in seven out of 46 (15%) mutant alleles. Login to comment 134 ABCA4 p.Gly818Glu The p.G818E mutation is located in the loop connecting transmembrane helices 5 and 6 and has been previously associated with a mild retinal phenotype (Cideciyan et al., 2009). Login to comment 135 ABCA4 p.Ala1773Val ABCA4 p.Tyr1779His ABCA4 p.Ile1775Asn Exon 38 was the exon most frequently mutated in our study: 12 out of 46 (26%) alleles, including eight p.A1773V, two p.I1775N, and two p.Y1779H alleles, were encoded by this segment. Login to comment 136 ABCA4 p.Arg1556Thr ABCA4 p.Trp1551* Notably, two novel mutations in exon 32, (predicting p.W1551* and p. R1556T) were demonstrated in the present work. Login to comment 138 ABCA4 p.Asn1868Ile ABCA4 p.Arg943Gln ABCA4 p.Ser2255Ile It is important to make note that three of the variants identified in this work, p.R943Q, p.N1868I, and p.S2255I have an allele frequency in the NHLBI Exome Sequencing Project of 3.2%, 4.8%, and 19% respectively, and thus they are most probably non-pathogenic variants. Login to comment 139 ABCA4 p.Asn1868Ile ABCA4 p.Arg943Gln ABCA4 p.Ser2255Ile ABCA4 p.Glu89* However, with the exception of sporadic case #7 who was homozygous for p.S2255I (sporadic case #7 in Table 1), all remaining 4 patients carrying one of such mutations also carry two additional deleterious ABCA4 mutations (sporadic cases #4, #3, and #20 in Table 1) or a null allele (p.E89*) combined with p.R943Q and p.N1868I (sporadic case #8). Login to comment 141 ABCA4 p.Asn1868Ile ABCA4 p.Arg943Gln Moreover, in vitro studies have shown that the ATPase activity of the p.R943Q protein function was reduced about 40% with respect to wild type ABCA4 (Su&#e1;rez et al., 2002) and carriers of p.N1868I variant exhibit a more than twofold risk of developing STGD than those carrying the normal homozygous variant (Aguirre-Lamban et al., 2011). Login to comment 142 ABCA4 p.Asn1868Ile ABCA4 p.Arg943Gln Thus, despite its prevalence in general population, the role of the p.R943Q and N1868I ABCA4 mutations in STGD disease is controversial. Login to comment 148 ABCA4 p.Ala1773Val Furthermore, our findings support the occurrence of a founder effect for the p.A1773V mutation in the Mexican population. Login to comment