ABCMdb

PMID: 18977788

Riveiro-Alvarez R, Aguirre-Lamban J, Lopez-Martinez MA, Trujillo-Tiebas MJ, Cantalapiedra D, Vallespin E, Avila-Fernandez A, Ramos C, Ayuso C
Frequency of ABCA4 mutations in 278 Spanish controls: an insight into the prevalence of autosomal recessive Stargardt disease.
Br J Ophthalmol. 2009 Oct;93(10):1359-64. Epub 2008 Oct 31., [PubMed]

Sentences

No. Mutations Sentence Comment

2 ABCA4 p.Arg1129Leu Control subjects were analysed by two different strategies: 200 individuals were screened for the p.Arg1129Leu mutation by denaturing-HPLC and sequencing; 78 individuals were tested for variants with the microarray and sequencing. Login to comment 3 ABCA4 p.Arg1129Leu Results: For the first strategy in control subjects, the p.Arg1129Leu variant was found in two heterozygous individuals, which would mean a carrier frequency for any variant of ,6.0% and a calculated arSTGD prevalence of 1:1000. Login to comment 10 ABCA4 p.Arg1129Leu In addition, heterozygote carrier frequency is particularly high in the general population.10 Previous mutational analyses performed in Spanish arSTGD patients led to the identification of a prevalent disease-associated allele, the p.Arg1129Leu variant.11 Because of the relatively large size of this gene, containing 50 exons, the molecular scanning of ABCA4 is particularly labour-intensive. Login to comment 23 ABCA4 p.Arg1129Leu First strategy As previously described,11 the frequency of the p.Arg1129Leu allele is notably high in Spanish patients. Login to comment 35 ABCA4 p.Arg1129Leu Of this spectrum of substitutions, the p.Arg1129Leu (c.3386G.T) allele accounted for 26% of the disease-associated alleles (fig 2). Login to comment 37 ABCA4 p.Arg1129Leu Controls Analysis of 400 chromosomes Because of its high frequency in the group of patients with arSTGD, we determined the presence of the p.Arg1129Leu mutation in 200 control individuals from Spain. Login to comment 39 ABCA4 p.Arg1129Leu Next, we extrapolated the carrier frequency for any ABCA4 variant (absolute mutant frequency; q value), considering the current frequency of the p.Arg1129Leu allele in arSTGD patients (15.7%), resulting in q = 0.032. Login to comment 47 ABCA4 p.Arg1129Leu Statistical analysis Differences between genotyping strategies in controls Calculated prevalence values resulting from both genotyping strategies (p.Arg1129Leu screening, prevalence: 1:1000 vs. Login to comment 50 ABCA4 p.Arg1129Leu ABCA4 p.Arg1129Leu Differences of the frequency of the p.Arg1129Leu allele between patients and controls In addition, the frequency of p.Arg1129Leu variant was tested between in arSTGD patients and controls. Login to comment 51 ABCA4 p.Arg1129Leu ABCA4 p.Arg1129Leu Differences of the frequency of the p.Arg1129Leu allele between patients and controls In addition, the frequency of p.Arg1129Leu variant was tested between in arSTGD patients and controls. Login to comment 59 ABCA4 p.Arg1129Leu In one strategy, the arSTGD prevalence was calculated over the frequency of the most common allele (p.Arg1129Leu) in 400 ethnically matched control chromosomes. Login to comment 60 ABCA4 p.Arg1129Leu In one strategy, the arSTGD prevalence was calculated over the frequency of the most common allele (p.Arg1129Leu) in 400 ethnically matched control chromosomes. Login to comment 67 ABCA4 p.Arg1129Leu In our Spanish arSTGD patients, the most frequent mutation was the missense p.Arg1129Leu variant, accounting for 26% of the disease-associated alleles (fig 2), that is approximately one out of about four (3.84) of the arSTGD alleles. Login to comment 68 ABCA4 p.Arg1129Leu In our Spanish arSTGD patients, the most frequent mutation was the missense p.Arg1129Leu variant, accounting for 26% of the disease-associated alleles (fig 2), that is approximately one out of about four (3.84) of the arSTGD alleles. Login to comment 70 ABCA4 p.Arg1129Leu The p.Arg1129Leu allele was found in two heterozygous individuals out of 278 (two heterozygous individuals out of 200 screened by dHPLC; zero individuals out of 78 screened by the ABCR400 chip), yielding an allelic frequency of 0.36%; this supports the notion of a pathogenic change as this variant is less frequent than 1%. Login to comment 71 ABCA4 p.Arg1129Leu ABCA4 p.Arg1129Leu ABCA4 p.Arg1129Leu Moreover, the biochemical characterisation of a recombinant ABCR protein with the p.Arg1129Leu mutation revealed a substantial reduction in both expression and ATP-binding activity.19 In our 133 STGD families, seven were homozygous for the p.Arg1129Leu allele (five of them have been described previously).11 In addition, haplotype analysis with markers flanking the ABCA4 gene (TEL-D1S435-D1S2804-ABCA4- D1S236-CEN) showed co-segregation of the disease within these families. Login to comment 72 ABCA4 p.Arg1129Leu ABCA4 p.Arg1129Leu Moreover, the biochemical characterisation of a recombinant ABCR protein with the p.Arg1129Leu mutation revealed a substantial reduction in both expression and ATP-binding activity.19 In our 133 STGD families, seven were homozygous for the p.Arg1129Leu allele (five of them have been described previously).11 In addition, haplotype analysis with markers flanking the ABCA4 gene (TEL-D1S435-D1S2804-ABCA4- D1S236-CEN) showed co-segregation of the disease within these families. Login to comment 77 ABCA4 p.Arg1129Leu Of these, the prevalent p.Arg1129Leu variant represented the 26% of the mutant alleles. Login to comment 78 ABCA4 p.Arg1129Leu Of these, the prevalent p.Arg1129Leu variant represented the 26% of the mutant alleles. Login to comment 83 ABCA4 p.Arg1129Leu ABCA4 p.Arg1129Leu However, these estimations of prevalence should be regarded with certain caution, as they depend highly on one assumption (the p.Arg1129Leu frequency in arSTGD patients should be proportional to the p.Arg1129Leu frequency in controls) that is never entirely fulfilled. Login to comment 84 ABCA4 p.Arg1129Leu ABCA4 p.Arg1129Leu However, these estimations of prevalence should be regarded with certain caution, as they depend highly on one assumption (the p.Arg1129Leu frequency in arSTGD patients should be proportional to the p.Arg1129Leu frequency in controls) that is never entirely fulfilled. Login to comment 96 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn ABCA4 p.Ala1038Val ABCA4 p.Gly863Ala ABCA4 p.Leu1970Phe ABCA4 p.Val2050Leu ABCA4 p.Arg212His ABCA4 p.Asn1868Ile ABCA4 p.Pro1948Leu ABCA4 p.Arg1300Gln ABCA4 p.Arg943Gln ABCA4 p.His423Arg ABCA4 p.Ser2255Ile ABCA4 p.Ile156Val ABCA4 p.Asn380Lys ABCA4 p.Gly221Arg These Table 1 ABCA4 sequence variants identified in Spanish control population Mutant alleles Nucleotide change Amino acid change Number of cases Number of alleles Frequency (%) Homozygous individuals Mutations* c.661G.A p.Gly221Arg 1 1 0.64 None c.1140T.A p.Asn380Lys 1 1 0.64 None c.2588G.C p.Gly863Ala 1 1 0.64 None c.3113C.T p.Ala1038Val 1 1 0.64 None c.3899G.A p.Arg1300Gln 1 1 0.64 None c.5882G.A p.Gly1961Glu 1 1 0.64 None c.5908C.T p.Leu1970Phe 1 1 0.64 None c.6148G.C p.Val2050Leu 1 1 0.64 None c.6529G.A p.Asp2177Asn 2 2 1.28 None Total 10 Polymorphisms{ c.466A.G p.Ile156Val 5 5 3.2 None c.635G.A p.Arg212His 5 6 3.84 1 c.1268A.G p.His423Arg 43 48 30.7 5 c.1269C.T p.His423His 2 2 1.28 None IVS10+5delG 34 36 23 2 c.2828G.A p.Arg943Gln 1 1 0.64 None c.4203C.A p.Pro1401Pro 3 3 1.9 None IVS33+48C.T 59 75 48 16 c.5603A.T p.Asn1868Ile 4 4 2.5 None c.5682G.C p.Leu1894Leu 29 35 22.4 6 c.5814A.G p.Leu1938Leu 27 33 21.1 6 c.5843 C.T p.Pro1948Leu 9 10 6.4 1 c.5844A.G p.Pro1948Pro 27 32 20.5 5 c.6069C.T p.Ile2023Ile 11 12 7.7 1 c.6249C.T p.Ile2083Ile 12 14 8.9 2 c.6285T.C p.Asp2095Asp 24 26 16.6 2 c.6764G.T p.Ser2255Ile 12 13 8.3 1 *A total of 15 mutant alleles were detected. Login to comment 97 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn ABCA4 p.Ala1038Val ABCA4 p.Gly863Ala ABCA4 p.Leu1970Phe ABCA4 p.Val2050Leu ABCA4 p.Arg212His ABCA4 p.Asn1868Ile ABCA4 p.Pro1948Leu ABCA4 p.Arg1300Gln ABCA4 p.Arg943Gln ABCA4 p.His423Arg ABCA4 p.Ser2255Ile ABCA4 p.Ile156Val ABCA4 p.Asn380Lys ABCA4 p.Gly221Arg These Table 1 ABCA4 sequence variants identified in Spanish control population Mutant alleles Nucleotide change Amino acid change Number of cases Number of alleles Frequency (%) Homozygous individuals Mutations* c.661G.A p.Gly221Arg 1 1 0.64 None c.1140T.A p.Asn380Lys 1 1 0.64 None c.2588G.C p.Gly863Ala 1 1 0.64 None c.3113C.T p.Ala1038Val 1 1 0.64 None c.3899G.A p.Arg1300Gln 1 1 0.64 None c.5882G.A p.Gly1961Glu 1 1 0.64 None c.5908C.T p.Leu1970Phe 1 1 0.64 None c.6148G.C p.Val2050Leu 1 1 0.64 None c.6529G.A p.Asp2177Asn 2 2 1.28 None Total 10 Polymorphisms{ c.466A.G p.Ile156Val 5 5 3.2 None c.635G.A p.Arg212His 5 6 3.84 1 c.1268A.G p.His423Arg 43 48 30.7 5 c.1269C.T p.His423His 2 2 1.28 None IVS10+5delG 34 36 23 2 c.2828G.A p.Arg943Gln 1 1 0.64 None c.4203C.A p.Pro1401Pro 3 3 1.9 None IVS33+48C.T 59 75 48 16 c.5603A.T p.Asn1868Ile 4 4 2.5 None c.5682G.C p.Leu1894Leu 29 35 22.4 6 c.5814A.G p.Leu1938Leu 27 33 21.1 6 c.5843 C.T p.Pro1948Leu 9 10 6.4 1 c.5844A.G p.Pro1948Pro 27 32 20.5 5 c.6069C.T p.Ile2023Ile 11 12 7.7 1 c.6249C.T p.Ile2083Ile 12 14 8.9 2 c.6285T.C p.Asp2095Asp 24 26 16.6 2 c.6764G.T p.Ser2255Ile 12 13 8.3 1 *A total of 15 mutant alleles were detected. 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