ABCMdb

ABCA4 p.Leu2060Arg

ClinVar:	c.6179T>G , p.Leu2060Arg ? , not provided
Predicted by SNAP2:	A: D (63%), C: N (53%), D: D (80%), E: D (63%), F: N (57%), G: D (80%), H: D (59%), I: N (87%), K: D (63%), M: N (87%), N: D (66%), P: D (71%), Q: D (53%), R: D (95%), S: D (66%), T: N (53%), V: N (72%), W: D (71%), Y: N (53%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: N, K: D, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: D, Y: D,

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[hide] Further associations between mutations and polymor... Invest Ophthalmol Vis Sci. 2011 Aug 5;52(9):6206-12. Print 2011 Aug. Aguirre-Lamban J, Gonzalez-Aguilera JJ, Riveiro-Alvarez R, Cantalapiedra D, Avila-Fernandez A, Villaverde-Montero C, Corton M, Blanco-Kelly F, Garcia-Sandoval B, Ayuso C
Further associations between mutations and polymorphisms in the ABCA4 gene: clinical implication of allelic variants and their role as protector/risk factors.
Invest Ophthalmol Vis Sci. 2011 Aug 5;52(9):6206-12. Print 2011 Aug., [PMID:21330655]

Abstract [show]
PURPOSE: Mutations in ABCA4 have been associated with autosomal recessive Stargardt disease, autosomal recessive cone-rod dystrophy, and autosomal recessive retinitis pigmentosa. The purpose of this study was to determine (1) associations among mutations and polymorphisms and (2) the role of the polymorphisms as protector/risk factors. METHODS: A case-control study was designed in which 128 Spanish patients and 84 control individuals were analyzed. Patient samples presented one or two mutated alleles previously identified using ABCR400 microarray and sequencing. RESULTS: A total of 18 previously described polymorphisms were studied in patients and control individuals. All except one presented a polymorphisms frequency higher than 5% in patients, and five mutations were found to have a frequency >5%. The use of statistical methods showed that the frequency of the majority of polymorphisms was similar in patients and controls, except for the IVS10+5delG, p.Asn1868Ile, IVS48+21C>T, and p.Arg943Gln polymorphisms. In addition, IVS48+21C>T and p.Arg943Gln were found to be in linkage disequilibrium with the p.Gly1961Glu and p.Arg602Trp mutations, respectively. CONCLUSIONS: Although the high allelic heterogeneity in ABCA4 and the wide spectrum of many common and rare polymorphisms complicate the interpretation of clinical relevance, polymorphisms were identified that may act as risk factors (p.Asn1868Ile) and others that may act as protection factors (p.His423Arg and IVS10+5 delG).

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72 Mutations and Polymorphisms in the Patient Cohort ABCA4 mutation screening demonstrated that the most frequent (Ͼ5%) disease-associated alleles were the following: p.Arg1129Leu, p.Gly1961Glu, p.Arg602Trp, c.3211insGT, and p.Leu2060Arg (Table 1; Fig. 1). Login to comment
83 Most Frequent ABCA4 Disease-Associated Alleles Identified in the Patient Cohort Exon Nucleotide Change Aminoacid Change Patients n (%) Allele Frequency n (%) Controls n (%) Allele Frequency n (%) P 23 c.3386GϾT p.Arg1129Leu 34 (26.6) 38 (14.8) 0 (0.0) 0 (0.0) 0.000 42 c.5882GϾA p.Gly1961Glu 18 (14.1) 18 (7.0) 1 (1.2) 1 (0.6) 0.001 13 c.1804CϾT p.Arg602Trp 8 (6.3) 9 (3.5) 0 (0.0) 0 (0.0) 0.020 22 c.3211insGT Frameshift 7 (5.5) 7 (2.7) 0 (0.0) 0 (0.0) 0.029 45 c.6179TϾG p.Leu2060Arg 7 (5.5) 7 (2.7) 0 (0.0) 0 (0.0) 0.029 Note that only the p.Gly1961Glu substitution was identified in both patients and control groups. Login to comment
96 p.Leu2060Arg The fifth most frequently detected mutation was p.Leu2060Arg (5.5%) (Table 1). Login to comment
98 However, p.His423Arg was less frequently detected among patients harboring p.Leu2060Arg, since the frequency of this occurrence was 14.3% (P ϭ 0.05) (Table 3). Login to comment
109 Association between the Most Frequent ABCA4 Polymorphisms and Mutations Patients Variants Frequency P Status Predicted Effect Mutation, n (%) p.Arg1129Leu 34 (26.6) Present polymorphisms p.His423Arg 94.1% 0.000 Associated Risk IVS33؉48C>T 100% 0.011 Associated Risk IVS10ϩ5delG 20.6% 0.049 Associated Protector p.Leu1938Leu 17.6% 0.033 Associated Protector p.Ser2255Ile 2.9% 0.054 Associated Protector Mutation, n (%) p.Gly1961Glu 18 (14.1) Present polymorphisms p.Pro1948Pro 94.7% 0.000 Associated Risk p.Leu1938Leu 89.5% 0.000 Associated Risk p.Asp2095Asp 78.9% 0.000 Associated Risk IVS48؉21C>T 70.0% 0.000 Associated Risk IVS10؉5delG 57.9% 0.008 Associated Risk p.His423Arg 31.6% 0.016 Associated Protector p.Asn1868Ile 18.7% 0.039 Associated Protector Mutation, n (%) p.Arg602Trp 8 (6.3%) Present polymorphisms p.Arg943Gln 62.5% 0.000 Associated Risk p.Pro1401Pro 25% 0.044 Associated Protector p.Leu1938Leu 0% 0.041 Associated Protector Mutation, n (%) c.3211insGT 7 (5.5%) Present polymorphisms p.His423Arg 100% 0.021 Associated Risk p.Asn1868Ile 100% 0.000 Associated Risk IVS10ϩ5delG 0% 0.047 Associated Protector Mutation, n (%) p.Leu2060Arg 7 (5.5%) Present polymorphisms p.Leu1938Leu 100% 0.000 Associated Risk p.Pro1948Leu 100% 0.000 Associated Risk p.His423Arg 14.3% 0.019 Associated Protector TABLE 4. Login to comment
114 This is the case of the p.His423Arg polymorphism and the p.Gly1961Glu and p.Leu2060Arg mutations (P ϭ 0.023; Table 3); in other cases, however, the same polymorphism was found in association with the pArg1129Leu and c.3211insGT mutations. Login to comment
116 As expected, no mutations were present in control samples, with the exception of p.Gly1961Glu (1.19%). Login to comment
118 The p.Gly1961Glu variant was found in 18 (out of 128) STGD patients and was considered a moderate allele.9 However, there is no linkage disequilibrium, since five out of 18 STGD patients did not carry the IVS48ϩ21CϾT polymorphism. Login to comment
129 The p.Arg943Gln polymorphism is in linkage disequilibrium with the p.Arg602Trp mutation in Spanish STGD (P Ͻ 0.001, Table 3). Login to comment
73 Mutations and Polymorphisms in the Patient Cohort ABCA4 mutation screening demonstrated that the most frequent (b0e;5%) disease-associated alleles were the following: p.Arg1129Leu, p.Gly1961Glu, p.Arg602Trp, c.3211insGT, and p.Leu2060Arg (Table 1; Fig. 1). Login to comment
84 Most Frequent ABCA4 Disease-Associated Alleles Identified in the Patient Cohort Exon Nucleotide Change Aminoacid Change Patients n (%) Allele Frequency n (%) Controls n (%) Allele Frequency n (%) P 23 c.3386Gb0e;T p.Arg1129Leu 34 (26.6) 38 (14.8) 0 (0.0) 0 (0.0) 0.000 42 c.5882Gb0e;A p.Gly1961Glu 18 (14.1) 18 (7.0) 1 (1.2) 1 (0.6) 0.001 13 c.1804Cb0e;T p.Arg602Trp 8 (6.3) 9 (3.5) 0 (0.0) 0 (0.0) 0.020 22 c.3211insGT Frameshift 7 (5.5) 7 (2.7) 0 (0.0) 0 (0.0) 0.029 45 c.6179Tb0e;G p.Leu2060Arg 7 (5.5) 7 (2.7) 0 (0.0) 0 (0.0) 0.029 Note that only the p.Gly1961Glu substitution was identified in both patients and control groups. Login to comment
134 This is the case of the p.His423Arg polymorphism and the p.Gly1961Glu and p.Leu2060Arg mutations (P afd; 0.023; Table 3); in other cases, however, the same polymorphism was found in association with the pArg1129Leu and c.3211insGT mutations. Login to comment

[hide] Spectrum of the ABCA4 gene mutations implicated in... Invest Ophthalmol Vis Sci. 2007 Mar;48(3):985-90. Valverde D, Riveiro-Alvarez R, Aguirre-Lamban J, Baiget M, Carballo M, Antinolo G, Millan JM, Garcia Sandoval B, Ayuso C
Spectrum of the ABCA4 gene mutations implicated in severe retinopathies in Spanish patients.
Invest Ophthalmol Vis Sci. 2007 Mar;48(3):985-90., [PMID:17325136]

Abstract [show]
PURPOSE: The purpose of this study is to describe the spectrum of mutations in the ABCA4 gene found in Spanish patients affected with several retinal dystrophies. METHODS: Sixty Spanish families with different retinal dystrophies were studied. Samples were analyzed for variants in all 50 exons of the ABCA4 gene by screening with the ABCR400 microarray, and results were confirmed by direct sequencing. Haplotype analyses were also performed. For those families with only one mutation detected by the microarray, denaturing (d)HPLC was performed to complete the mutational screening of the ABCA4 gene. RESULTS: The sequence analysis of the ABCA4 gene led to the identification of 33 (27.5%) potential disease-associated alleles among the 60 patients. These comprised 16 distinct sequence variants in 25 of the 60 subjects investigated. For autosomal recessive cone-rod dystrophy (arCRD), we found that 50% of the CRD families with the mutation had two recurrent changes (2888delG and R943Q). For retinitis pigmentosa (RP) and autosomal dominant macular dystrophy (adMD), one putative disease-associated allele was identified in 9 of the 27 and 3 of the 7 families, respectively. CONCLUSIONS: In the population studied, ABCA4 plays an important role in the pathogenesis of arCRD. However, mutations in this gene are less frequently identified in other retinal dystrophies, like RP or adMD, and therefore it is still not clear whether ABCA4 is involved as a modifying factor or the relationship is a fortuitous association.

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56 TABLE 1. Genetic Analyses of ABCA4 Mutations in Three Families with Autosomal Dominant Macular Dystrophy Family Allele 1 Allele 2 Haplotype AnalysisNucleotide Change Amino Acid Change Nucleotide Change Amino Acid Change ADDM-59 [5582G3A; 6764G3T] [G1961E; S22551] Excluded ADDM-92 466A3G I156V Not done ADDM-105 2828G3A R943Q Not done No change has been detected as allele 2. Login to comment
57 TABLE 2. Genetic Analyses of ABCA4 Mutations in 13 arCRD Families Family Allele 1 Allele 2 Haplotype AnalysisNucleotide Change Amino Acid Change Nucleotide Change Amino Acid Change ARDM-79 2888delG Frameshift 2888delG Frameshift Cosegregates ARDM-85 6764G3T S2255I (likely nonpathogenic) Not detected Not done* ARDM-86 2888delG Frameshift 2888delG Frameshift Cosegregates ARDM-99 4297G3A V1433I Not detected Not done* ARDM-126 [2828G3A; 5929G3A] [R943Q; G1977S] [2828G3A; 5929G3A] [R943Q; G1977S] Cosegregates ARDM-133 32T3C L11P 2888delG Frameshift Cosegregates ARDM-134 2828G3A R943Q Excluded ARDM-174 4918C3T R1640W c.6147؉2T3A Splice Cosegregates ARDM-176 2888delG Frameshift 6179T3G L2060R Cosegregates RP-267 5041del 15 pb Frameshift 5041del 15 pb Frameshift Cosegregates RP-577 1140T3A N380K Not detected Not done* SRP-964 2828G3A R943Q Not detected Not done* B210 2828G3A R943Q 2701A3G T901A Not done* The mutation detected by dHPLC is in bold. Login to comment
108 In the two 2888delG compound heterozygous families, one of them showed the missense mutation L11P, which affects a conserved amino acid localized in the intracytoplasmic compartment,8 as a second allele, and the other family harbored the L2060R mutation, which produces an alteration in the charge of the mutated amino acid that has been associated with the CRD phenotype.20 In this work, we found that the diagnosis of the proband from family ARDM-79 had changed from arSTGD to arCRD. Login to comment
106 In the two 2888delG compound heterozygous families, one of them showed the missense mutation L11P, which affects a conserved amino acid localized in the intracytoplasmic compartment,8 as a second allele, and the other family harbored the L2060R mutation, which produces an alteration in the charge of the mutated amino acid that has been associated with the CRD phenotype.20 In this work, we found that the diagnosis of the proband from family ARDM-79 had changed from arSTGD to arCRD. Login to comment

[hide] Spectrum of ABCA4 (ABCR) gene mutations in Spanish... Hum Mutat. 2001 Jun;17(6):504-10. Paloma E, Martinez-Mir A, Vilageliu L, Gonzalez-Duarte R, Balcells S
Spectrum of ABCA4 (ABCR) gene mutations in Spanish patients with autosomal recessive macular dystrophies.
Hum Mutat. 2001 Jun;17(6):504-10., [PMID:11385708]

Abstract [show]
The ABCA4 gene has been involved in several forms of inherited macular dystrophy. In order to further characterize the complex genotype-phenotype relationships involving this gene, we have performed a mutation analysis of ABCA4 in 14 Spanish patients comprising eight STGD (Stargardt), four FFM (fundus flavimaculatus), and two CRD (Cone-rod dystrophy) patients. SSCP (single-strand conformation polymorphism) analysis and DNA sequencing of the coding and 5' upstream regions of this gene allowed the identification of 16 putatively pathogenic alterations, nine of which are novel. Most of these were missense changes, and no patient was found to carry two null alleles. Overall, the new data agree with a working model relating the different pathogenic phenotypes to the severity of the mutations. When considering the information presented here together with that of previous reports, a picture of the geographic distribution of three particular mutations emerges. The R212C change has been found in French, Italian, Dutch, German, and Spanish but not in British patients. In the Spanish collection, R212C was found in a CRD patient, indicating that it may be a rather severe change. In contrast, c.2588G>C, a very common mild allele in the Dutch population, is rarely found in Southern Europe. Interestingly, the c.2588G>C mutation has been found in a double mutant allele together with the missense R1055W. Finally, the newly described L1940P was found in two unrelated Spanish patients, and may be a moderate to severe allele.

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41 Mutations L686S, c.2888delG, T1253L, c.4253 +5G>A, N1799D, N1805D, L1940P , and L2060R were confirmed by TaqI, Sau96I, HgaI, HhaI, MboI, TaqI, HaeIII, and MspI digestion, respectively. Login to comment
59 Pathogenic Mutations In the absence of a functional assay, it is difficult to relate the structural alteration with the TABLE 1. Summary of the Pathogenic Variants Found in the Screening of the ABCA4 Gene Family (NAS) Paternal allele (E) Maternal allele (E) Onset (years) Phenotype SB1 c.3211-3212insGT (22) R212C (6) 9 CRD M266 (2) c.4253+5G>A (28) L2060R (46) 7/4 CRD SM3 [R152Q (5); R2107H (46)] [R152Q (5); R2107H (46)] 7 STGD SZ2 L1940P (41) ND 8 STGD SM1 N1799D (38) ND 9 STGD SM2 c.2888delG (19) [R1055W (21); C.2588G>C (17)] 11 STGD SP1 ND ND 12 STGD SZ3 ND ND 12 STGD M280 N1805D (39) N1805D (39) 14 STGD SB2 (2) R1108C (22) L686S (14) 18/11 STGD SZ4 ND ND 20/28 FFM SP2 ND ND 21 FFM SM4 [T1253L (25); G1961E (42)] ND 38 FFM SZ1 L1940P (41) ND 28 FFM Novel putative pathogenic variants are depicted in bold type and their corresponding nucleotide changes are as follows: L686S=c.2057T>C; R1055W=c.3163C>T; T1253L=c.3758C>T; N1799D=c.5396A>G; N1805D=c.5413A>G; L1940P=c.5819T>C; L2060R=c.6179T>G. Login to comment
106 In family M266, the association of c.4253+ 5G>A and L2060R with CRD suggests that both could be ranked as moderately severe mutations. Login to comment