ABCMdb

PMID: 17325136

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., [PubMed]

Sentences

No. Mutations Sentence Comment

9 ABCA4 p.Arg943Gln 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). Login to comment 55 ABCA4 p.Gly1961Glu ABCA4 p.Arg943Gln ABCA4 p.Ile156Val TABLE 1. Genetic Analyses of ABCA4 Mutations in Three Families with Autosomal Dominant Macular Dystrophy Family Allele 1 Allele 2 Haplotype Analysis Nucleotide 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 56 ABCA4 p.Gly1961Glu ABCA4 p.Arg1640Trp ABCA4 p.Gly1977Ser ABCA4 p.Gly1977Ser ABCA4 p.Leu11Pro ABCA4 p.Thr901Ala ABCA4 p.Arg943Gln ABCA4 p.Arg943Gln ABCA4 p.Arg943Gln ABCA4 p.Arg943Gln ABCA4 p.Arg943Gln ABCA4 p.Arg943Gln ABCA4 p.Leu2060Arg ABCA4 p.Ser2255Ile ABCA4 p.Val1433Ile ABCA4 p.Ile156Val ABCA4 p.Asn380Lys 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 ABCA4 p.Arg1640Trp ABCA4 p.Gly1977Ser ABCA4 p.Gly1977Ser ABCA4 p.Leu11Pro ABCA4 p.Thr901Ala ABCA4 p.Arg943Gln ABCA4 p.Arg943Gln ABCA4 p.Arg943Gln ABCA4 p.Arg943Gln ABCA4 p.Arg943Gln ABCA4 p.Leu2060Arg ABCA4 p.Ser2255Ile ABCA4 p.Val1433Ile ABCA4 p.Asn380Lys 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 65 ABCA4 p.Gly1961Glu ABCA4 p.Ser2255Ile In family ADDM-59, a complex allele [G1961E; S2255I] was detected in the index patient, but not in her affected daughter, suggesting no cosegregation of the disease within the family. Login to comment 66 ABCA4 p.Gly1961Glu ABCA4 p.Ser2255Ile In family ADDM-59, a complex allele [G1961E; S2255I] was detected in the index patient, but not in her affected daughter, suggesting no cosegregation of the disease within the family. Login to comment 67 ABCA4 p.Ile156Val For family ADDM-92, a mutation in the heterozygous state, I156V, was detected. Login to comment 68 ABCA4 p.Arg943Gln ABCA4 p.Ile156Val For family ADDM-92, a mutation in the heterozygous state, I156V, was detected. Login to comment 69 ABCA4 p.Arg943Gln Besides, a mild allele [R943Q] was detected in family ADDM-105. Login to comment 85 ABCA4 p.Gly1961Glu ABCA4 p.Val767Asp ABCA4 p.Thr901Ala ABCA4 p.Arg943Gln ABCA4 p.Ser2255Ile ABCA4 p.Ser2255Ile ABCA4 p.Ser2255Ile ABCA4 p.Ser2255Ile ABCA4 p.Ile156Val ABCA4 p.Ile156Val TABLE 3. Genetic Analyses of ABCA4 Changes in Nine Families with Autosomal Recessive RP Family Allele 1 Allele 2 Nucleotide Change Amino Acid Change Nucleotide Change Amino Acid Change SRP-716 6764G3T S2255I (likely nonpathogenic) c.858 d19;8T3G SRP-766 2300T3A V767D c.858 d19;8T3G SRP-775 466A3G I156V c.858 d19;8T3G SRP-818 6764G3T S2255I (likely nonpathogenic) SRP-834 c.5547af9;5G3A Splice acceptor SRP-854 6764G3T S2255I B57 466A3G I156V B173 2828G3A R943Q G5466A L1821L B278 2701A3G T901A [G1961E; S2255I] did not support the pathologic role of this mutation in the family. Login to comment 86 ABCA4 p.Arg152* ABCA4 p.Ile156Val ABCA4 p.Ile156Val In family ADDM-92, we detected the mutation I156V, which has been associated with a STGD recessive phenotype.21 The R152X mutation (located in exon 5, close to I156V) was present in a family with dominant STGD that demonstrated genetic linkage to the STGD region on 6q. FIGURE 2. Login to comment 87 ABCA4 p.Gly1961Glu ABCA4 p.Val767Asp ABCA4 p.Thr901Ala ABCA4 p.Arg943Gln ABCA4 p.Ser2255Ile ABCA4 p.Ser2255Ile ABCA4 p.Ser2255Ile ABCA4 p.Ser2255Ile ABCA4 p.Ile156Val ABCA4 p.Ile156Val TABLE 3. Genetic Analyses of ABCA4 Changes in Nine Families with Autosomal Recessive RP Family Allele 1 Allele 2 Nucleotide Change Amino Acid Change Nucleotide Change Amino Acid Change SRP-716 6764G3T S2255I (likely nonpathogenic) c.858 ؉8T3G SRP-766 2300T3A V767D c.858 ؉8T3G SRP-775 466A3G I156V c.858 ؉8T3G SRP-818 6764G3T S2255I (likely nonpathogenic) SRP-834 c.5547ϩ5G3A Splice acceptor SRP-854 6764G3T S2255I B57 466A3G I156V B173 2828G3A R943Q G5466A L1821L B278 2701A3G T901A [G1961E; S2255I] did not support the pathologic role of this mutation in the family. Login to comment 88 ABCA4 p.Arg152* ABCA4 p.Ile156Val ABCA4 p.Ile156Val In family ADDM-92, we detected the mutation I156V, which has been associated with a STGD recessive phenotype.21 The R152X mutation (located in exon 5, close to I156V) was present in a family with dominant STGD that demonstrated genetic linkage to the STGD region on 6q. FIGURE 2. Login to comment 91 ABCA4 p.Arg943Gln In fact, it has already been demonstrated that the ABCA4 and STGD3 genes can interact with each other, increasing the severity of the macular phenotype.12 In family ADDM-105, the R943Q mutation was detected. Login to comment 93 ABCA4 p.Arg943Gln In fact, it has already been demonstrated that the ABCA4 and STGD3 genes can interact with each other, increasing the severity of the macular phenotype.12 In family ADDM-105, the R943Q mutation was detected. Login to comment 94 ABCA4 p.Gly863Ala Other studies have shown this variant to be associated with G863A, leading to a severer pathogenic state in humans. Login to comment 95 ABCA4 p.Arg943Gln ABCA4 p.Arg943Gln Therefore, we speculate about two possibilities: First, the R943Q change could be paired with a severer mutation not found in our study; or second, R943Q could have a modulating effect on another gene implicated in adMD, not discovered yet. Login to comment 96 ABCA4 p.Gly863Ala Other studies have shown this variant to be associated with G863A, leading to a severer pathogenic state in humans. Login to comment 97 ABCA4 p.Arg943Gln ABCA4 p.Arg943Gln ABCA4 p.Arg943Gln ABCA4 p.Ile156Val Therefore, we speculate about two possibilities: First, the R943Q change could be paired with a severer mutation not found in our study; or second, R943Q could have a modulating effect on another gene implicated in adMD, not discovered yet. Login to comment 99 ABCA4 p.Arg943Gln ABCA4 p.Ile156Val In the case of family ADDM-92, which had the I156V mutation, the clinical phenotype seemed to be severer than that in family ADDM105, which presented the mild allele R943Q. Login to comment 105 ABCA4 p.Gly1977Ser ABCA4 p.Gly1977Ser ABCA4 p.Arg943Gln ABCA4 p.Arg943Gln For the [G1977S; R943Q] complex allele found in homozygosis, expression analysis of the G1977S mutation has determined that it causes the inhibition of ATPase by retinal,24 whereas R943Q leads to a reduced nucleotidase activity and nucleotide-binding capacity.22 The affected patients had an age at onset between 9 and 10 years and described night blindness at approximately 18 years of age. Login to comment 106 ABCA4 p.Leu11Pro ABCA4 p.Leu2060Arg 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 107 ABCA4 p.Gly1977Ser ABCA4 p.Gly1977Ser ABCA4 p.Arg943Gln ABCA4 p.Arg943Gln For the [G1977S; R943Q] complex allele found in homozygosis, expression analysis of the G1977S mutation has determined that it causes the inhibition of ATPase by retinal,24 whereas R943Q leads to a reduced nucleotidase activity and nucleotide-binding capacity.22 The affected patients had an age at onset between 9 and 10 years and described night blindness at approximately 18 years of age. Login to comment 108 ABCA4 p.Leu11Pro ABCA4 p.Leu2060Arg 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 109 ABCA4 p.Arg1640Trp The family ARDM 174 presented two mutations, one the missense mutation R1640W detected by the ABCA400 microarray and with an unknown effect in the ABCR function, and the TABLE 4. Login to comment 112 ABCA4 p.Arg1640Trp ABCA4 p.Thr901Ala ABCA4 p.Arg943Gln The family ARDM 174 presented two mutations, one the missense mutation R1640W detected by the ABCA400 microarray and with an unknown effect in the ABCR function, and the TABLE 4. Login to comment 114 ABCA4 p.Arg943Gln ABCA4 p.Arg943Gln ABCA4 p.Ser2255Ile ABCA4 p.Ser2255Ile In all the cases, they were missense mutations (Table 1), although two of them (R943Q and S2255I) are still controversial: R943Q reduces the ATPase activity, and S2255I is supposed to have limited pathogenicity. Login to comment 115 ABCA4 p.Thr901Ala ABCA4 p.Arg943Gln ABCA4 p.Ser2255Ile The last arCRD family studied also presented two missense mutations, namely T901A and R943Q, the latter described as reducing the ATPase activity in 40% and producing minimal defects in nucleotide binding,22 being categorized as a mild mutation. Login to comment 117 ABCA4 p.Arg943Gln ABCA4 p.Arg943Gln ABCA4 p.Ser2255Ile ABCA4 p.Ser2255Ile In all the cases, they were missense mutations (Table 1), although two of them (R943Q and S2255I) are still controversial: R943Q reduces the ATPase activity, and S2255I is supposed to have limited pathogenicity. Login to comment 118 ABCA4 p.Ser2255Ile Thus, such alleles would not be expected to cause disease if paired themselves, but could cause disease if paired with another allele of higher pathogenicity.25 Expression analysis of S2255I has not been reported, but, as proposed by Webster et al.,25 we cannot exclude a limited pathologic effect of this allele in those cases presenting a severer phenotype. Login to comment 120 ABCA4 p.Ser2255Ile In three families we identified only the controversial change S2255I, but as we pointed out before, we could not exclude this mutation as having a role in the pathogenesis of the disease. Login to comment 121 ABCA4 p.Ser2255Ile The percentage of allele detection was 13% to 16%, depending on the inclusion of the S2255I change. Login to comment 123 ABCA4 p.Ser2255Ile In three families we identified only the controversial change S2255I, but as we pointed out before, we could not exclude this mutation as having a role in the pathogenesis of the disease. Login to comment 124 ABCA4 p.Ser2255Ile The percentage of allele detection was 13% to 16%, depending on the inclusion of the S2255I change. Login to comment