ABCMdb

PMID: 10396622

Shroyer NF, Lewis RA, Allikmets R, Singh N, Dean M, Leppert M, Lupski JR
The rod photoreceptor ATP-binding cassette transporter gene, ABCR, and retinal disease: from monogenic to multifactorial.
Vision Res. 1999 Jul;39(15):2537-44., [PubMed]

Sentences

No. Mutations Sentence Comment

68 ABCA4 p.Gly1961Glu ABCA4 p.Asp2177Asn The two most common AMD-associated mutations have similar frequencies in the Utah and Boston cohorts: D2177N was identified in five patients from Utah and two patients from Boston; G1961E was identified in two patients from Utah and four patients from Boston. Login to comment 101 ABCA4 p.Pro1380Leu Cosegregation of a mutant ABCR allele, P1380L, was observed with both disease phenotypes (Fig. 1). Login to comment 105 ABCA4 p.Trp821Arg ABCA4 p.Trp821Arg ABCA4 p.Trp821Arg ABCA4 p.Trp821Arg ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu The proband AR534-05 had two independent allelic mutations: a 4139CT transition which by conceptual translation results in the missense amino acid substitution of leucine for proline at codon 1380 (P1380L; Fig. 1); and a 2461TA transversion, resulting in a predicted amino acid substitution of arginine for tryptophan at codon 821 (W821R; Fig. 1). Login to comment 106 ABCA4 p.Pro1380Leu ABCA4 p.Glu1122Lys ABCA4 p.Glu1122Lys ABCA4 p.Glu1122Lys ABCA4 p.Glu1122Lys The proband`s affected paternal cousins AR534-10 and AR534-12 were each compound heterozygotes for two transition mutations, one (P1380L; Fig. 1) inherited from their mother, the other 3364GA, resulting in a predicted amino acid substitution of lysine for glutamate at codon 1122 (E1122K; Fig. 1), inherited from their father. Login to comment 108 ABCA4 p.Pro1380Leu The grandmother AR534-07 with AMD shared the P1380L mutation (Fig. 1) but had only polymorphisms in her other ABCR allele, confirming her heterozygous state. Login to comment 110 ABCA4 p.Pro1380Leu However, the mutation P1380L has been seen in three unrelated STGD pedigrees (Lewis et al., 1999). Login to comment 112 ABCA4 p.Pro1380Leu To investigate further the frequency of the P1380L allele, which is due to a base change that eliminates an MspI recognition site, 80 ophthalmoscopically normal individuals over the age of 65 were screened for this alteration by MspI digestion of PCR products encompassing exon 28 (data not shown). Login to comment 140 ABCA4 p.Trp821Arg ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu 2537-25442542 Table 1 Base alteration Amino acid changeIndividual sequence Disease phenotype Mutation type 3364 GA E1122K534-12 MissenseSTGD P1380L Missense4139 CT W821R Missense534-05 STGD 2461 TA 4139 CT P1380L Missense None5682 GC Silent 5814 AG None Silent None Silent534-07 AMD 3294 CT 4139 CT P1380L Missense 5603 AT N18681* Polymorphism SilentNone5682 GC * This base alteration found in 29/220 controls. Login to comment 141 ABCA4 p.Trp821Arg ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Pro1380Leu ABCA4 p.Glu1122Lys Table 1 Base alteration Amino acid change Individual sequence Disease phenotype Mutation type 3364 G]A E1122K 534-12 Missense STGD P1380L Missense 4139 C]T W821R Missense 534-05 STGD 2461 T]A 4139 C]T P1380L Missense None 5682 G]C Silent 5814 A]G None Silent None Silent 534-07 AMD 3294 C]T 4139 C]T P1380L Missense 5603 A]T N18681* Polymorphism Silent None 5682 G]C * This base alteration found in 29/220 controls. Login to comment 142 ABCA4 p.Gly1961Glu ABCA4 p.Leu1970Phe ABCA4 p.Arg1898His ABCA4 p.Arg1129Leu ABCA4 p.Glu471Lys Conclusions We reported elsewhere that seven alterations in ABCR (R1898H, G1961E, 6519del11bp, E471K, R1129L, 5196+1GA, and L1970F) are associated with STGD in compound heterozygous states and with AMD in an apparent heterozygous state (Allikmets et al., 1997a; Lewis et al., 1999). Login to comment 143 ABCA4 p.Gly1961Glu ABCA4 p.Gly1961Glu ABCA4 p.Leu1970Phe ABCA4 p.Arg1898His ABCA4 p.Arg1129Leu ABCA4 p.Glu471Lys In addition, we previously showed that the most common mutant ABCR allele (G1961E) identified in a cohort of 150 families was also one of the most frequently identified disease associated ABCR alterations in a cohort of 167 AMD patients (Allikmets et al., 1997a; Lewis et al., 1999). Login to comment 144 ABCA4 p.Gly1961Glu In addition, we previously showed that the most common mutant ABCR allele (G1961E) identified in a cohort of 150 families was also one of the most frequently identified disease associated ABCR alterations in a cohort of 167 AMD patients (Allikmets et al., 1997a; Lewis et al., 1999). Login to comment