Newfoundland Rod-Cone Dystrophy, an Early-Onset Retinal Dystrophy, Is Caused by Splice-Junction Mutations in RLBP1 Erica R. Eichers, Jane S. Green, David.

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Newfoundland Rod-Cone Dystrophy, an Early-Onset Retinal Dystrophy, Is Caused by Splice-Junction Mutations in RLBP1 Erica R. Eichers, Jane S. Green, David W. Stockton, Christopher S. Jackman, James Whelan, J. Arch McNamara, Gordon J. Johnson, James R. Lupski, Nicholas Katsanis The American Journal of Human Genetics Volume 70, Issue 4, Pages 955-964 (April 2002) DOI: 10.1086/339688 Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 1 Fundus appearance at early, middle, and late stages of NFRCD. The left eyes of NF-001-p09, at age 54 years, exhibiting RPA and scallop-bordered atrophy inferonasally (A and B), of NF-001-p24 at age 34, with RPA (C), of NF-004-p02, at age 66 years, with peripheral lacunar atrophy (D), and of NF-001-p18, at ages 27 years (E) and 46 years (F), showing progression from RPA to advanced atrophy. Also shown is a composite of the fundus of NF-001-p18, at age 27 years (G). The American Journal of Human Genetics 2002 70, 955-964DOI: (10.1086/339688) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 2 Visual-field defects in NFRCD with Goldmann perimeter: NF-001-p16, at age 26 years, with visual acuity 6/6, showing ring scotoma at 6–25 degrees (a), NF-001-p24, at age 34 years, with visual acuity 6/15, ring scotoma at 1–30 degrees (b), NF-001-p09, at age 54 years, with visual acuity 6/60, showing the central 10 degrees and peripheral islands only (c), and NF-004-p01, at age 57 years, with visual acuity restricted to detection of hand motion, peripheral islands only (d). The American Journal of Human Genetics 2002 70, 955-964DOI: (10.1086/339688) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 3 Mutation and haplotype data for six Newfoundland pedigrees diagnosed with NFRCD. All individuals were genotyped for D15S205 and D15S127 and were sequenced for RLBP1. Haplotypes were then constructed for D15S205-SpliceMut1-SpliceMut2-D15S127, with polymorphic alleles expressed in terms of base pairs. SpliceMut1 = 324G→A; SpliceMut2 = IVS3+2 T→C. Each colored bar represents a unique haplotype: yellow = 135-324G→A-wt-142; blue = 124-324G→A-wt-134; red = 159-wt-IVS3+2 T→C-136; green = 135-wt- IVS3+2 T→C-140; gray = non–disease-associated haplotypes. The American Journal of Human Genetics 2002 70, 955-964DOI: (10.1086/339688) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 4 Location of mutations in RLBP1, and pedigrees harboring the mutations. A, Two splice mutations observed at the exon 3/intron 3 junction and predicted to activate a cryptic splice site 6 bp into intron 3. This splice site will create a transcript that, if translated, will produce a protein that terminates early in exon 4. SpliceMut1 = 324G→A; SpliceMut2 = IVS3+2 T→C. B, Subsets of the large pedigree NF-001 and of pedigrees NF-005 and NF-008. Patients NF-001-p01 and NF-001-p02 are homozygous for the 324G→A mutation. NF-001-p38 is homozygous for the IVS3+2 T→C mutation, whereas NF-001-p45 is heterozygous for each mutation. Patients in NF-005 and NF-008 are heterozygous for both alterations. The American Journal of Human Genetics 2002 70, 955-964DOI: (10.1086/339688) Copyright © 2002 The American Society of Human Genetics Terms and Conditions