Mutations in LRP5 or FZD4 Underlie the Common Familial Exudative Vitreoretinopathy Locus on Chromosome 11q Carmel Toomes, Helen M. Bottomley, Richard.

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Mutations in LRP5 or FZD4 Underlie the Common Familial Exudative Vitreoretinopathy Locus on Chromosome 11q Carmel Toomes, Helen M. Bottomley, Richard M. Jackson, Katherine V. Towns, Sheila Scott, David A. Mackey, Jamie E. Craig, Li Jiang, Zhenglin Yang, Richard Trembath, Geoffrey Woodruff, Cheryl Y. Gregory-Evans, Kevin Gregory-Evans, Michael J. Parker, Graeme C.M. Black, Louise M. Downey, Kang Zhang, Chris F. Inglehearn The American Journal of Human Genetics Volume 74, Issue 4, Pages 721-730 (April 2004) DOI: 10.1086/383202 Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 1 Clinical appearance of FEVR. Fundus photograph shows a fold of retinal tissue due to vitreoretinal traction originating from the temporal periphery. This obscures the posterior pole of the right eye and therefore compromises the visual acuity. The American Journal of Human Genetics 2004 74, 721-730DOI: (10.1086/383202) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 2 Schematic diagram of the LRP5 protein showing the location of the mutations within the protein domains. The six YWTD repeats are shown as a hexagon to represent their β-propeller structure, whereas the EGF domains are represented as gray blocks. The American Journal of Human Genetics 2004 74, 721-730DOI: (10.1086/383202) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 3 FEVR caused by mutations in LRP5. A, Sequence traces of the six mutations identified and the corresponding wild-type alleles. The mutation-sequence trace for exon 18 was obtained from a cloned PCR product, so only the disease allele is shown. Other mutations were identified from directly sequenced PCR products and therefore appear as heterozygous changes. B, Mutations segregating in two pedigrees with FEVR. Unaffected individuals (unblackened); affected individuals (blackened); individuals asymptomatic for FEVR (blackened circle in square). Family 1 shows the results of a restriction digest assay through use of HphI, the recognition site of which is abolished by the mutation. The arrow indicates the undigested product present in affected individuals. Family 2 shows an SSCP trace (arrow indicates the aberrant shift). In family 2, an asterisk (*) indicates individuals affected by low bone mass. C, Protein-sequence alignment of human LRP5 (h) with homologues from human and other species: Mus musculus (m), X. laevis (x), Drosophila melanogaster (“arrow”), and Anopheles gambiae str. (“mosquito”). (GenBank accession numbers for all species appear in the “Electronic-Database Information” section.) Only 20 amino acid residues surrounding each mutation are shown. Conserved amino acid residues are highlighted. The positions of the missense mutations T173M, Y1168H, and C1361G are indicated. Both Y1168H and C1361G affect highly conserved amino acids, whereas T173M occurs at a less well-conserved residue. The American Journal of Human Genetics 2004 74, 721-730DOI: (10.1086/383202) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 4 Homology model of LRP5 YWTD-EGF domain 1. A,ClustalW alignment of the sequence from the YWTD-EGF domain, from LDL-R against the four YWTD-EGF domains found in LRP5. Amino acids are numbered in accordance with Swiss-Prot accession number P01130 (LDL-R) and GenBank accession number NP_002326 (LRP5). The amino acids highlighted in cyan correspond to the location of the T173M and Y1168H missense changes identified in the present study. The residues highlighted in pink correspond to the location of the missense mutations shown elsewhere to cause increased bone density (D111Y, G171V, G171R, A214T, A214V, A242T, and T253I) (Boyden et al. 2002; Little et al. 2002; Van Wesenbeeck et al. 2003) and OPPG (R570W, R494Q, and V667M) (Gong et al. 2001). The boxes correspond to the six YWTD-repeats present in the β-propeller module. The LDL-R and model LRP5 domain 1 share 37% sequence identity over 310 residues. B, Surface representation of the LRP5 YWTD-EGF domain 1. The model is based on the alignment shown in panel A. The location of mutations listed in panel A are highlighted on the surface in cyan and pink (numbers correspond to the amino acid residues). The blue backbone ribbon represents the ligand-binding domains R4 and R5 of LDL-R and illustrates how these interact with the propeller domain in LDL-R (Rudenko et al. 2002). Six of the missense mutations are located on the surface of the LRP5 YWTD-EGF domain 1 structure at a site corresponding to the protein-protein interface surface between the R4 and R5 ligand-binding domains and the propeller domain of LDL-R. (Figure prepared using GRASP [Nicholls et al. 1991]) The American Journal of Human Genetics 2004 74, 721-730DOI: (10.1086/383202) Copyright © 2004 The American Society of Human Genetics Terms and Conditions