Figure 1.

A FZD5 frameshift mutation identified in a family with autosomal dominant coloboma. (A) Six- and three-generation family pedigrees of Family 3483 and Family 111, respectively. The dotted line links these independently ascertained pedigrees carrying the same mutation on an identical haplotype. This link is plausible based on the history obtained from both Mennonite families, with the likely linking individual (Family 3483 II:4) having emigrated from Europe to North America. For Family 3483, ocular images from the affected individuals are shown adjacent to the cognate pedigree symbol. Coloboma patient numbers indicate individuals whose exomes were sequenced. Otherwise, Sanger sequencing was used for segregation analysis, which reveals high (0.8) but incomplete penetrance, as indicated by two obligate carriers that are unaffected. The pedigree key is in the top left corner. (B) Representative images showing eye malformations in affected individuals from Family 111. The LOD score for the combined pedigree is shown below the family tree. (C) Chromatopherogram of the frameshift FZD5 mutation (c.656delCinsAG). (D) Schematic of the human FZD5 gene with hg19 coordinates on chromosome 2. This gene is transcribed in the antisense direction relative to the genomic coordinate numbering. The position of the cDNA mutation is indicated in the ORF, which is entirely contained in the second exon. Below are diagrammatic representations of the WT and ‘mutant’ FZD5 peptides. The WNT-binding domain (dark blue box) is common to both, and the seven transmembrane domains (orange boxes) are present only in the WT protein of 585 residues. The mutation results in the truncation at Ala219 (substituted to Glu) with an aberrant extension of 48 residues (red box), resulting in a protein of 266 amino acids.