Identification of FZD4 and LRP5 mutations in 11 of 49 families with familial exudative vitreoretinopathy

Abstract

Purpose: To identify mutations in FZD4 and LRP5 in 49 Chinese families with familial exudative vitreoretinopathy (FEVR) and to reveal the mutation spectrum and frequency of these genes in the Chinese population.

Methods: Clinical data and genomic DNA were collected for patients from 49 families with FEVR. The coding exons and adjacent intronic regions of FZD4 and LRP5 were amplified with polymerase chain reaction, and the resulting amplicons were analyzed with Sanger sequencing.

Results: Eleven mutations were detected in 11 of the 49 families (22.4%), including five mutations in the FZD4 gene in six families and six mutations in the LRP5 gene in five families. Of the 11 mutations, eight were novel. Two families had the same FZD4 mutation, and one family had compound heterozygous mutations in LRP5. The phenotypes of the patients with the mutations showed great variability.

Conclusions: Our findings provide an overview of the mutation spectrum and frequency of FZD4 and LRP5 in Chinese patients with FEVR and emphasize the complexity of FEVR mutations and phenotypes.

Figure 1

Eleven mutations identified in FZD4 and LRP5 genes of 49 families with FEVR. The columns from left to right display the family number, the mutation designation, and sequence chromatography from patients and normal controls.

Figure 2

Pedigrees of 11 families with FZD4 or LRP5 mutations. A + sign represents a normal allele, and a - sign indicates a variant. The proband in family QT191 had compound heterozygous mutation, while his mother had a heterozygous c.2484C>G: variant and his father had a heterozygous c.2626G>A variant. The squares brackets around II:1 in family QT476 indicated an adopted proband.

Figure 3

Protein alignment for the novel missense mutations identified in FZD4 and LRP5. Nonconserved amino acid residues are boxed. The residues with mutations are highly conserved. FZD4 orthologs included Homo sapiens (NP_036325.2), Pan troglodytes (XP_001175326.1), Mus musculus (NP_032081.2), Rattus norvegicus (NP_072145.1), Bos taurus (NP_001193198.1), Equus caballus (XP_001489854.1), Canis familiaris (XP_848753.1), Gallus gallus (NP_989430.1), and Danio rerio (XP_002664771.1). The LRP5 orthologs are from Homo sapiens (NP_002326.2), Pan troglodytes (XP_508605.2), Mus musculus (NP_032539.1), Rattus norvegicus (NP_001099791.2), Bos taurus (XP_614220.3), Gallus gallus (NP_001012915.1), and Danio rerio (NP_001170929.1).

Figure 4

Ocular changes in affected individuals with an FZD4 or LRP5 mutation. The individual ID is indicated on the top left of each picture, which is the same as in Figure 2 and Table 2. Signs of FEVR included retinal detachment (top left), falciform retinal fold (top middle), temporal dragging of optic disc (top right), peripheral avascular zone and brush-like peripheral vessels (middle left), shell-like peripheral vessel terminatio and neovascularization (center), peripheral fibrovascular proliferation (middle right), lens dislocation (bottom left), peripheral exudates (bottom middle), temporal dragging of optic disc, and peripheral fibrous proliferation (bottom right).