WNT1 mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta

Abstract

Osteogenesis imperfecta (OI) is a heritable disorder that ranges in severity from death in the perinatal period to an increased lifetime risk of fracture. Mutations in COL1A1 and COL1A2, which encode the chains of type I procollagen, result in dominant forms of OI, and mutations in several other genes result in recessive forms of OI. Here, we describe four recessive-OI-affected families in which we identified causative mutations in wingless-type MMTV integration site family 1 (WNT1). In family 1, we identified a homozygous missense mutation by exome sequencing. In family 2, we identified a homozygous nonsense mutation predicted to produce truncated WNT1. In family 3, we found a nonsense mutation and a single-nucleotide duplication on different alleles, and in family 4, we found a homozygous 14 bp deletion. The mutations in families 3 and 4 are predicted to result in nonsense-mediated mRNA decay and the absence of WNT1. WNT1 is a secreted signaling protein that binds the frizzled receptor (FZD) and the coreceptor low-density lipoprotein-receptor-related protein 5 (LRP5). Biallelic loss-of-function mutations in LRP5 result in recessive osteoporosis-pseudoglioma syndrome with low bone mass, whereas heterozygous gain-of-function mutations result in van Buchem disease with elevated bone density. Biallelic loss-of-function mutations in WNT1 result in a recessive clinical picture that includes bone fragility with a moderately severe and progressive presentation that is not easily distinguished from dominant OI type III.

Figure 1

Pedigrees of the Families Affected by WNT1 Mutations Families 1 (A), 2 (B), 3 (C), and 4 (D). For family 1, exome sequences were determined for individuals IV-2 and IV-4. Arrows indicate the proband from each family, and the asterisks indicate the individuals studied from each family.

Figure 2

Radiographs of Affected Individuals with WNT1 Mutations (A) Radiographs taken in the mid 20s of individual IV-3 in family 1. There is marked bowing of the long bones in each extremity, low bone density, and striking scoliosis of the spine. (B) Radiographs taken when II-6 (proband) from family 2 was 18 months of age show diminished mineralization of all long bones, bowing of several long bones, very marked bilateral angulation of the proximal femur, thin ribs, diminished calvarial mineralization, lack of bone modeling, and scoliosis. (C) In radiographs taken of individual II-3 from family 2, the progression of scoliosis over the first year of life is apparent. There is marked change in bone structure and an increase in femoral bowing over 7 years. (D) At the age of 7 months, individual II-1 from family 4 has decreased bone mineralization, platyspondyly, almost absent calvarial mineralization, but maintenance of long-bone structure with the exception of the fracture in the right radius.

Figure 3

WNT1 Mutations in Each Family (A) Exon-intron structure and mutations in WNT1 in four families. Color coding is as follows: purple, family 1; red, family 2; black, family 3; and blue, family 4. (B) Sequence images of mutations in each family. Chromatograms labeled with N represent the normal reference sequence.