A polyadenylation site variant causes transcript-specific BMP1 deficiency and frequent fractures in children.

We had previously published the clinical characteristics of a bone fragility disorder in children that was characterized mainly by lower extremity fractures and a mineralization defect in bone tissue but not on the growth plate level. We have now performed whole-exome sequencing on four unrelated individuals with this phenotype. Three individuals were homozygous for a nucleotide change in BMP1, affecting the polyadenylation signal of the transcript that codes for the short isoform of BMP1 (BMP1-1) (c.*241T>C). In skin fibroblasts of these individuals, we found low levels of BMP1-1 transcript and protein. The fourth individual was compound heterozygous for the c.*241T>C variant in BMP1-1 and a variant in BMP1 exon 15 (c.2107G>C) that affected splicing in both BMP1-1 and the long isoform of BMP1 (BMP1-3). Both the homozygous 3'UTR variant and the compound heterozygous variants were associated with impaired procollagen type I C-propeptide cleavage, as the amount of free C-propeptide in the supernatant of skin fibroblasts was less than in controls. Peripheral quantitative computed tomography showed that all individuals had elevated volumetric cortical bone mineral density. Assessment of iliac bone samples by histomorphometry and quantitative backscattered electron imaging indicated that the onset of mineralization at bone formation sites was delayed, but that mineralized matrix was hypermineralized. These results show that isolated lack of BMP1-1 causes bone fragility in children.