Two novel compound heterozygous BMP1 mutations in a patient with osteogenesis imperfecta: a case report

Abstract

BackgroundOsteogenesis imperfecta (OI) is a collagen-related bone dysplasia leading to a susceptibility to fractures. OI can be caused by mutations in several genes including BMP1. It encodes two isoforms, bone morphogenetic protein 1 (BMP1) and mammalian tolloid (mTLD); both have proteolytic activity to remove the C-propeptide from procollagen.Case presentationWe report a Thai OI patient who had his first fracture at the age of three months. Using next generation sequencing, we successfully identified two novel compound heterozygous BMP1 mutations. One mutation, c.796_797delTT (p.Phe266Argfs*25) affects both BMP1 and mTLD isoforms, while the other, c.2108-2A > G, affects only the BMP1 isoform. Preservation of the mTLD may explain the relatively less severe clinical phenotype in this patient. Intravenous bisphosphonate was given from the age of 8 months to 5 years. He was free from fractures for 9 months before discontinuation.ConclusionThis case expands the mutation spectrum of BMP1, strengthens the correlation between genotype and phenotype, and supports the benefits of bisphosphonate in OI patients with BMP1 mutations.

Mutations That Alter the Carboxy-Terminal-Propeptide Cleavage Site of the Chains of Type I Procollagen Are Associated With a Unique Osteogenesis Imperfecta Phenotype

“…Asharani and colleagues found detectable plasma P1CP at levels just below the normal range in two patients with mutations that affected the signal peptide of BMP1, which confirmed that cleavage of the C‐propeptide occurred, suggesting that alternate enzymes facilitated the event. To date, 18 people with OI due to BMP1 mutations have been described . They share some phenotypic features with those with substrate alterations—white sclerae and absence of dentinogenesis imperfecta—but their fracture phenotype is more severe: 28% had fractures in utero or at birth and 85% had fractured by the age of 2 years.…”

“…To date, 18 people with OI due to BMP1 mutations have been described. (30)(31)(32)(33)(34)(35)(36)(37) They share some phenotypic features with those with substrate alterationswhite sclerae and absence of dentinogenesis imperfecta-but their fracture phenotype is more severe: 28% had fractures in utero or at birth and 85% had fractured by the age of 2 years. High bone density has been found in some, but not all, patients with BMP1 mutations.…”

A novel mutation in COL1A2 leads to osteogenesis imperfecta/Ehlers-Danlos overlap syndrome with brachydactyly

“…Genotype-phenotype correlation gives clues to general developmental biology and is important for genetic counseling 25, 26. It has been shown that the mutations affecting glycine residues in the Gly-X-Y triplet domain of the type I collagen triple helix, compared with haploinsufficiency mutations, are responsible for more severe phenotypes including extensive skeletal abnormalities, low bone mineral density, short stature, dentinogenesis imperfecta, and scoliosis 27, 28.…”

Mutations That Alter the Carboxy-Terminal-Propeptide Cleavage Site of the Chains of Type I Procollagen Are Associated With a Unique Osteogenesis Imperfecta Phenotype

“…To date, 18 people with OI due to BMP1 mutations have been described. (30)(31)(32)(33)(34)(35)(36)(37) They share some phenotypic features with those with substrate alterations-white sclerae and absence of dentinogenesis imperfecta-but their fracture phenotype is more severe: 28% had fractures in utero or at birth and 85% had fractured by the age of 2 years. High bone density has been found in some, but not all, patients with BMP1 mutations.…”