Bone Abstracts

Background: Osteogenesis imperfecta (OI) is a rare disease characterized by increased fracture rate and bone deformities. Patients are classified by phenotype and most are affected by mutations in COL1A1/2.

Patients with OI type V present with specific clinical symptoms including hyperplastic callus formation, only mildly decreased height, metaphyseal lines and a calcification of the membrane interossea of the forearm. The disease causing mutation for OI type V was unknown till now.

Objective: Identification of the mutation causing OI type V.

Patients/methods: In one patient (age 4.8 years) with clinical signs of OI type V we performed ‘whole exome sequencing’ to identify the underlying mutation Additionally, the phenotypical healthy parents were analyzed for ‘de novo mutations’. A second patient with clinically proven OI type V (15.1 years of age) and his unaffected parents were analyzed per Sanger sequencing.

Results: Using whole exome sequencing we identified a ‘de novo mutation’ in the 5′-UTR region of IFITM5, a bone-specific gene. The mutation was 14 bp above the regular startcodon. Exactly the same mutation was found in our second patient. Therefore this mutation could be described as the causative mutation for OI type V. This mutation leads to a new startcodon. Further functional analysis could proof that this codon is predominantly used in vitro. The additional five aminoacids (M-A-L-E-P) will be added to the den N-terminus and change its function as a transmembrane receptor interacting with the osteoblastogenesis.

Conclusions: Using whole exome sequencing and Sanger sequencing we were able to identify the molecular reason for OI type V. The dominant mutation leads to the creation of a new startcodon, which prolong the resulting transmembrane receptor IFITM5 by five aminoacids. By now for all clinically defined types of OI the molecular reasons are known.