A Mutation in the 5′-UTR of IFITM5 Creates an In-Frame Start Codon and Causes Autosomal-Dominant Osteogenesis Imperfecta Type V with Hyperplastic Callus

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A Mutation in the 5′-UTR of IFITM5 Creates an In-Frame Start Codon and Causes Autosomal-Dominant Osteogenesis Imperfecta Type V with Hyperplastic Callus Oliver Semler, Lutz Garbes, Katharina Keupp, Daniel Swan, Katharina Zimmermann, Jutta Becker, Sandra Iden, Brunhilde Wirth, Peer Eysel, Friederike Koerber, Eckhard Schoenau, Stefan K. Bohlander, Bernd Wollnik, Christian Netzer The American Journal of Human Genetics Volume 91, Issue 2, Pages 349-357 (August 2012) DOI: 10.1016/j.ajhg.2012.06.011 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Pictures of the Affected Individuals Enrolled in the Study (A) Radiograph of the femur of proband 2, showing a thickening of the cortical bone on the medial side (arrows) and a hyperplastic callus at the distal part of the thigh (asterisks). (B) Radiograph of the lateral spine of proband 2 with signs of vertebral fractures and wedge-shaped and biconcave deformities (arrows). (C) Radiograph of the right thigh of proband 1 at the age of 2.6 years, showing a hyperplastic callus. At the distal end of the femur, a metaphyseal band (arrow), which is a typical sign of OI type V, is visible. As a result of dislocation of the bone after a fracture, a surgical treatment involving the insertion of two rods was necessary. (D) Photograph documenting the swelling of the right thigh of proband 1. The American Journal of Human Genetics 2012 91, 349-357DOI: (10.1016/j.ajhg.2012.06.011) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 Confirmation of the Heterozygous 5′-UTR IFITM5 Mutation in the Two Proband-Parent Trios and Prediction of Its Impact on IFITM5 (A) Validation of the IFITM5 mutation in the 5′-UTR by Sanger sequencing of genomic DNA isolated from peripheral blood. Electropherograms of proband 1 and her parents are shown. The position of the heterozygous c.−14C>T mutation is indicated by the red arrow. The mutation is clearly absent in both parents, confirming its de novo occurrence in proband 1. The bases marked in yellow indicate the position of the reference ATG; numbers indicate the distance to the reference ATG. (B) Identification of the identical IFITM5 c.−14C>T mutation in proband 2. Electropherograms obtained by Sanger sequencing of genomic DNA of proband 2 and his parents are shown. Again, the mutation is absent in both parents, thereby proving its de novo occurrence. The bases marked in yellow indicate the position of the reference ATG; numbers indicate the distance to the reference ATG. (C) Comparison of the ideal Kozak sequence [A/G]XXATGG with the reference ATG of IFITM5 and with the newly formed upstream ATG at position −14. In the left part of the diagram, the alignment of the mutated 5′-UTR of IFITM5 is given, and the alignment of the reference ATG is depicted on the right. Matching bases between the Kozak sequence and the genomic DNA are connected by dashed lines, and the respective ATG codons are underlined. The position of the c.−14C>T mutation is highlighted in yellow. (D) Predicted protein structure of the altered IFITM5. Both transmembrane domains are marked in yellow, and the helical intracellular domain is highlighted in orange. Numbers indicate the amino acids flanking individual domains. The 5 amino acids that would be added by the c.−14C>T mutation are marked in red. The blue and gray boxes indicate the acetyl residue predicted to be added to the wild-type and altered protein, respectively. The American Journal of Human Genetics 2012 91, 349-357DOI: (10.1016/j.ajhg.2012.06.011) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 Functional Assay for the c.−14C>T Mutation HEK293T cells were cultured in Dulbecco's Modified Eagle Media (DMEM, Life Technologies, Darmstadt, Germany) containing 10% fetal bovine serum (FBS, Life Technologies, Darmstadt, Germany) and antibiotics. FuGENE HD transfection reagent (Roche, Mannheim, Germany) was used for transient transfection of these cells either with an IFITM5 wild-type (WT) expression vector or with one of the construct variants containing the 5′-UTR mutation c.−14C>T. The cells were lysed after 30 hr, and proteins were separated by SDS-PAGE with 4%–12% Bis-Tris gels (Life Technologies, Darmstadt, Germany). Immunoblot analysis with HA antibodies (Roche Diagnostics, Mannheim, Germany) allowed detection of C-terminally tagged IFITM5 (upper panel). Loading of equal protein amounts was confirmed by β-actin detection in the whole-cell lysates (lower panel). The American Journal of Human Genetics 2012 91, 349-357DOI: (10.1016/j.ajhg.2012.06.011) Copyright © 2012 The American Society of Human Genetics Terms and Conditions