A Novel IFITM5 Mutation in Severe Atypical Osteogenesis Imperfecta Type VI Impairs Osteoblast Production of Pigment Epithelium‐Derived Factor. (June 2014)

• Record Type: Journal Article
• Authors: Farber, Charles R; Reich, Adi; Barnes, Aileen M; Becerra, Patricia; Rauch, Frank; Cabral, Wayne A; Bae, Alison; Quinlan, Aaron; Glorieux, Francis H; Clemens, Thomas L; Marini, Joan C
• Is Part Of: Journal of bone and mineral research. Volume 29:Number 6(2014:Jun.)
• Page Start: 1402
• Page End: 1411
• Publication Date: 2014-06
• Subjects: Bones -- Metabolism -- Periodicals; Mineral metabolism -- Periodicals; 612.392
• DOI: 10.1002/jbmr.2173
• Languages: English
• ISSNs: 0884-0431

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>ABSTRACT</title> <sec id="jbmr2173-sec-0001" sec-type="section"> <p>Osteogenesis imperfecta (OI) types V and VI are caused, respectively, by a unique dominant mutation in <italic>IFITM5</italic>, encoding BRIL, a transmembrane ifitm‐like protein most strongly expressed in the skeletal system, and recessive null mutations in <italic>SERPINF1</italic>, encoding pigment epithelium‐derived factor (PEDF). We identified a 25‐year‐old woman with severe OI whose dermal fibroblasts and cultured osteoblasts displayed minimal secretion of PEDF, but whose serum PEDF level was in the normal range. <italic>SERPINF1</italic> sequences were normal despite bone histomorphometry consistent with type VI OI and elevated childhood serum alkaline phosphatase. We performed exome sequencing on the proband, both parents, and an unaffected sibling. <italic>IFITM5</italic> emerged as the candidate gene from bioinformatics analysis, and was corroborated by membership in a murine bone co‐expression network module containing all currently known OI genes. The de novo <italic>IFITM5</italic> mutation was confirmed in one allele of the proband, resulting in a p.S40L substitution in the intracellular domain of BRIL but was absent in unaffected family members. <italic>IFITM5</italic> expression was normal in proband fibroblasts and osteoblasts, and BRIL protein level was similar to control in differentiated proband osteoblasts on Western blot and in permeabilized mutant osteoblasts by microscopy. In contrast, <italic>SERPINF1</italic> expression was decreased in proband osteoblasts; PEDF was barely detectable in conditioned media of proband cells. Expression and secretion of type I collagen was similarly decreased in proband osteoblasts; the expression pattern of several osteoblast markers largely overlapped reported values from cells with a primary PEDF defect. In contrast, osteoblasts from a typical case of type V OI, with an activating mutation at the 5'‐terminus of BRIL, have increased <italic>SERPINF1</italic> expression and PEDF secretion during osteoblast differentiation. Together, these data suggest that BRIL and PEDF have a relationship that connects the genes for types V and VI OI and their roles in bone mineralization. © 2014 American Society for Bone and Mineral Research.</p> </sec> </abstract>