title: A novel mutation in LEPRE1 that eliminates only the KDEL ER- retrieval sequence causes non-lethal osteogenesis imperfecta.
abstract: Prolyl 3-hydroxylase 1 (P3H1), encoded by the LEPRE1 gene, forms a molecular complex with cartilage-associated protein (CRTAP) and cyclophilin B (encoded by PPIB) in the endoplasmic reticulum (ER). This complex is responsible for one step in collagen post-translational modification, the prolyl 3-hydroxylation of specific proline residues, specifically α1(I) Pro986. P3H1 provides the enzymatic activity of the complex and has a Lys-Asp-Glu-Leu (KDEL) ER-retrieval sequence at the carboxyl terminus. Loss of function mutations in LEPRE1 lead to the Pro986 residue remaining unmodified and lead to slow folding and excessive helical post-translational modification of type I collagen, which is seen in both dominant and recessive osteogenesis imperfecta (OI). Here, we present the case of siblings with non-lethal OI due to novel compound heterozygous mutations in LEPRE1 (c.484delG and c.2155dupC). The results of RNA analysis and real-time PCR suggest that mRNA with c.2155dupC escapes from nonsense-mediated RNA decay. Without the KDEL ER- retrieval sequence, the product of the c.2155dupC variant cannot be retained in the ER. This is the first report of a mutation in LEPRE1 that eliminates only the KDEL ER-retrieval sequence, whereas other functional domains remain intact. Our study shows, for the first time, that the KDEL ER- retrieval sequence is essential for P3H1 functionality and that a defect in KDEL is sufficient for disease onset.
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Takagi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ishii
authors.forename: Aileen M
authors.initials: AM
authors.lastname: Barnes
authors.forename: Maryann
authors.initials: M
authors.lastname: Weis
authors.forename: Naoko
authors.initials: N
authors.lastname: Amano
authors.forename: Mamoru
authors.initials: M
authors.lastname: Tanaka
authors.forename: Ryuji
authors.initials: R
authors.lastname: Fukuzawa
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.forename: David R
authors.initials: DR
authors.lastname: Eyre
authors.forename: Joan C
authors.initials: JC
authors.lastname: Marini
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Hasegawa
mesh_terms: D024042:Collagen Type I / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics*; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000235:genetics*; D064828:Prolyl Hydroxylases; D011499:Protein Processing, Post-Translational; D011509:Proteoglycans / Q000235:genetics*
chemical_list: D024042:Collagen Type I; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D064828:Prolyl Hydroxylases; C485657:P3H1 protein, human