Recessive osteogenesis imperfecta caused by LEPRE1 mutations: clinical documentation and identification of the splice form responsible for prolyl 3-hydroxylation

成骨不全 先证者 生物 剪接 复合杂合度 遗传学 突变 外显子跳跃 互补 Ⅰ型胶原 内科学 内分泌学 分子生物学 医学 外显子 基因 表型 选择性拼接 解剖
作者
Andy Willaert,Fransiska Malfait,Sofie Symoens,Kris Gevaert,Hülya Kayserili,André Megarbané,Geert Mortier,JG Leroy,Paul Coucke,Anne De Paepe
出处
期刊:Journal of Medical Genetics [BMJ]
卷期号:46 (4): 233-241 被引量:90
标识
DOI:10.1136/jmg.2008.062729
摘要

Recessive forms of osteogenesis imperfecta (OI) may be caused by mutations in LEPRE1, encoding prolyl 3-hydroxylase-1 (P3H1) or in CRTAP, encoding cartilage associated protein. These proteins constitute together with cyclophilin B (CyPB) the prolyl 3-hydroxylation complex that hydroxylates the Pro986 residue in both the type I and type II collagen alpha1-chains.We screened LEPRE1, CRTAP and PPIB (encoding CyPB) in a European/Middle Eastern cohort of 20 lethal/severe OI patients without a type I collagen mutation.Four novel homozygous and compound heterozygous mutations were identified in LEPRE1 in four probands. Two probands survived the neonatal period, including one patient who is the eldest reported patient (17 7/12 years) so far with P3H1 deficiency. At birth, clinical and radiologic features were hardly distinguishable from those in patients with autosomal dominant (AD) severe/lethal OI. Follow-up data reveal that the longer lived patients develop a severe osteochondrodysplasia that overlaps with, but has some distinctive features from, AD OI. A new splice site mutation was identified in two of the four probands, affecting only one of three LEPRE1 mRNA splice forms, detected in this study. The affected splice form encodes a 736 amino acid (AA) protein with a "KDEL" endoplasmic reticulum retention signal. While western blotting and immunocytochemical analysis of fibroblast cultures revealed absence of this P3H1 protein, mass spectrometry and SDS-urea-PAGE data showed severe reduction of alpha1(I)Pro986 3-hydroxylation and overmodification of type I (pro)collagen chains in skin fibroblasts of the patients.These findings suggest that the 3-hydroxylation function of P3H1 is restricted to the 736AA splice form.

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