Title
Recessive osteogenesis imperfecta caused by **LEPRE1** mutations : clinical documentation and identification of the splice form responsible for prolyl 3-hydroxylation Recessive osteogenesis imperfecta caused by **LEPRE1** mutations : clinical documentation and identification of the splice form responsible for prolyl 3-hydroxylation
Author
Faculty/Department
Faculty of Medicine and Health Sciences
Publication type
article
Publication
London ,
Subject
Human medicine
Source (journal)
Journal of medical genetics. - London
Volume/pages
46(2009) :4 , p. 233-241
ISSN
0022-2593
ISI
000265011000003
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Abstract
Background: 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 α1-chains. Methods: 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. Results: 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 (177/12 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 α1(I)Pro986 3-hydroxylation and overmodification of type I (pro)collagen chains in skin fibroblasts of the patients. Conclusion: These findings suggest that the 3-hydroxylation function of P3H1 is restricted to the 736AA splice form.
E-info
https://repository.uantwerpen.be/docman/iruaauth/042765/fe9c40d5a70.pdf
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