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

(2009) JOURNAL OF MEDICAL GENETICS. 46(4). p.233-241
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Abstract
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 alpha 1-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 (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 alpha 1(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.
Keywords
ENZYMES, PROTEIN, MEMBRANE-ASSOCIATED PROTEOGLYCAN, DEFICIENCY, FAMILY, CRTAP

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MLA
Willaert, Andy et al. “Recessive Osteogenesis Imperfecta Caused by LEPRE1 Mutations: Clinical Documentation and Identification of the Splice Form Responsible for Prolyl 3-hydroxylation.” JOURNAL OF MEDICAL GENETICS 46.4 (2009): 233–241. Print.
APA
Willaert, A., Malfait, F., Symoens, S., Gevaert, K., Kayserili, H., Megarbane, A., Mortier, G., et al. (2009). Recessive osteogenesis imperfecta caused by LEPRE1 mutations: clinical documentation and identification of the splice form responsible for prolyl 3-hydroxylation. JOURNAL OF MEDICAL GENETICS, 46(4), 233–241.
Chicago author-date
Willaert, Andy, Fransiska Malfait, Sofie Symoens, Kris Gevaert, H. Kayserili, A. Megarbane, Geert Mortier, J. G. Leroy, Paul Coucke, and Anne De Paepe. 2009. “Recessive Osteogenesis Imperfecta Caused by LEPRE1 Mutations: Clinical Documentation and Identification of the Splice Form Responsible for Prolyl 3-hydroxylation.” Journal of Medical Genetics 46 (4): 233–241.
Chicago author-date (all authors)
Willaert, Andy, Fransiska Malfait, Sofie Symoens, Kris Gevaert, H. Kayserili, A. Megarbane, Geert Mortier, J. G. Leroy, Paul Coucke, and Anne De Paepe. 2009. “Recessive Osteogenesis Imperfecta Caused by LEPRE1 Mutations: Clinical Documentation and Identification of the Splice Form Responsible for Prolyl 3-hydroxylation.” Journal of Medical Genetics 46 (4): 233–241.
Vancouver
1.
Willaert A, Malfait F, Symoens S, Gevaert K, Kayserili H, Megarbane A, et al. Recessive osteogenesis imperfecta caused by LEPRE1 mutations: clinical documentation and identification of the splice form responsible for prolyl 3-hydroxylation. JOURNAL OF MEDICAL GENETICS. TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND: B M J PUBLISHING GROUP, BRITISH MED ASSOC HOUSE; 2009;46(4):233–41.
IEEE
[1]
A. Willaert et al., “Recessive osteogenesis imperfecta caused by LEPRE1 mutations: clinical documentation and identification of the splice form responsible for prolyl 3-hydroxylation,” JOURNAL OF MEDICAL GENETICS, vol. 46, no. 4, pp. 233–241, 2009.
@article{602663,
  abstract     = {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 alpha 1-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 (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 alpha 1(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.},
  author       = {Willaert, Andy and Malfait, Fransiska and Symoens, Sofie and Gevaert, Kris and Kayserili, H. and Megarbane, A. and Mortier, Geert and Leroy, J. G. and Coucke, Paul and De Paepe, Anne},
  issn         = {0022-2593},
  journal      = {JOURNAL OF MEDICAL GENETICS},
  keywords     = {ENZYMES,PROTEIN,MEMBRANE-ASSOCIATED PROTEOGLYCAN,DEFICIENCY,FAMILY,CRTAP},
  language     = {eng},
  number       = {4},
  pages        = {233--241},
  publisher    = {B M J PUBLISHING GROUP, BRITISH MED ASSOC HOUSE},
  title        = {Recessive osteogenesis imperfecta caused by LEPRE1 mutations: clinical documentation and identification of the splice form responsible for prolyl 3-hydroxylation},
  url          = {http://dx.doi.org/10.1136/jmg.2008.062729},
  volume       = {46},
  year         = {2009},
}

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