CRTAP and LEPRE1 mutations in recessive osteogenesis imperfecta.
Autosomal dominant osteogenesis imperfecta (OI) is caused by mutations in the genes (COL1A1 or COL1A2) encoding the chains of type I collagen. Recently, dysregulation of hydroxylation of a single proline residue at position 986 of both the triple-helical domains of type I collagen alpha1(I) and type II collagen alpha1(II) chains has been implicated in the pathogenesis of recessive forms of OI. Two proteins, cartilage-associated protein (CRTAP) and prolyl-3-hydroxylase-1 (P3H1, encoded by the LEPRE1 gene) form a complex that performs the hydroxylation and brings the prolyl cis-trans isomerase cyclophilin-B (CYPB) to the unfolded collagen. In our screen of 78 subjects diagnosed with OI type II or III, we identified three probands with mutations in CRTAP and 16 with mutations in LEPRE1. The latter group includes a mutation in patients from the Irish Traveller population, a genetically isolated community with increased incidence of OI. The clinical features resulting from CRTAP or LEPRE1 loss of function mutations were difficult to distinguish at birth. Infants in both groups had multiple fractures, decreased bone modeling (affecting especially the femurs), and extremely low bone mineral density. Interestingly, "popcorn" epiphyses may reflect underlying cartilaginous and bone dysplasia in this form of OI. These results expand the range of CRTAP/LEPRE1 mutations that result in recessive OI and emphasize the importance of distinguishing recurrence of severe OI of recessive inheritance from those that result from parental germline mosaicism for COL1A1 or COL1A2 mutations.
Baldridge
Dustin
D
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Schwarze
Ulrike
U
Morello
Roy
R
Lennington
Jennifer
J
Bertin
Terry K
TK
Pace
James M
JM
Pepin
Melanie G
MG
Weis
Maryann
M
Eyre
David R
DR
Walsh
Jennifer
J
Lambert
Deborah
D
Green
Andrew
A
Robinson
Haynes
H
Michelson
Melonie
M
Houge
Gunnar
G
Lindman
Carl
C
Martin
Judith
J
Ward
Jewell
J
Lemyre
Emmanuelle
E
Mitchell
John J
JJ
Krakow
Deborah
D
Rimoin
David L
DL
Cohn
Daniel H
DH
Byers
Peter H
PH
Lee
Brendan
B
D003094:Collagen / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D003241:Consanguinity; D021983:Cyclophilins / Q000235:genetics; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008562:Membrane Glycoproteins / Q000235:genetics*; D018832:Molecular Chaperones; D010013:Osteogenesis Imperfecta / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D011296:Prenatal Diagnosis; D064828:Prolyl Hydroxylases; D011509:Proteoglycans / Q000235:genetics*
C108053:CRTAP protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D016326:Extracellular Matrix Proteins; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D011509:Proteoglycans; C081786:cyclophilin B; D003094:Collagen; D064828:Prolyl Hydroxylases; C485657:P3H1 protein, human; D021983:Cyclophilins