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.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Dustin
D
Baldridge
Ulrike
U
Schwarze
Roy
R
Morello
Jennifer
J
Lennington
Terry K
TK
Bertin
James M
JM
Pace
Melanie G
MG
Pepin
Maryann
M
Weis
David R
DR
Eyre
Jennifer
J
Walsh
Deborah
D
Lambert
Andrew
A
Green
Haynes
H
Robinson
Melonie
M
Michelson
Gunnar
G
Houge
Carl
C
Lindman
Judith
J
Martin
Jewell
J
Ward
Emmanuelle
E
Lemyre
John J
JJ
Mitchell
Deborah
D
Krakow
David L
DL
Rimoin
Daniel H
DH
Cohn
Peter H
PH
Byers
Brendan
B
Lee
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