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CRTAP, Cartilage Deficiency in Ostegenesis Imperfecta

« Back to Volume 23, Issue 2, June 2007 - Table of Contents

Lethal osteogenesis imperfecta ([OI] type II of the modified Sillence classification of OI, OMIM 166210, Table) is most commonly an autosomal dominantly transmitted disorder due to heterozygous loss of function in one of the 2 genes controlling the synthesis of type I collagen (COL1A1, chromosome 17q21.31-q22.05, OMIM 120150; COL1A2, chromosome 7q22.1, OMIM 120160).¹ As a result of decreased collagen synthesis, there is decreased bone matrix (osteoid) and deficient mineralization of such severity as to result in fractures in utero and postnatally and deformations of the chest leading to respiratory insufficiency and early death in neonates with type II OI. Type I collagen has a triple helical structure comprised of 2 collagen type I-α1 and one collagen type I-α2 proteins composed of tripeptide repeats of glycine and 2 additional amino acid - often proline, hydroxyproline, or lysine. Post translational modifications of type I procollagen include hydroxylation of proline and lysine residues carried out by prolyl and lysyl hydroxylases, an essential step for normal collagen folding and stability. Prolyl 3-hydroxylase 1 ([P3H1], also termed leprecan [LEPRE1] chromosome 1p34, OMIM 610339) specifically hydroxylates the proline residue at codon 986 in bone collagen α1(I), a reaction that requires interaction of P3H1 with cartilage-associated protein ([CRTAP], chromosome 3p22, OMIM 605497) and cyclophilin B (chromosome 15, OMIM 123841). CRTAP is expressed in the proliferative zone of developing cartilage and at the chondro-osseous junction where its function has been obscure; cyclophilin B possesses peptidyl-prolyl cis-trans isomerase activity. Morello et al generated Crtap “knock-out” mice that displayed an osteochondrodysplasia (kyphoscoliosis, shortening of the proximal segment of the limbs consistent with rhizomelia) and severe osteopenia, the latter due to reduced production and alteration in the quality of osteoid and consequently decreased rate of mineral deposition. Mice deficient in Crtap did not have the 3-hydroxyl modification of proline near the carboxyl terminus of bone collagen α1(I) leading to abnormal structure of the collagen fibril - namely increased hydroxylation of lysine residues. These changes resulted in defective mineralization of bone collagen type I.

A recessive form of lethal OI of unknown pathogenesis in which detailed analyses of COL1A1 and COL1A2 have been normal has also been recorded. The present investigators studied the structure of CRTAP in 11 patients with the recessive form of lethal OI or severe OI type III. In 4 infants with multiple fractures of the long bones resulting in rhizomelic shortening of the limbs with externally rotated and abducted legs, poorly mineralized calvaria and ribs, proptotic eyes, and white or light blue sclerae (rather than the more intense blue of classical type II OI), a specific defect in hydroxylation of proline at codon 986 in bone collagen α1(I) was demonstrated. This proved due to loss-of-function mutations in CRTAP: frameshift (c.879delT); 16 bp duplication in exon 1; nonsense (Gly276Stop); missense (Met1Ile); splice donor site of exon 1 at the first intronic nucleotide (IVS1+1GC). All mutations interfered with effective hydroxylation of the proline residue at codon 986 of bone collagen α1(I).

Morello et al also demonstrated that patients with OI type VII (OMIM 610682) have a homozygous mutation in CRTAP. OI type VII is an autosomal recessive disorder in which fractures are present at birth but the frequency of fractures declines with advancing age - particularly after adolescence; the sclerae are slightly bluish; there is progressive skeletal deformation that leads to rhizomelic shortening of the limbs and restricted ambulation. Genotyping of COL1A1 and COL1A2 has been normal in these subjects. OI type VII patients have an inclusion of 73 bp of intron 1 into the genome of CRTAP due to alteration of one nucleotide (c.472 - 1021CG) that generates a cryptic splice donor site that extends exon 2. However, this alteration contains a frameshift that permits more rapid degradation of CRTAP and consequently leads to decreased 3-hydroxylation of proline 986 in bone collagen α1(I). Thus, inactivating mutations in CRTAP can result in at least 2 clinically distinct forms of osteogenesis imperfecta as do mutations in COL1A1 and COL1A2.

Morello R, Bertin TK, Chen Y, et al. CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive osteogenesis imperfecta. Cell. 2006;127;291-304.

Barnes AM, Chang W, Morello R, et al. Deficiency of cartilage-associated protein in lethal osteogenesis imperfecta. N Engl J Med. 2006;355:2757-64.

Editor’s Comment

The melding of clinical acumen with the disciplines of molecular biology and cellular genetics has permitted further understanding of the critical post-translational modifications that collagens α1(I) and α(2)I normally undergo while forming collagen type I demonstrating once more the value of the study of rare “experiments of nature.” It seems likely that abnormalities of the genes encoding P3H1 and cyclophilin B may be identified in other patients with lethal OI type II or other forms of OI. Such studies may also serve as the basis for development of drugs that can modify collagen in a beneficial manner. The currently employed classification of OI is that of Sillence with modifications (Table). It may be anticipated that the classification of OI will be reorganized and related to the genetic mutation(s) and molecular biology of the various clinical disorders.

Allen W. Root, MD

Editor’s Note: For a comprehensive review, refer to the article “Growth in Osteogenesis Imperfecta” in this issue of GGH.²

References - (linked to )

« Back to Volume 23, Issue 2, June 2007 - Table of Contents

Last Updated: 2/2/2011