Alternative titles; symbols
HGNC Approved Gene Symbol: CRTAP
Cytogenetic location: 3p22.3 Genomic coordinates (GRCh38): 3:33,114,014-33,147,773 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p22.3 | Osteogenesis imperfecta, type VII | 610682 | Autosomal recessive | 3 |
Castagnola et al. (1997) isolated a mouse Crtap cDNA from a subtracted library specific for mRNAs highly expressed in hypertrophic chondrocytes compared to proliferating and early differentiating chondrocytes. Using a mouse Crtap clone to screen a human fetal brain cDNA library, Tonachini et al. (1999) identified human CRTAP cDNA clones. Human CRTAP encodes a deduced 401-amino acid protein with a putative signal peptide of 26 amino acids. CRTAP contains 2 potential N-glycosylation signals. CRTAP shares 89% amino acid sequence identity with mouse Crtap and 51% identity with the chick homolog. The mouse and human genes contain a C-terminal region of approximately 120 amino acids not present in the chick protein.
Using Northern blot analysis of human tissues, Tonachini et al. (1999) detected 2-kb and 4-kb CRTAP transcripts in brain, heart, kidney, lung, small intestine, and skeletal muscle. In all tissues except brain, the 2-kb transcript was more abundant. Using immunohistochemistry, the authors detected CRTAP expression in articular chondrocytes. In mouse, Morello et al. (1999) detected 3 Crtap transcripts in a range of tissues, including all mouse embryonic cartilages. In chick, Castagnola et al. (1997) detected a single Crtap transcript in a broad range of embryonic tissues with the strongest expression in the developing cartilage. They detected expression in the extracellular matrix of the forming cartilage surrounding the notochord, the developing sclera, the sphenoid and mandibular cartilage, the long bone cartilage, and the developing sternal cartilage.
Using RNA in situ hybridization, Morello et al. (2006) showed that Crtap is highly expressed in mouse growth plate proliferating chondrocytes and in cells at the chondroosseous junction. At embryonic day 15.5, it is expressed strongly in the presumptive bone collar of the diaphyses, where vascular and osteoblast invasion is initiated. Its expression is low in hypertrophic chondrocytes, and RT-PCR analysis confirmed expression in both osteoclasts and osteoblasts. Most of the Crtap protein is located within cells, although some signal was detected in the extracellular matrix. Morello et al. (2006) also determined that CRTAP forms a complex with prolyl 3-hydroxylase-1 (610339) and cyclophilin-B (123841).
By FISH, Tonachini et al. (1999) mapped the human CRTAP gene to chromosome 3p22. By the same method, Morello et al. (1999) mapped the mouse homolog to a region showing homology of synteny on chromosome 9F3-F4.
In fibril-forming types I (see 120150) and II (see 120140) collagen, prolyl 3-hydroxylation (P3H1/LEPRE1; 610339) occurs uniquely at proline-986 in the triple-helical domain of the alpha-1 chain. Because Crtap-null mice exhibit an osteochondrodysplasia with severe osteopenia and lack prolyl 3-hydroxylation of fibrillar type I and II collagens, Morello et al. (2006) investigated the CRTAP gene in cases of human autosomal recessive osteogenesis imperfecta (OI). They found mutations in patients with osteogenesis imperfecta type VII (610682).
Barnes et al. (2006) screened skin samples from 10 children with lethal or severe osteogenesis imperfecta who had type I collagen with a normal primary structure and identified CRTAP mutations in 3 of the infants who had reduced levels of CRTAP expression. Barnes et al. (2006) noted that some patients with autosomal recessive lethal OI carried CRTAP mutations that were partially functional, whereas others had null CRTAP mutations, excess modification of type I collagen, and a condition that was lethal in the first year of life.
Chang et al. (2010) investigated the interaction of complex components in fibroblasts from osteogenesis imperfecta types VII and VIII (610915) patients. Both CRTAP and P3H1 were absent or reduced on Western blots and by immunofluorescence microscopy in cells containing null mutations in either gene. Levels of P3H1 or CRTAP transcripts, however, were normal in CRTAP- or LEPRE1-null cells, respectively. Stable transfection of a CRTAP or P3H1 expression construct into cells with null mutations for the transfected cDNA restored both CRTAP and P3H1 protein levels. Normalization of collagen helical modification in transfected CRTAP-null cells demonstrated that the restored proteins functioned effectively as a complex. Chang et al. (2010) concluded that CRTAP and P3H1 are mutually stabilized in the collagen prolyl 3-hydroxylation complex, which may provide an underlying mechanism for the overlapping phenotype of types VII and VIII OI.
Valli et al. (2012) reported a 7-year-old Egyptian boy with nonlethal OI type VII caused by a homozygous null mutation in the CRTAP gene (605497.0007). The mutation resulted in reduction of CRTAP transcript levels to approximately 10% of normal levels and undetectable CRTAP protein in fibroblasts. The abnormal posttranslational modification of the patient's type I collagen was typical for OI type VII, with alpha-1(I)pro986 3-hydroxylation reduced to 5% of normal, and full helical overmodification indicated by 40% hydroxylysine levels. By immunofluorescence of long-term cultures, Valli et al. (2012) also identified a severe deficiency (10-15% of control) of collagen deposited in extracellular matrix, with disorganization of the minimal fibrillar network. Quantitative pulse-chase experiments corroborated deficiency of matrix deposition, rather than increased matrix turnover. Valli et al. (2012) concluded that defects of extracellular matrix, as well as intracellular defects in collagen modification, contribute to the pathology of OI type VII.
In a 12-year-old girl with an osteogenesis imperfecta-like phenotype, who was born to first-cousin parents of Asian Pakistani origin, Balasubramanian et al. (2015) identified homozygosity for a truncating mutation (E40X; 605497.0009) in the CRTAP gene. The parents were heterozygous for the mutation. The authors classified the disorder as a form of Cole-Carpenter syndrome (see 112240).
Morello et al. (2006) found that loss of Crtap in mice causes an osteochondrodysplasia characterized by severe osteoporosis and decreased osteoid production. CRTAP can form a complex with P3H1 (610339) and cyclophilin B (CYPB; 123841), and Crtap -/- bone and cartilage collagens showed decreased prolyl 3-hydroxylation. Moreover, mutant collagen showed evidence of overmodification, and collagen fibrils in mutant skin had increased diameter consistent with altered fibrillogenesis.
In genomic DNA from an affected member of a large consanguineous Quebec family with osteogenesis imperfecta type VII (OI7; 610682) described by Ward et al. (2002), Morello et al. (2006) identified homozygosity for a single-nucleotide change (-1021C-G) in intron 1 of the CRTAP gene consistent with activation of a cryptic splice donor site and the inclusion of a 73-bp cryptic exon (position -1094 to -1021 5-prime of exon 2) into the CRTAP cDNA. This longer transcript contained a frameshift and was predicted to become degraded by the nonsense-mediated decay mechanism.
In a consanguineous family in which 4 pregnancies were affected with severe osteogenesis imperfecta type VII (OI7; 610682), Morello et al. (2006) found a homozygous single-basepair deletion in exon 4 (879delT) of the CRTAP gene in affected individuals. This deletion caused a frameshift with a premature termination codon 15 amino acids downstream and was expected to cause a null allele due to nonsense-mediated decay. The parents were asymptomatic but were carriers for the deletion. Biochemical and MS/MS analysis of collagen from cultured fibroblasts from the proband confirmed collagen overmodification and showed that the target proline was underhydroxylated. CRTAP protein could not be identified in fibroblasts from 1 affected individual. Real-time PCR performed on RNA extracted from cultured fibroblasts showed that they contained 10% of the amount seen in the OI type VII cells and about 1% of that seen in control cells.
In a Pakistani infant with lethal osteogenesis imperfecta type VII (OI7; 610682), Barnes et al. (2006) described a homozygous mutation in the splice donor site of exon 1 of the CRTAP gene: IVS1+1G-C. Both parents, who were second cousins, were heterozygous for the mutation. The boy was born at 35 weeks' gestation after an induced vaginal delivery. Prenatal ultrasonography showed severe micromelia of the arms and legs. The eyes showed proptosis and white sclerae. Radiographic survey revealed over 20 fractures of long bones and ribs. The child died at 10 months of age.
In an infant daughter of nonconsanguineous black parents with osteogenesis imperfecta type VII (OI7; 610682), Barnes et al. (2006) found a point mutation in the CRTAP gene that caused a gln276-to-stop (Q276X) substitution in exon 4. The eyes showed proptosis and the sclerae were white. The limbs were deformed, and radiographic survey showed fractures of multiple bones. Cardiac catheterization on day 18 revealed absent right pulmonary artery with a collateral vessel from the proximal descending aorta supplying the trilobed right lung, hypoplastic pulmonary veins, and systemic pulmonary hypertension. The girl died at day 80 from respiratory insufficiency.
In affected members of a Saudi family with OI7, Shaheen et al. (2012) identified a homozygous 826C-T transition in the CRTAP gene, resulting in a Q276X mutation. The proband displayed severe prenatal onset of fractures and died during the neonatal period.
In a daughter of consanguineous parents of German descent, Barnes et al. (2006) found that recessive lethal osteogenesis imperfecta type VII (OI7; 610682) was caused by compound heterozygous mutations in the CRTAP gene. From her father, she inherited a point mutation in the CRTAP start codon (AUG to AUA), causing a met1-to-ile substitution (M1I) that was expected to eliminate the initiation of CRTAP translation. From her mother, she inherited a 16-nucleotide duplication in exon 1 (605947.0006), which shifted the reading frame and resulted in a premature termination codon in exon 2.
For discussion of the 16-bp duplication in the CRTAP gene that was found in compound heterozygous state in a patient with lethal osteogenesis imperfecta type VII (OI7; 610682) by Barnes et al. (2006), see 605497.0005.
In a 7-year-old Egyptian boy with nonlethal osteogenesis imperfecta type VII (OI7; 610682), Valli et al. (2012) identified a homozygous null mutation in exon 1 of the CRTAP gene (118_133del16insTACCC). The mutation shifts the CRTAP reading frame, leading to a premature termination codon, 117 codons downstream of the mutation in exon 2. The parents were heterozygous for the mutation.
In affected members of a Saudi family with osteogenesis imperfecta type VII (OI7; 610682), Shaheen et al. (2012) identified homozygosity for a 561T-G transversion in the CRTAP gene, resulting in a tyr187-to-ter (Y187X) substitution. The proband had severe neonatal onset of fractures, blue sclera, and dentinogenesis imperfecta, with no hearing or other organ involvement.
In a 12-year-old girl with an osteogenesis imperfecta-like phenotype (OI7; 610682), who was born to first-cousin parents of Asian Pakistani origin, Balasubramanian et al. (2015) identified homozygosity for a c.118G-T transversion (c.118G-T, NM_006371.4) in exon 1 of the CRTAP gene, resulting in a glu40-to-ter (E40X) substitution. The parents were heterozygous for the mutation. The authors classified the disorder as a form of Cole-Carpenter syndrome (see 112240).
Balasubramanian, M., Pollitt, R. C., Chandler, K. E., Mughal, M. Z., Parker, M. J., Dalton, A., Arundel, P., Offiah, A. C., Bishop, N. J. CRTAP mutation in a patient with Cole-Carpenter syndrome. Am. J. Med. Genet. 167A: 587-591, 2015. [PubMed: 25604815] [Full Text: https://doi.org/10.1002/ajmg.a.36916]
Barnes, A. M., Chang, W., Morello, R., Cabral, W. A., Weis, M., Eyre, D. R., Leikin, S., Makareeva, E., Kuznetsova, N., Uveges, T. E., Ashok, A., Flor, A. W., Mulvihill, J. J., Wilson, P. L., Sundaram, U. T., Lee, B., Marini, J. C. Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta. New Eng. J. Med. 355: 2757-2764, 2006. [PubMed: 17192541] [Full Text: https://doi.org/10.1056/NEJMoa063804]
Castagnola, P., Gennari, M., Morello, R., Tonachini, L., Marin, O., Gaggero, A., Cancedda, R. Cartilage associated protein (CASP) is a novel developmentally regulated chick embryo protein. J. Cell Sci. 110: 1351-1359, 1997. [PubMed: 9217321] [Full Text: https://doi.org/10.1242/jcs.110.12.1351]
Chang, W., Barnes, A. M., Cabral, W. A., Bodurtha, J. N., Marini, J. C. Prolyl 3-hydrolase 1 and CRTAP are mutually stabilizing in the endoplasmic reticulum collagen prolyl 3-hydroxylation complex. Hum. Molec. Genet. 19: 223-234, 2010. [PubMed: 19846465] [Full Text: https://doi.org/10.1093/hmg/ddp481]
Morello, R., Bertin, T. K., Chen, Y., Hicks, J., Tonachini, L., Monticone, M., Castagnola, P., Rauch, F., Glorieux, F. H., Vranka, J., Bachinger, H. P., Pace, J. M., Schwarze, U., Byers, P. H., Weis, M., Fernandes, R. J., Eyre, D. R., Yao, Z., Boyce, B. F., Lee, B. CRTAP is required for prolyl 3-hydroxylation and mutations cause recessive osteogenesis imperfecta. Cell 127: 291-304, 2006. [PubMed: 17055431] [Full Text: https://doi.org/10.1016/j.cell.2006.08.039]
Morello, R., Tonachini, L., Monticone, M., Viggiano, L., Rocchi, M., Cancedda, R., Castagnola, P. cDNA cloning, characterization and chromosome mapping of Crtap encoding the mouse cartilage associated protein. Matrix Biol. 18: 319-324, 1999. [PubMed: 10429950] [Full Text: https://doi.org/10.1016/s0945-053x(99)00002-5]
Shaheen, R., Alazami, A. M., Alshammari, M. J., Faqeih, E., Alhashmi, N., Mousa, N., Alsinani, A., Ansari, S., Alzahrani, F., Al-Owain, M., Alzayed, Z. S., Alkuraya, F. S. Study of autosomal recessive osteogenesis imperfecta in Arabia reveals a novel locus defined by TMEM38B mutation. J. Med. Genet. 49: 630-635, 2012. [PubMed: 23054245] [Full Text: https://doi.org/10.1136/jmedgenet-2012-101142]
Tonachini, L., Morello, R., Monticone, M., Skaug, J., Scherer, S. W., Cancedda, R., Castagnola, P. cDNA cloning, characterization and chromosome mapping of the gene encoding human cartilage associated protein (CRTAP). Cytogenet. Cell Genet. 87: 191-194, 1999. [PubMed: 10702664] [Full Text: https://doi.org/10.1159/000015463]
Valli, M., Barnes, A. M., Gallanti, A., Cabral, W. A., Viglio, S., Weis, M. A., Makareeva, E., Eyre, D., Leikin, S., Antoniazzi, F., Marini, J. C., Mottes, M. Deficiency of CRTAP in non-lethal recessive osteogenesis imperfecta reduces collagen deposition into matrix. Clin. Genet. 82: 453-459, 2012. [PubMed: 21955071] [Full Text: https://doi.org/10.1111/j.1399-0004.2011.01794.x]
Ward, L. M., Rauch, F., Travers, R., Chabot, G., Azouz, E. M., Lalic, L., Roughley, P. J., Glorieux, F. H. Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease. Bone 31: 12-18, 2002. [PubMed: 12110406] [Full Text: https://doi.org/10.1016/s8756-3282(02)00790-1]