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COLLAGEN TRIPLE-HELIX REPEAT-CONTAINING PROTEIN 1; CTHRC1

COLLAGEN TRIPLE-HELIX REPEAT-CONTAINING PROTEIN 1; CTHRC1

HGNC Approved Gene Symbol: CTHRC1Cytogenetic location: 8q22.3 Genomic coordinates (GRCh38): 8:103,371,537-103,382,988 (from NCBI)▼ DescriptionCTHRC1 is speci...

HGNC Approved Gene Symbol: CTHRC1

Cytogenetic location: 8q22.3 Genomic coordinates (GRCh38): 8:103,371,537-103,382,988 (from NCBI)

▼ Description
CTHRC1 is specifically expressed in vascular calcifications of carotid artery lesions and may contribute to vascular remodeling of injured arteries (Pyagay et al., 2005).

▼ Cloning and Expression
By suppressive subtractive hybridization to identify genes preferentially expressed in balloon-injured rat arteries, Pyagay et al. (2005) cloned Cthrc1. Using 5-prime RACE, they cloned human CTHRC1 from smooth muscle cell RNA. The deduced 243-amino acid human protein has an N-terminal signal peptide and a short collagen (see COL1A1; 120150) domain containing gly-X-Y repeats. Northern blot analysis revealed Cthrc1 expression in rat lung and brain, with much lower levels in other tissues examined. In situ hybridization and immunohistochemistry localized rat Cthrc1 mRNA and protein to blood vessel adventitia at 8 and 14 days after balloon injury, with lower levels in developing neointima. Significantly less Cthrc1 mRNA expression was detected 4 weeks after injury. Rat Cthrc1 protein was not detected in normal arteries. Immunohistochemistry of human carotid artery lesion endarterectomy samples detected CTHRC1 in vascular calcifications, particularly at the outer margins of the calcification fronts, and in chondrocyte-like cells surrounding the calcified tissue. Human CTHR1 was not detected in noncalcified plaque regions.

▼ Gene Function
By SDS-PAGE, glycosidase treatment, and collagenase analysis, Pyagay et al. (2005) found that in vitro translated rat Cthrc1 was glycosylated and formed a trimer, rendering it susceptible to cleavage by collagenase (see 120353). Endogenous Cthrc1 mRNA levels increased in NIH3T3 mouse fibroblasts following stimulation with BMP4 (112262) or TGFB1 (190180). Scratch wound assays using Cthrc1-overexpressing rat smooth muscle cells and mouse primary embryonic fibroblasts showed that Cthrc1 promoted cell migration.

Yamamoto et al. (2008) found that Cthrc1 -/- mice appeared normal and were fertile, but Cthrc1 -/- Vangl2 (600533) +/- mice displayed defects in planar cell polarity comparable to those in Vangl2 -/- mice, including midbrain neural tube closure defects and misorientation of cochlear sensory hair cells. Since planar cell polarity requires Wnt signaling, Yamamoto et al. (2008) examined interaction of mouse Cthrc1 with several components of the Wnt signaling pathway in transfected HEK293T cells. They found that cell surface-anchored Cthrc1 bound to specific Wnt proteins (e.g., WNT3A; 606359), Fzd proteins (e.g., FZD3; 606143), and Ror2 (602337), and that Cthrc1 enhanced the interaction of Wnt proteins with Fzd-Ror2 by forming the Cthrc1-Wnt-Fzd-Ror2 complex. Consistent with these findings, Ror2 -/- mice also showed planar cell polarity-related abnormalities in the inner ear. Yamamoto et al. (2008) concluded that CTHRC1 is a Wnt cofactor that selectively activates the Wnt/planar cell polarity pathway by stabilizing ligand-receptor interaction.

▼ Mapping
The International Radiation Hybrid Mapping Consortium mapped the CTHRC1 gene to chromosome 8 (RH102528).

▼ Molecular Genetics
Orloff et al. (2011) identified a germline gln44-to-pro (Q44P; 610635.0001) mutation in the CTHRC1 gene in 1 (1.1%) of 116 patients of European descent with Barrett esophagus and/or esophageal adenocarcinoma (614266). The mutation was not found in 125 controls. The same mutation was found in 1 (1.7%) of 58 independent cases in a replication study. This genomic region was studied after being identified by genomewide linkage analysis of 21 concordant and 11 discordant sib pairs with the disorder. Orloff et al. (2011) suggested that variation in the CTHRC1 gene may be important in the host tissue repair response to gastroesophageal reflux disease (GERD; 109350).

▼ ALLELIC VARIANTS ( 1 Selected Example):

.0001 BARRETT ESOPHAGUS/ESOPHAGEAL ADENOCARCINOMA
CTHRC1, GLN44PRO
Orloff et al. (2011) identified a germline 131A-C transversion in exon 1 of the CTHRC1 gene, resulting in a gln44-to-pro (Q44P) substitution, in 1 (1.1%) of 116 patients of European descent with Barrett esophagus and/or esophageal adenocarcinoma (614266). The mutation was not found in 125 controls. The same mutation was found in 1 (1.7%) of 58 independent cases in a replication study. This genomic region was studied after being identified by genomewide linkage analysis of 21 concordant and 11 discordant sib pairs with the disorders. Orloff et al. (2011) suggested that variation in the CTHRC1 gene may be important in the host tissue repair response to gastroesophageal reflux disease (GERD).

Tags: 8q22.3