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Neurogenetics
Published in John W. Scadding, Nicholas A. Losseff, Clinical Neurology, 2011
Sonia Gandhi, Sarah Tabrizi, Nicholas Wood
Bethlem myopathy is an autosomal dominant disorder with onset at any age. It is characterized by a proximal myopathy and joint contractures, which clinically overlaps with the EMDM phenotype. It is caused by mutations in one of three different genes for collagen type 6: COL6A1, COL6A2 or COL6A3.
Whole-exome screening for primary congenital glaucoma in Lebanon
Published in Ophthalmic Genetics, 2023
Nadine J. Makhoul, Zahi Wehbi, Dalia El Hadi, Baha Noureddine, Rose-Mary Boustany, Christiane Al-Haddad
Five candidate genes were mutated in five families (Table 3 and Figure 4). All variants were missense mutations, with only one being homozygous. The latter was in the COL6A3 gene. The variant COL6A3 p.R544W (NM_004369.3:c.1630C>T) was detected in proband of Family 6, a consanguineous family. The unaffected parents and sister who also carried the heterozygous mutation, suggesting an autosomal recessive mode of inheritance. The variant was only found in 1/152248 alleles in gnomAD, with no homozygotes observed. The mutation occurred in a highly conserved residue (Figure 2), and 10 mutation prediction tools suggested pathogenicity. This study uncovered another mutation in the collagen-encoding gene, COL1A1. The heterozygous variant COL1A1 p.R528H (NM_000088.3:c.1583 G>A) was detected in the proband of Family 2 who also carried the heterozygous CYP1B1 p.R368G mutation. The unaffected mother and siblings also harbored the COL1A1 p.R528H variant. Detection of heterozygous variants in WDR36, FOXC2 and MAF genes transpired in Family 7, 8 and 9, respectively. Finding of variants in these genes in at least one unaffected member of the three families suggested they were less likely to be pathogenic.
Identification of Missense Extracellular Matrix Gene Variants in a Large Glaucoma Pedigree and Investigation of the N700S Thrombospondin-1 Variant in Normal and Glaucomatous Trabecular Meshwork Cells
Published in Current Eye Research, 2022
Mary K. Wirtz, Renee Sykes, John Samples, Beth Edmunds, Dongseok Choi, Douglas R. Keene, Sara F. Tufa, Ying Ying Sun, Kate E. Keller
Our study also implicated a rare COL6A3 variant, rs112913396, as a POAG-associated gene in this family. This missense SNP is different to the one identified in a recent IOP GWAS study, rs7599762, which is located in an intron.32 The D563G change is in the 3rd vWFA domain of the α3(VI) chain. Collagen type VI interacts with several other ECM proteins associated with basement membranes.72 Furthermore, collagen type VI accumulates in plaque material underlying the inner wall of Schlemm’s canal in glaucomatous TM.16 Here, our immunofluorescence and electron microscopy data show there is a major reduction in COL6A3 deposition by GTM cells compared to NTM cells. Because the alpha 3 chain is required for assembly of the full heterotrimeric collagen type VI molecule,73 this suggests that GTM cells may have an overall reduction of collagen type VI. Ultrastructurally, there was a reduction in COL6A3-containing microfibrils in GTM cells, the periodic COL6A3 immunolabeling was disrupted and the microfibrils appeared disorganized compared to NTM cells. Because other ECM proteins such as decorin and biglycan bind to collagen type VI,74 the observed ultrastructural changes likely have profound effects on the overall organization of ECM components in the TM.
The potential of circulating cell free RNA as a biomarker in cancer
Published in Expert Review of Molecular Diagnostics, 2019
Ka Wan Emily Cheung, Sin-yu Rachel Choi, Lok Ting Claire Lee, Nga Lam Ella Lee, Hin Fung Tsang, Yin Tung Cheng, William Chi Shing Cho, Elaine Yue Ling Wong, Sze Chuen Cesar Wong
Furthermore, using enzyme-linked immunosorbent assay (ELISA) and real-time PCR, the diagnostic value and clinical significance of the collagen type VI alpha 3 chain (COL6A3), which was found to be highly expressed in pancreatic ductal adenocarcinomas (PDA) was investigated by Kang et al. 2014 [124]. Using the human COL6A3 ELISA commercial kit, the average COL6A3 expression level from the sera of 44 PDA patients and 46 patients with benign lesions [124] was obtained. Results showed that the presence of COL6A3 mRNA was significantly elevated in the sera from PDA patients compared to patients with benign lesions (p = 0.0035) [124]. Moreover, the average COL6A3 expression level between PDA patients and healthy individuals yielded an even greater significant difference (p = 0.0001); therefore, these results showed that COL6A3 mRNA may be a potential diagnostic biomarker in pancreatic cancer [124].