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New Structural and Single Nucleotide Mutations in Type I and Type II Collagens in Taiwanese Children With Type I and Type II Collagenopathies.

ABSTRACT: Collagenopathy is a rare genetic condition characterized by abnormality in either collagen structure or metabolism. Variations in its clinical presentations highlight diversity in the genetic causes and potential existence of concurrent mutations. Through whole exome sequencing (WES) complemented with multiplex ligation-dependent probe amplification, we identified the genetic etiologies for six cases with osteogenesis imperfecta (OI) in COL1A1 (p.T1298N, p.Q1280Pfs^∗51, and p.G557Vfs^∗23) and COL1A2 (c.1-1677_133-441del) as well as three cases with spondyloepiphyseal dysplasia congenita in COL2A1 (p.G1041S, p.G654S, and p.G441A). Co-occurrence of COL1A1 and WNT1 mutations was found in a patient with a mild OI phenotype but severe osteoporosis. These findings extended the pathogenic variant spectrum of COL1A1, COL1A2, and COL2A1 for type I and type II collagenopathies. Although WES provides a fast and accurate method to identify the genetic causes in most of the patients with type I and type II collagenopathies, its limitation of detecting CNVs because of variable capturing uniformity should be kept in mind when interpreting the results. Taken together, we demonstrate that multiple genetic characterizing technologies can provide an accurate and efficient molecular diagnostic of new genetic variants in disease-causing genes that are compatible with clinical phenotypes.

SUBMITTER: Tsai MC

PROVIDER: S-EPMC8355745 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe vitreoretinal interface is the border of the cortical vitreous and the inner surface of the retina. The adhesion of the cortical vitreous to the ILM, namely vitreoretinal adhesion, involves a series of complex molecular adhesion mechanisms and has been considered as an important pathogenic factor in many vitreoretinal diseases. The presence of type VI collagen at the vitreoretinal interface and its possible interaction with collagens and glycoproteins indicates that type VI collagen may contribute to the vitreoretinal adhesion.PurposeTo clarify the ultrastructural location of type VI collagen and its relationship to type II and IV collagens at the vitreoretinal interface.MethodsThe ultrastructural localization of type II, IV and VI collagens in the adult human vitreoretinal interface of five donor eyes was evaluated by transmission electron microscopy using immunogold labeling.ResultsIn the pre-equatorial region, we observed densely packed vitreous lamellae with a partly intraretinal course containing type II and VI collagens, reticular structures containing type IV and VI collagens and a thin inner limiting membrane (ILM) containing type IV and VI collagens in a linear distribution pattern. From the anterior to the posterior retina, the linear pattern of type IV and VI collagen labeling gradually became more diffusely present throughout the entire thickness of the ILM.ConclusionsThe presence of type VI collagen in vitreous lamellae penetrating the ILM into the superficial retina suggests that type VI collagen may be involved in the organization of vitreous fibers into lamellae and in the adhesion of the vitreous fibers to the retina. The close relation of type VI to type IV collagen in the ILM suggests that type VI collagen is an important collagen type in the ILM. The topographic variations of type IV and VI collagens in the different regions of the ILM suggest a regional heterogeneity of the ILM. The reticular labeling pattern of type IV and VI collagens observed in the anterior vitreous are highly similar to labeling patterns of blood vessel walls. In the anterior vitreous, they may represent remnants of the regressed embryonic hyaloid blood vessel system. Their presence is in support of the theory on interactive remodeling of the developing vitreous as opposed to the main stream theory of displacement and compression of the primary by the secondary vitreous.

Project description:BackgroundGallstones are abnormal masses caused by impaired metabolism of cholesterol, bilirubin, or bile salts in the gallbladder or biliary tract. ATP-binding cassette subfamily G member 8 (ABCG8) is a protein that regulates cholesterol efflux from the liver. Genome-wide association studies (GWAS) and meta-analyses of GWAS revealed the ABCG8 rs11887534 variant as the most common genetic determinant of gallstones in humans. These findings have not been extensively replicated in Taiwanese. Therefore, we appraised the relationship between gallstones and rs11887534 in a relatively large Taiwanese sample.MethodsWe retrieved data collected through questionnaires, physical and biochemical tests from the Taiwan Biobank Bank (TWB). The study participants comprised 7388 men and 13,880 women who voluntarily enrolled in the Taiwan Biobank project between 2008 and 2019. Gallstones were self-reported.ResultsThe overall sample size was 21,268 comprising 938 gallstone patients and 20,330 non-gallstone individuals. Among the participants, 20,640 had the GG and 628 had the GC + CC genotype. At p-value < 0.05, the baseline genotypes and gallstone status between men and women were not significantly different. The risk of gallstones was higher in participants having the GC + CC compared to the GG genotype: odds ratio (OR); 95% confidence interval (CI) = 1.698; 1.240-2.325), but was lower in men compared to women (OR = 0.763; 95% CI = 0.638-0.913). Compared to men with the rs11887534 GG genotype, women with the GG and GC + CC genotypes had a higher risk of gallstone (OR; 95% CI = 1.304; 1.087-1.565 for GG and 2.291; 1.514-3.467 for GC + CC). The positive association between GC + CC and gallstones was retained after we restricted the analysis to the female participants (OR; 95% CI = 1.789 = 1.208-2.648). Hormone use was associated with an elevated risk of gallstones (OR; 95% CI = 1.359; 1.107-1.668). Relative to GG and no hormone use, we found a significantly high risk among hormone users with the GC + CC genotype (OR; 95% CI = 3.596; 1.495-8.650).ConclusionsThe rs11887534 GC + CC genotype was independently associated with a higher risk of gallstones. This risk was much higher among women, especially those who used hormones for various gynecological purposes.

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New Structural and Single Nucleotide Mutations in Type I and Type II Collagens in Taiwanese Children With Type I and Type II Collagenopathies.

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