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Advances in Non-Invasive Diagnosis of Single-Gene Disorders and Fetal Exome Sequencing
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Liesbeth Vossaert, Roni Zemet, Ignatia B. Van den Veyver
One of the clinically validated NIPD tests for autosomal dominant disorders is for variants in genes that cause, primarily de novo, dominant skeletal dysplasias, such as specific pathogenic variants in FGFR3, which cause achondroplasia and thanatophoric dysplasia, and skeletal dysplasias with very different severity and prognosis. Other examples include variants in COL1A1 and COL1A2, which cause osteogenesis imperfecta that can present as a severe lethal form or milder form. Thus, early exact molecular diagnosis is important for pregnancy management decisions and counseling, and cfDNA-based NIPD for FGFR3 variants has now been reported with sensitivities and specificities up to 100% for common hotspot variants,17,50 and for COL1A1 and COL1A2 variants.15,51
The locomotor system
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Osteogenesis imperfecta results from mutations in the structural genes for type I collagen. Type I collagen is composed of two proteins – pro-1 and pro-2 – encoded by two genes COL1A1 and COL1A2, which are located on chromosomes 17 and 7, respectively. Two pro-1 chains and one pro-2 chain twist together to form a triple helix. Numerous mutations including gene deletions, insertions, and duplications have been described, but most cases are caused by single-point mutations. In the mild form of osteogenesis imperfecta (type 1) the collagen is of normal type, but is present in reduced amounts. This is often due to mutations that knock out one copy of the COL1A1 gene, leading to diminished production of the collagen α1 chain. Thus, although the amount of bone is reduced, it is structurally normal. In contrast, in the more severe forms, mutations within the collagen genes result in abnormal collagen protein chains, which combine to form an abnormal triple helix. The resulting collagen is structurally weaker, and also turns over more rapidly. In the more severe forms, the most common defects are single-base mutations that result in the substitution of a glycine amino acid by a larger amino acid such as asparagine. Glycine is essential in the formation of the collagen triple helix. The closer the mutation is to the carboxy-terminal end of the chain, from which the helix winds up, and the larger the substituting amino acid, the more badly affected is the collagen formed.
Genetics
Published in Manoj Ramachandran, Tom Nunn, Basic Orthopaedic Sciences, 2018
Peter Calder, Harish Hosalkar, Aresh Hashemi-Nejad
In more severe types of OI, there are mutations of either the COL1A1 or the COL1A2 gene, resulting in a mixture of normal and abnormal collagen chains. The α1 chains are long molecules consisting of 338 repeating triplet amino acid sequences, usually glycine, proline and hydroxyproline. The most common mutation is the substitution of the small glycine molecule with a larger amino acid. This results in 50% of abnormal α1 and α2 chains being formed. These abnormal chains bind to form an abnormal collagen molecule that interferes with the extracellular matrix formation by impairing the function of the normal α1 chains.
Curcumin Suppresses TGF-β2-Induced Proliferation, Migration, and Invasion in Lens Epithelial Cells by Targeting KCNQ1OT1/miR-377-3p/COL1A2 Axis in Posterior Capsule Opacification
Published in Current Eye Research, 2022
Accumulating studies indicated that miRNAs can regulate gene expression by targeting the 3’ untranslated region (3’UTR) of protein-coding messenger RNAs (mRNAs), thereby leading to the degradation or translational repression of mRNAs.23 Collagen type I (COL1), a member of the collagen family, is an important component of the extracellular matrix and consists of COL1 alpha 1 (COL1A1) and COL1 alpha 2 (COL1A2).24 Previous studies have shown that TGF-β2 can up-regulate COL1A2 expression in lens epithelial cells.25,26 Through searching starBase database, we found that the 3’UTR of COL1A2 possessed the potential binding sequence with miR-377-3p. In this study, we tested the interaction between COL1A2 and miR-377-3p and further explored their functional correlation in PCO progression.
A novel variant in TGFBI causes keratoconus in a two-generation Chinese family
Published in Ophthalmic Genetics, 2022
Qinghong Lin, Lin Zheng, Zhengwei Shen
The genomic DNA of all subjects was extracted from peripheral blood leukocytes using QIAamp DNA Blood Mini Kits (Qiagen Science, Germantown, Md., USA). The genomic DNA of KC patients from the two-generation family underwent ES. The ES of the genomic DNA of the proband (II:2) and two other members in the family (I:1 and II:3) was performed using the HiSeq2000 (Illumina, USA) with 101 base pairs paired-end reads. The enrichment of exonic sequences was achieved using the SureSelectXT Human All Exon V.2 Kit (50 Mb; Agilent Technologies, Inc., Santa Clara, CA, USA). ES data processing, base calling, and primary data analysis were performed using the Illumina Real-Time Analysis version 1.12.4 and Illumina’s CASAVA pipeline 1.8.2 with default parameters. The paired-end reads were aligned to the reference human genome (hg19/GRCh37) using the Burrows–Wheeler Aligner (BWA v0.7.17) KC-associated and/or CCT-associated variants with a minor allele frequency of ≤1% in the 1000 Genomes, ExAC, and HapMap populations were extracted from the exome sequencing data. Clinically relevant variants that were previously reported (such as COL1A2), and those present in affected subjects at frequencies of ≤1% were examined in the 1000 Genomes Project. Potentially pathogenic variants that were only shared by patient II:2, I:1 and II:3 were considered as preliminary candidate variants (Table 1).
Pathophysiology of respiratory failure in patients with osteogenesis imperfecta: a systematic review
Published in Annals of Medicine, 2021
S. Storoni, S. Treurniet, D. Micha, M. Celli, M. Bugiani, J. G. van den Aardweg, E. M. W. Eekhoff
Osteogenesis Imperfecta (OI) is a rare inheritable condition commonly caused by mutations in genes (COL1A1 and COL1A2) encoding collagen type I which is essential for healthy bone formation. Clinically, OI is primarily characterized by bone fragility, small stature, skeletal deformity, ligament laxity, blue sclerae, dentinogenesis imperfecta, hearing impairment, and cardiopulmonary disease. According to the Sillence classification OI type I is the least severe form and is mostly characterized by an insufficient level of synthesized collagen leading to a limited number of fractures. OI type II, III, and IV are mainly characterized by structural alterations in type I collagen; OI type II is perinatally lethal, OI type III is characterized by progressive deformations, multiple fractures, very short stature, and wheelchair dependency and type IV is relatively mild with a variable number of fractures [1–6].