COL1A1 GENE POLYMORPHISM IN MATERNITY PATIENTS WITH SOFT TISSUE INJURIES

The aim of the paper is to determine the impact of COL1A1 gene polymorphism on soft tissue injuries in maternity patients. Materials and Methods. The study involved 62 maternity patients who were divided into 2 groups. The first group included 45 patients (72.5 %) without type 1 collagen mutation, alpha 1 Sp1-polymorphism (G2046T) G/G. The second group consisted of 16 patients (27.5 %) with mutation in COL1A1 gene, Sp1-polymorphism (G2046T) G/T. During the study, a homozygous mutation, Sp1-polymorphism (G2046T) T/T was observed in one patient. Age, parity and mean fetal weight of women were comparable. Results. In patients with the COL1A1 mutation, Sp1-polymorphism (G2046T), the incidence of soft tissue birth injuries was 2.3 times higher than in those without such a mutation. Thus, it was confirmed that COL1A1 gene mutation contributes to the soft tissue trauma of the birth canal. It can be regarded as a prognostic criterion and as a basis for preventive measures during pregnancy. Conclusion. Birth trauma risks remain a controversial issue. One of the factors may be COL1A1 gene mutation. Key words: birth trauma, pelvic floor muscle insufficiency, collagen 1 gene polymorphism (COL1A1). Цель работы – определить роль полиморфизма гена COL1A1 у женщин с родовыми травмами мягких тканей родовых путей. Материалы и методы. В исследовании приняло участие 62 родильницы, которые были разделены на 2 группы. В первую группу включены 45 (72,5 %) родильниц, у которых мутация коллагена типа 1, альфа 1 Sp1-polymorphism (G2046T) G/G не обнаружена. Во второй группе, состоящей из 16 (27,5 %) родильниц, обнаружена мутация гена COL1A1 Sp1-polymorphism (G2046T) G/T. В процессе проведения исследования у одной пациентки обнаружена гомозиготная мутация Sp1-polymorphism (G2046T) T/T. Пациентки были сопоставимы по возрасту, паритету и средней массе плода. Результаты. У пациенток с мутацией COL1A1 Sp1-polymorphism (G2046T) частота родовых травм мягких тканей оказалась в 2,3 раза выше, чем у пациенток без мутации. Таким образом, подтверждено, что мутация данного гена имеет определенное значение в реализации риска травм мягких тканей родовых путей, что может послужить прогностическим критерием и основанием для проведения профилактических мероприятий в период беременности. Выводы. Вопрос о рисках родового травматизма остается спорным. Одним их факторов может явиться мутация гена COL1A1. Ключевые слова: родовой травматизм, недостаточность мышц тазового дна, полиморфизм гена коллагена 1 (COL1A1).

COL1A1 Gene Expression in Hepatitis B Virus (HBV) Related Hepatocellular Carcinoma (HCC) Egyptian's Patients

Introduction: Collagens are the most abundant proteins in the human body, accounting for one-third of total proteins. Over the last few years, accumulated evidence have indicated that some collagens are differentially expressed in cancer. The aim of the study was to assess COL1A1 gene expression as a novel marker for the progression of hepatitis B cirrhosis into hepatocellular carcinoma. Methods: This cohort study included 348 subjects and was conducted between May 2018 and June 2019. Subjects were divided into 4 groups: group1 included HBV positive hepatocellular carcinoma patients “HCC” (n= 87), group II included HBV positive patients with liver cirrhosis “LC” (n = 87), group III included chronic hepatitis B patients with neither HCC nor cirrhosis “ C-HBV” (n = 87) and group IV consisted of healthy volunteers as controls (n = 87). Fasting venous blood samples (10 ml) were collected from each participant in this study and were used for assessment of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, albumin and alfa-fetoprotein (AFP). Another portion of blood was collected in 2 vacutainer tubes containing EDTA, one for Complete blood count and the other for gene expression of COL1A1. Results: The gene expression of collagen was 6.9 ± 8.8 in group 1 (HBV positive hepatocellular carcinoma patients) and this was a significant increase in comparison with the other groups. In group 2 (HBV positive patients with liver cirrhosis), the gene expression (collagen) was 3.7±1.5 and it was significantly increased when compared with group 4 (healthy volunteers). Conclusion: COL1A1 gene expression can be used as an indicator of the progression of hepatitis B cirrhosis into hepatocellular carcinoma.

Osteogenesis imperfecta: a literature review and a clinical case of a perinatal-lethal type of disease

The article presents the modern views of clinicians and geneticists on one of the most severe genetic disorders of skeletal and connective tissues - osteogenesis imperfecta. The review provided the literature data that showed the incidence rates, genetic heterogeneity of osteogenesis imperfecta, as well as the role of some proteins involved in the construction of bone tissue, as well as a clinical classification of the main types of the disorder. The authors described a clinical case: a girl with typical clinical and radiological manifestations of the rarest of all types of osteogenesis imperfecta - type II (perinatal-lethal, congenital osteogenesis imperfecta, Vrolik’s syndrome). The child’s diagnosis was verified by a parallel DNA sequence analysis which showed a heterozygous mutation in exon 29 (c.1966G> A) of COL1A1 gene not previously described in the literature. It caused the substitution of glycine for serine at position 656. The role of antenatal diagnostics and the importance of medical genetic counselling of the family before planning the next pregnancy due to the existing risk of re-birth of a sick child is outlined. Due to the fact that majority of the patients with the most prognostically unfavourable type II osteogenesis imperfecta, as a rule, die in utero, the described case of observation of the girl with typical clinical and X-ray signs of the disorder for almost 3 months of postpartum period is extremely rare and highly indicative. The detection of the heterozygous mutation in exon 29 (c.1966G > A) of COL1A1 gene by a parallel DNA sequence analysis which was not previously described in the literature gives an additional significance to the described observation.

Chondrogenic Potential of Human Dental Pulp Stem Cells Cultured as Microtissues

Several tissue engineering stem cell-based procedures improve hyaline cartilage repair. In this work, the chondrogenic potential of dental pulp stem cell (DPSC) organoids or microtissues was studied. After several weeks of culture in proliferation or chondrogenic differentiation media, synthesis of aggrecan and type II and I collagen was immunodetected, and SOX9, ACAN, COL2A1, and COL1A1 gene expression was analysed by real-time RT-PCR. Whereas microtissues cultured in proliferation medium showed the synthesis of aggrecan and type II and I collagen at the 6th week of culture, samples cultured in chondrogenic differentiation medium showed an earlier and important increase in the synthesis of these macromolecules after 4 weeks. Gene expression analysis showed a significant increase of COL2A1 after 3 days of culture in chondrogenic differentiation medium, while COL1A1 was highly expressed after 14 days. Cell-cell proximity promotes the chondrogenic differentiation of DPSCs and important synthesis of hyaline chondral macromolecules.

Restoration of Osteogenesis by CRISPR/Cas9 Genome Editing of the Mutated COL1A1 Gene in Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a genetic disease characterized by bone fragility and repeated fractures. The bone fragility associated with OI is caused by a defect in collagen formation due to mutation of COL1A1 or COL1A2. Current strategies for treating OI are not curative. In this study, we generated induced pluripotent stem cells (iPSCs) from OI patient-derived blood cells harboring a mutation in the COL1A1 gene. Osteoblast (OB) differentiated from OI-iPSCs showed abnormally decreased levels of type I collagen and osteogenic differentiation ability. Gene correction of the COL1A1 gene using CRISPR/Cas9 recovered the decreased type I collagen expression in OBs differentiated from OI-iPSCs. The osteogenic potential of OI-iPSCs was also recovered by the gene correction. This study suggests a new possibility of treatment and in vitro disease modeling using patient-derived iPSCs and gene editing with CRISPR/Cas9.

Candidate genes and single-nucleotide gene variants associated with muscle and tendon injuries in cyclic sports athletes

Sports injuries prevention is one of the key issues of the training process and reducing the risk of developing anxiety and depressive disorders in professional athletes. One of peculiarities of sports injuries is the loss of the ability to train in view of the tendon-ligamentous apparatus integrity, joints, muscles or bones violation. In cyclic sports, the most common are injuries to the ankle joint, injuries to muscles and tendons, and sprains. Injuries to ligaments and tendons are the result of multifactorial problems, including the discrepancy between training effects and the genetically determined capabilities of the athlete's body. Sports injuries consequences are determined by complex interactions between the athlete's genotype and environmental factors, in particular training influences. (1) Background: to review scientific articles on the problem of research on candidate genes and single-nucleotide variants (SNVs) of genes associated with muscle, tendon, and ligament injuries in cyclic sports athletes. (2) Methods: a search of articles for the period from 2008 to 2020 was conducted in the databases e-LIBRARY, SCOPUS, Web of Science, Google Scholar, Clinical keys, PubMed using the keywords: personalized medicine, genetics, candidate genes, single-nucleotide variant, polymorphism, muscle, tendon, injury, athlete. (3) Results: Studies have shown that muscle and tendon injuries in cyclical sports athletes are associated with SNV rs1800012, rs1107946 of the COL1A1 gene, SNV rs12722 of the COL5A1 gene, SNV rs679620 of the MMR3 gene, SNV rs2289360 of the ELN gene, SNV rs143383 of the GDF5 gene. The most studied polymorphisms are rs1800012, rs1107946 of the COL1A1 gene, rs12722 of the COL5A1 gene, and rs143383 of the GDF5 gene. The variable results of associative genetic studies and genome-wide studies are most likely due to the racial and ethnic heterogeneity of the samples and differences in the study design. (4) Conclusions: Identification of genetic markers associated with injuries and diseases of the musculoskeletal system, ligamentous apparatus, and the ability of tissue to regenerate can help sports doctors and coaches develop personalized strategies to prevent or reduce muscles, joints, and ligaments diseases in athletes. The translation of these research results into the training and treatment process is important for improving cyclic sports athletes' performance, reducing their professional mala-daptation and anxiety and depressive disorders development risk.

Further Evidence of a Recessive Variant in COL1A1 as an Underlying Cause of Ehlers–Danlos Syndrome: A Report of a Saudi Founder Mutation

Ehlers–Danlos syndrome (EDS) is a group of clinically and genetically heterogeneous disorder of soft connective tissues. The hallmark clinical features of the EDS are hyperextensible skin, hypermobile joints, and fragile vessels. It exhibits associated symptoms including contractures of muscles, kyphoscoliosis, spondylodysplasia, dermatosparaxis, periodontitis, and arthrochalasia. The aim of this study is to determine the exact subtype of EDS by molecular genetic testing in a family segregating EDS in an autosomal recessive manner. Herein, we describe a family with two individuals afflicted with EDS. Whole exome sequencing identified a homozygous missense mutation (c.2050G > A; p.Glu684Lys) in the COL1A1 gene in both affected individuals, although heterozygous variants in the COL1A1 are known to cause EDS. Recently, only one report showed homozygous variant as an underlying cause of the EDS in two Saudi families. This is the second report of a homozygous variant in the COL1A1 gene in a family of Saudi origin. Heterozygous carriers of COL1A1 variant are asymptomatic. Interestingly, the homozygous variant identified previously and the one identified in this study are same (c.2050G > A). The identification of a unique homozygous mutation (c.2050G > A) in three Saudi families argues in favor of a founder effect.

Homozygous HESX1 and COL1A1 Gene Variants in a Boy with Growth Hormone Deficiency and Early Onset Osteoporosis

We report on a patient born to consanguineous parents, presenting with Growth Hormone Deficiency (GHD) and osteoporosis. SNP-array analysis and exome sequencing disclosed long contiguous stretches of homozygosity and two distinct homozygous variants in HESX1 (Q6H) and COL1A1 (E1361K) genes. The HESX1 variant was described as causative in a few subjects with an incompletely penetrant dominant form of combined pituitary hormone deficiency (CPHD). The COL1A1 variant is rare, and so far it has never been found in a homozygous form. Segregation analysis showed that both variants were inherited from heterozygous unaffected parents. Present results further elucidate the inheritance pattern of HESX1 variants and recommend assessing the clinical impact of variants located in C-terminal propeptide of COL1A1 gene for their potential association with rare recessive and early onset forms of osteoporosis.

The role of collagen protein genes in the development of pelvic floor dysfunction in women

Коллагеновые волокна играют существенную роль в формировании связочного аппарата тазового дна. Однако, проведенные ранее исследования не дают точного ответа о роли полиморфных вариантов генов коллагена в дисфункции тазового дна. Целью настоящего исследования было определить ассоциацию однонуклеотидных полиморфизмов rs1800012 гена COL1A1, rs1800255 и rs1801184 гена COL3A1, rs2236479 гена COL18A1 и их сочетаний c пролапсом тазовых органов (ПТО) и стрессовым недержанием мочи (НМ). Группу исследования составили 150 пациенток с ПТО и/или НМ. В группу контроля вошли 100 пациенток без тазовой дисфункции. Пациентки были сопоставимы по возрасту и внешним факторам риска. Ассоциаций между полиморфизмами rs1800012 гена COL1A1, rs1800255 и rs1801184 гена COL3A1, rs2236479 гена COL18A1 и тазовой дисфункцией выявлено не было. Collagen fibers play a significant role in the formation of the ligamentous apparatus of the pelvic floor. However, previous studies do not give an exact answer about the role of polymorphic variants of collagen genes on pelvic floor dysfunction. The aim of this study was to determine the association of single nucleotide polymorphisms rs1800012 of the COL1A1 gene, rs1800255 and rs1801184 of the COL3A1 gene, rs2236479 of the COL18A1 gene and their combinations with pelvic organ prolapse (POP) and stress urinary incontinence (SUI). The study group consisted of 150 patients with POP and/or SUI. The control group included 100 patients without pelvic dysfunction. Patients were comparable in age and external risk factors.All patients received a buccal epithelium for analysis. Sequencing was carried out by the Sanger method. Association between the rs1800012 polymorphisms of the COL1A1 gene, rs1800255 and rs1801184 of the COL3A1 gene, rs2236479 of the COL18A1 gene and pelvic dysfunction were not detected.