A novel COL1A1 deletion/insertion pathogenic variant in a patient with osteogenesis imperfecta.
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ABSTRACT:
SUBMITTER: Yamada C
PROVIDER: S-EPMC9297176 | biostudies-literature | 2022
REPOSITORIES: biostudies-literature
Publications
A novel <i>COL1A1</i> deletion/insertion pathogenic variant in a patient with osteogenesis imperfecta.
Yamada Chieko C Kubota Takuo T Ishimi Takeshi T Takeyari Shinji S Yamamoto Kenichi K Nakayama Hirofumi H Ohata Yasuhisa Y Fujiwara Makoto M Kitaoka Taichi T Ozono Keiichi K
Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology 20220617 3
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Project description:BackgroundOsteogenesis imperfecta (OI), a rare autosomal inheritable disorder characterized by bone fragility and skeletal deformity, is caused by pathogenic variants in genes impairing the synthesis and processing of extracellular matrix protein collagen type I. With the use of next-generation sequencing and panels approaches, an increasing number of OI patients can be confirmed and new pathogenic variants can be discovered. This study sought to identify pathogenic gene variants in a Chinese family with OI I.MethodsWhole-exome sequencing was used to identify pathogenic variants in the proband, which is confirmed by Sanger sequencing and cosegregation analysis; MES, HSF, and Spliceman were used to analyze this splicing variant；qRT-PCR was performed to identify the mRNA expression level of COL1A1 in patient peripheral blood samples; Minigene splicing assay was performed to mimic the splicing process of COL1A1 variants in vitro; Analysis of evolutionary conservation of amino acid residues and structure prediction of the mutant protein.ResultsA novel splicing pathogenic variant (c.3814+1G>T) was identified in this OI family by using whole-exome sequencing, Sanger sequencing, and cosegregation analysis. Sequencing of RT-PCR products from the COL1A1 minigene variant reveals a 132-nucleotide (nt) insertion exists at the junction between exons 48 and exon 49 of the COL1A1 cDNA. Splicing assay indicates that the mutated minigene produces an alternatively spliced transcript which may cause a frameshift resulting in early termination of protein expression. The molecular analysis suggested that the altered amino acid is located at the C-terminus of type I procollagen.ConclusionOur study reveals the pathogenesis of a novel COL1A1 splicing pathogenic variant c.3814+1G>T in a Chinese family with OI I.
| S-EPMC7507304 | biostudies-literature
Project description:Osteogenesis imperfecta (OI) is characterized by fractures and progressive bone deformities. Fracture rates peak during the toddler and adolescent years and decline during adulthood but do not stop entirely. We describe a kindred, the affected members of which were the mother and two sons, who presented with an apparently unique phenotype of OI. Our patients demonstrated a pattern of prenatal bone deformities followed by multiple, nontraumatic long bone fractures within the first two years of life and then an absence of nontraumatic fractures thereafter. No extra-skeletal manifestations have been noted to date. The mother did not receive bisphosphonate therapy but had no nontraumatic fractures after the age of five months. Intravenous bisphosphonate therapy was started for both sons within two months of birth, with the most recent infusions at age 18 months and 28 months in Patients 2 and 3, respectively. Two patients harbored a variant of uncertain significance in the COL1A1 gene. This heterozygous variant, c.3548C>T; p.(Pro1183Leu), is listed in the OI Variant Database as affecting only one other individual with osteopenia. We describe three family members with a unique presenting phenotype of OI, characterized by cessation of nontraumatic fractures after the first two years of life.
| S-EPMC8186326 | biostudies-literature
Project description: Not available
| S-EPMC10653333 | biostudies-literature
Project description:BackgroundOsteogenesis imperfecta (OI) is a rare heterogeneous genetic disorder commonly autosomal dominant with variants in the COL1A1 and COL1A2 genes. It is characterized by bone fragility and deformity, recurrent fractures, blue sclera, dentinogenesis imperfecta, short stature, and progressive deafness.Case presentationWe present a novel splicing mutation in the COL1A1 gene (c.2398-1G > C) in a 6-year-old Ecuadorian girl with fractures after light pressure and blue sclera. We identified the pathogenic variant, performed a literature review of splice variants, and recognized their location in the COL1A1 functional domains.ConclusionWe describe the first clinical description of a patient with OI type 1 caused by a splice variant in intron 34 of COL1A1 gene and identify that most of them are localized in the triple-helical region domain. We suggest that the splice variant in signal peptide, von Willebrand factor type C, and nonhelical regions maintain their functionality or that individuals affected with severe cases die early in development and are not reported.
| S-EPMC9632975 | biostudies-literature
Project description:Osteogenesis imperfecta (OI) is a hereditary bone disorder caused by defects of type I collagen. Although up to 90% of patients harbor pathogenic variants in the COL1A1/2 gene, which codes for collagen α1/2 chains, the spectrum of OI genotypes may differ between populations, and there is academic controversy around OI genotype-phenotype correlations. In the current study, 94 Ukrainian OI families were interviewed. Clinical and genealogical information was collected from patients in spoken form, and their phenotypes were described. To identify the spectrum of collagen I pathogenic variants, COL1A1/2 mutational analysis with Sanger sequencing was performed on the youngest affected individual of every family. Of the 143 patients investigated, 67 (46.85%) had type I OI, 24 (16.78%) had type III, 49 (34.27%) had type IV, and III (2.10%) had type V. The mean number of fractures suffered per patient per year was 1.32 ± 2.88 (type I 0.50 ± 0.43; type III 3.51 ± 6.18; type IV 1.44 ± 1.77; and type 5 0.77 ± 0.23). 87.23% of patients had skeletal deformations of different severity. Blue sclera, dentinogenesis imperfecta, and hearing loss were present in 87%, 55%, and 22% of patients, respectively. COL1A1/2 pathogenic variants were harbored by 60 patients (63.83%). 27 pathogenic variants are described herein for the first time. The majority of the pathogenic variants were located in the COL1A1 gene (76.19%). Half (49.21%) of the pathogenic variants were represented by structural variants. OI phenotype severity was highly correlated with type of collagen I defect. The current article presents an analysis of the clinical manifestations and COL1A1/2 mutational spectrum of 94 Ukrainian OI families with 27 novel COL1A1/2 pathogenic variants. It is hoped that this data and its analysis will contribute toward the increased understanding of the phenotype development and genetics of the disorder.
| S-EPMC6696896 | biostudies-literature
Project description:Osteogenesis imperfecta (OI) is a rare congenital disorder characterized by bone fragility and fractures, and associated with bone deformity, short stature, dentin, ligament and blue‑gray eye sclera. OI is caused by a heterozygous mutation in collagen α‑1(I) chain (COL1A1) or collagen α‑2(I) chain (COL1A2) genes that encode α chains of type I collagen. Collagen α chain peptide contains an N‑propeptide, which has a role in assembly and processing of collagen. Point mutations in the N‑propeptide domain appear to trigger OI. In the present study, a novel heterozygous missense mutation, c.281T>A (p.Val94Asp), was identified in the von Willebrand C domain of N‑terminal of type I collagen in an individual with type IV OI. The majority of N‑terminal mutations are associated with OI/Ehlers‑Danlos syndrome (EDS); however, in the present study, the affected individual did not suffer from EDS and the level of serum phosphorus of the patient was low (0.67 mmol/l). A number of clinical phenotypes were observed at the same variation site or in the same region on the polypeptide chain of COL1A, which suggests that additional genetic and environmental factors may influence the severity of OI. The present study may provide insight into the phenotype‑genotype association in collagen-associated diseases and improve clinical diagnosis of OI.
| S-EPMC5802218 | biostudies-literature
Project description:Osteogenesis imperfecta (OI) is a family of genetic disorders associated with bone loss and fragility. Mutations associated with OI have been found in genes encoding the type I collagen chains. People with OI type I often produce insufficient α1-chain type I collagen because of frameshift, nonsense, or splice site mutations in COL1A1 or COL1A2. This report is of a Chinese daughter and mother who had both experienced two bone fractures. Because skeletal fragility is predominantly inherited, we focused on identifying mutations in COL1A1 and COL1A2 genes. A novel mutation in COL1A1, c.700delG, was detected by genomic DNA sequencing in the mother and daughter, but not in their relatives. The identification of this mutation led to the conclusion that they were affected by mild OI type I. Open reading frame analysis indicated that this frameshift mutation would truncate α1-chain type I collagen at residue p263 (p.E234KfsX264), while the wild-type protein would contain 1,464 residues. The clinical data were consistent with the patients' diagnosis of mild OI type I caused by haploinsufficiency of α1-chain type I collagen. Combined with previous reports, identification of the novel mutation COL1A1-c.700delG in these patients suggests that additional genetic and environmental factors may influence the severity of OI.
| S-EPMC4415561 | biostudies-literature
Project description:Osteogenesis imperfecta (OI) is a heterogeneous disorder that is characterized by bone fragility and systemic complications, and is mainly caused by gene mutations in COL1A1 or COL1A2. A novel COL1A1 splicing mutation, c.750+2T>A, was identified in a Japanese OI family. Only the proband in this family showed various complications, such as heart valve diseases and severe scoliosis. The clinical heterogeneity in the family is discussed in this study.
| S-EPMC5352948 | biostudies-other
Project description:Approximately 90% of patients with osteogenesis imperfecta (OI) exhibit dominant COL1A1 or COL1A2 mutations; however, molecular analysis is difficult because these genes span 51 and 52 exons, respectively. We devised a PCR-denaturing high-performance liquid chromatography (DHPLC) procedure to analyze the COL1A1 or COL1A2 coding regions and validated it using 130 DNA samples from individuals without OI, 25 DNA samples from two cells to investigate the procedure's potential for preimplantation diagnosis, and DNA samples from 10 patients with OI. Three novel intronic variants in vitro were expressed using a minigene assay to assess their effects on splicing. The procedure is rapid, inexpensive, and reproducible. Analysis of samples from individuals without OI revealed six novel and some known polymorphisms useful for linkage diagnosis because of high heterozygosity. Analysis of two-cell samples confirmed the known genotype in 24 of 25 experiments; DNA failed to amplify in only one case. No incidence of allele dropout was recorded. DHPLC revealed six novel mutations, three of which were intronic, in all patients with OI, and these results were confirmed by means of COL1A1 and COL1A2 direct sequencing. Expression of intronic mutations demonstrated that variant 804 + 2_804 + 3delTG in intron 11 disrupts normal splicing, thereby leading to formation of two alternative products. Variants c.3046-4_3046-5dupCT (COL1A1) and c.891 + 77A>T (COL1A2) did not affect splicing. The described DHPLC protocol combined with the minigene assay may contribute to molecular diagnosis in OI. Moreover, this protocol will aid in counseling about prenatal and preimplantation diagnosis.
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Project description:Osteogenesis imperfecta IIC (OI IIC), which is a rare variant of lethal OI that has been considered to be an autosomal recessive trait, is characterized by twisted, slender long bones with dense metaphyseal margins. Here, we report a typical case of OI IIC caused by a novel heterozygous mutation in the C-propeptide region of COL1A1. OI IIC seems to be caused by a dominant mutation of COL1A1.
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