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Case Report: A Novel COL1A1 Missense Mutation Associated With Dentineogenesis Imperfecta Type I.

ABSTRACT: Background: Osteogenesis imperfecta (OI) is a clinical and genetic disorder that results in bone fragility, blue sclerae and dentineogenesis imperfecta (DGI), which is mainly caused by a mutation in the COL1A1 or COL1A2 genes, which encode type I procollagen. Case Report: A missense mutation (c.1463G > C) in exon 22 of the COL1A1 gene was found using whole-exome sequencing. However, the cases reported herein only exhibited a clinical DGI-I phenotype. There were no cases of bone disease or any other common abnormal symptom caused by a COL1A1 mutation. In addition, the ultrastructural analysis of the tooth affected with non-syndromic DGI-I showed that the abnormal dentine was accompanied by the disruption of odontoblast polarization, a reduced number of odontoblasts, a reduction in hardness and elasticity, and the loss of dentinal tubules, suggesting a severe developmental disorder. We also investigated the odontoblast differentiation ability using dental pulp stem cells (DPSCs) that were isolated from a patient with DGI-I and cultured. Stem cells isolated from patients with DGI-I are important to elucidate their pathogenesis and underlying mechanisms to develop regenerative therapies. Conclusion: This study can provide new insights into the phenotype-genotype association in collagen-associated diseases and improve the clinical diagnosis of OI/DGI-I.

SUBMITTER: Zeng Y

PROVIDER: S-EPMC8260930 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Marfan syndrome (MFS) is a heritable disorder of connective tissue resulting from pathogenic variants of the fibrillin-1 gene (FBN1). Neonatal Marfan syndrome (nMFS) is rare and the most severe form of MFS, involving rapidly progressive cardiovascular dysfunction leading to death during early childhood. The constant enrichment of the nMFS mutation spectrum is helpful to improve our understanding of genotype-phenotype correlations in the disease. Herein, we report a novel dominant mutation in exon 26 of FBN1 (c.3331 T?>?C) in a sporadic case with nMFS.An 8-month-old Han Chinese girl presented with the classic nMFS phenotype, including prominent manifestations of bone overgrowth, aortic root dilatation, and multiple cardiac valve dysfunctions. Genetic analysis revealed that she was heterozygous for a de novo FBN1 missense mutation (c.3331 T?>?C). The mutation leads to the substitution of a highly conserved FBN1 cysteine residue (p.Cys1111Arg), which is likely to severely perturb the FBN1 structure because of an alteration of the disulfide bond pattern in the calcium-binding epidermal growth factor-like (cbEGF) 12 domain. This variant was absent in 208 ethnically matched controls, providing further evidence that it may be causative of nMFS. An analysis of nMFS-associated mutations from the UMD-FBN1 database indicates that those de novo mutations altering disulfide bonds or Ca(2+) binding sites of the cbEGF domains encoded by exons 25-33, and a lack of phenotypic heterogeneity may be associated with an increased risk for nMFS.We diagnosed an infant with rare nMFS showing rapidly progressive cardiovascular dysfunction and widely systemic features. As the only causal FBN1 mutation identified in the patient, the missense mutation c.3331 T?>?C (p.Cys1111Arg) was associated with the severe phenotype of MFS. However, the pathogenicity of the novel mutation needs further confirmation in other patients with nMFS. Our review of the prominent characteristics of nMFS mutations relative to classic or incomplete MFS-related mutations will be helpful for the recognition of novel nMFS-associated variants.

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Case Report: A Novel COL1A1 Missense Mutation Associated With Dentineogenesis Imperfecta Type I.

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