Mechanistic insights into the cellular effects of a novelFN1variant associated with a spondylometaphyseal dysplasia
| Autor: | Ruth Sheffer, D. Ovadia, S. Wientroub, Vardiella Meiner, E.B. Cadoff, Jean E. Schwarzbauer |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Mutant Matrix (biology) Osteochondrodysplasias Article Extracellular matrix 03 medical and health sciences 0302 clinical medicine Mutant protein Exome Sequencing Genetics Humans Genetic Predisposition to Disease Child Alleles Genetic Association Studies Genetics (clinical) Exome sequencing Extracellular Matrix Proteins biology Endoplasmic reticulum Genetic Variation Fibroblasts Immunohistochemistry Phenotype Molecular biology Fibronectins Radiography Fibronectin 030104 developmental biology Child Preschool Mutation biology.protein 030217 neurology & neurosurgery |
| Zdroj: | Clinical Genetics. 94:429-437 |
| ISSN: | 0009-9163 |
| DOI: | 10.1111/cge.13424 |
| Popis: | Spondylometaphyseal dysplasia (SMD) is characterized by developmental changes in long bones and vertebrae. It has large phenotypic diversity and multiple genetic causes, including a recent link to novel variants in the extracellular matrix (ECM) protein fibronectin (FN), a regulator of ECM assembly and key link between the ECM and proper cell function. We identified a patient with a unique SMD, similar to SMD with corner fractures. The patient has been followed over 19 years and presents with short stature, genu varum, kyphoscoliosis, and pectus carinatum. Radiography shows metaphyseal changes that resolved over time, vertebral changes, and capitular avascular necrosis. Whole exome sequencing identified a novel heterozygous FN1 variant (p.Cys97Trp). Using mass spectroscopy, mutant FN was detected in plasma and in culture medium of primary dermal fibroblasts isolated from the patient, but mutant protein was much less abundant than wild type FN. Immunofluorescence and immunoblotting analyses show that mutant fibroblasts assemble significantly lower amounts of FN matrix than wild type cells, and mutant FN was preferentially retained within the endoplasmic reticulum. This work highlights the importance of FN in skeletal development, and its potential role in the pathogenesis of a subtype of SMD. |
| Databáze: | OpenAIRE |
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