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Clinical and functional characterization of COL2A1 p.Gly444Ser variant: From a fetal phenotype to a previously undisclosed postnatal phenotype.
Marchionni, Enrica; D'Apice, Maria Rosaria; Lupo, Viviana; Lattanzi, Giovanna; Mattioli, Elisabetta; Lisignoli, Gina; Gabusi, Elena; Pepe, Gerardo; Helmer Citterich, Manuela; Campione, Elena; Nardone, Anna Maria; Spitalieri, Paola; Pucci, Noemi; Cocciadiferro, Dario; Picchi, Eliseo; Garaci, Francesco; Novelli, Antonio; Novelli, Giuseppe.
Afiliación
  • Marchionni E; Medical Genetics Unit, Policlinico Tor Vergata, University of Rome Tor Vergata, Rome, Italy.
  • D'Apice MR; Medical Genetics Unit, Policlinico Tor Vergata, University of Rome Tor Vergata, Rome, Italy.
  • Lupo V; Medical Genetics Unit, Policlinico Tor Vergata, University of Rome Tor Vergata, Rome, Italy.
  • Lattanzi G; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
  • Mattioli E; CNR Institute of Molecular Genetics "Luigi Luca Cavalli-Sforza" Unit of Bologna, Bologna, Italy.
  • Lisignoli G; Istituto Ortopedico Rizzoli, Bologna, Italy.
  • Gabusi E; CNR Institute of Molecular Genetics "Luigi Luca Cavalli-Sforza" Unit of Bologna, Bologna, Italy.
  • Pepe G; Istituto Ortopedico Rizzoli, Bologna, Italy.
  • Helmer Citterich M; IRCCS Istituto Ortopedico Rizzoli, Laboratorio di Immunoreumatologia e Rigenerazione Tissutale Bologna, Italy.
  • Campione E; IRCCS Istituto Ortopedico Rizzoli, Laboratorio di Immunoreumatologia e Rigenerazione Tissutale Bologna, Italy.
  • Nardone AM; Department of Biology, University of Rome Tor Vergata, Rome, Italy.
  • Spitalieri P; Department of Biology, University of Rome Tor Vergata, Rome, Italy.
  • Pucci N; Dermatologic Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
  • Cocciadiferro D; Medical Genetics Unit, Policlinico Tor Vergata, University of Rome Tor Vergata, Rome, Italy.
  • Picchi E; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
  • Garaci F; Diagnostic Imaging Unit, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
  • Novelli A; Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
  • Novelli G; Diagnostic Imaging Unit, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy.
Bone Rep ; 19: 101728, 2023 Dec.
Article en En | MEDLINE | ID: mdl-38076483
COL2A1 gene encodes the alpha-1 chain of type-II procollagen. Heterozygous pathogenic variants are associated with the broad clinical spectrum of genetic diseases known as type-II collagenopathies. We aimed to characterize the NM_001844.5:c.1330G>A;p.Gly444Ser variant detected in the COL2A1 gene through trio-based prenatal exome sequencing in a fetus presenting a severe skeletal phenotype at 31 Gestational Weeks and in his previously undisclosed mild-affected father. Functional studies on father's cutaneous fibroblasts, along with in silico protein modeling and in vitro chondrocytes differentiation, showed intracellular accumulation of collagen-II, its localization in external Golgi vesicles and nuclear morphological alterations. Extracellular matrix showed a disorganized fibronectin network. These results showed that p.Gly444Ser variant alters procollagen molecules processing and the assembly of mature type-II collagen fibrils, according to COL2A1-chain disorganization, displayed by protein modeling. Clinical assessment at 38 y.o., through a reverse-phenotyping approach, revealed limp gait, short and stocky appearance. X-Ray and MRI showed pelvis asymmetry with severe morpho-structural alterations of the femoral heads bilaterally, consistent with a mild form of type-II collagenopathy. This study shows how the fusion of genomics and clinical expertise can drive a diagnosis supported by cellular and bioinformatics studies to effectively establish variants pathogenicity.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Bone Rep Año: 2023 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Bone Rep Año: 2023 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Estados Unidos