Clinical and Functional Characterization of P.Gly444Ser Variant: From a Fetal Phenotype to a Previously Undisclosed Postnatal Phenotype

Overview

Journal Bone Rep

Date 2023 Dec 11

PMID 38076483

Authors

Enrica Marchionni

Maria Rosaria DApice

Viviana Lupo

Giovanna Lattanzi

Elisabetta Mattioli

Gina Lisignoli

Elena Gabusi

Gerardo Pepe

Manuela Helmer Citterich

Elena Campione

Anna Maria Nardone

Paola Spitalieri

Noemi Pucci

Dario Cocciadiferro

Eliseo Picchi

Francesco Garaci

Antonio Novelli

Giuseppe Novelli

Affiliations

Soon will be listed here.

Abstract

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 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 protein modeling and 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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