Élargissement du spectre moléculaire des aggrécanopathies : étude de 24 patients présentant des variants significatifs de l'ACAN

Objectif(s) de la recherche et intérêt pour la santé publique

Finalité de l'étude

Objectifs poursuivis

Domaines médicaux investigués

Bénéfices attendus

Introduction

Longitudinal bone growth, driven by chondrogenesis at the growth plate, is regulated by complex interactions among endocrine, paracrine, and cellular factors. Pathogenic variants affecting these pathways can lead to growth delays and skeletal defects. Short stature, often resulting from these issues, accounts for 3% of referrals to paediatric endocrinologists. However, in most cases (80%), no specific cause is found after clinical investigation and standard tests. These cases are diagnosed as idiopathic short stature (ISS), which includes patients with constitutional delays in growth and development, familial short stature, and those with subtle signs of skeletal dysplasia that
are not easily identifiable.
Aggrecan is a major component of the extracellular matrix of the growth plate and articular cartilage. It is a proteoglycan composed of a core protein and covalently attached glycosaminoglycan chains. Its core protein, approximately 230 kDa, can have up to 130 glycosaminoglycan chains, reaching a total molecular mass of about 2,200 kDa. It features three globular domains (G1, G2, and G3), two glycosaminoglycan-attachment domains: keratan sulfate (KS) and chondroitin sulfate (CS), and an interglobular domain (IGD) between G1 and G2. Aggrecan is encoded by a single gene on chromosome 15 in humans, named ACAN, with a highly conserved genomic structure across species. ACAN has 18 exons and has the translation initiation codon, located in exon 2. The aggrecan protein has a major role in making its aggregates highly hydrated and enabling cartilage to bear loads. Aggrecan also regulates growth factors and signalling molecules, crucial for cartilage and bone development.

Objectif principal
Establishing a correlation between the phenotype and the genotype

Objectif(s) secondaire(s)
Expanding the molecular spectrum of aggrecanopathies