Skeletal Dysplasias Caused by Sulfation Defects

Abstract

Proteoglycans (PGs) are macromolecules present on the cell surface and in the extracellular matrix that confer specific mechanical, biochemical, and physical properties to tissues. Sulfate groups present on glycosaminoglycans, linear polysaccharide chains attached to PG core proteins, are fundamental for correct PG functions. Indeed, through the negative charge of sulfate groups, PGs interact with extracellular matrix molecules and bind growth factors regulating tissue structure and cell behavior. The maintenance of correct sulfate metabolism is important in tissue development and function, particularly in cartilage where PGs are fundamental and abundant components of the extracellular matrix. In chondrocytes, the main sulfate source is the extracellular space, then sulfate is taken up and activated in the cytosol to the universal sulfate donor to be used in sulfotransferase reactions. Alteration in each step of sulfate metabolism can affect macromolecular sulfation, leading to the onset of diseases that affect mainly cartilage and bone. This review presents a panoramic view of skeletal dysplasias caused by mutations in genes encoding for transporters or enzymes involved in macromolecular sulfation. Future research in this field will contribute to the understanding of the disease pathogenesis, allowing the development of targeted therapies aimed at alleviating, preventing, or modifying the disease progression.

Fetal presentation of chondrodysplasia with joint dislocations, GPAPP type, caused by novel biallelic IMPAD1 variants

“…A somewhat similar findings of elbow joint dysplasia was documented in prenatal case with biallelic DTDST variants (Miller et al, 2008). This combination of elbow joint dysplasia and the characteristic fifth toe deformity appear to be distinctive findings in IMPAD1-related chondrodysplasia and joint dislocations GPAPP type (observed in both prenatal and postnatal period), differentiating it from other disorders of sulfation (Paganini et al, 2020).…”

Mutations in GRK2 cause Jeune syndrome by impairing Hedgehog and canonical Wnt signaling

“…Finally, a severe under‐sulfation of extracellular matrix proteoglycans was found in the ATD cartilage, and in the cartilaginous micromass cultures generated from Grk2‐null or Grk2‐inhibited cells (Fig 3D–F), suggesting that GRK2 regulates proteoglycan metabolism. The maintenance of proteoglycan homeostasis is important for the cartilage growth, as numerous skeletal dysplasias associate with deficient sulfation (Paganini et al , 2020). Apart from organization of the extracellular matrix network, the sulfated proteoglycans also promote the Ihh and TGFβ signaling, which is essential for chondrocyte proliferation and differentiation (Klüppel et al , 2005; Cortes et al , 2009; Gualeni et al , 2010).…”

Bi-allelic Pathogenic Variants in HS2ST1 Cause a Syndrome Characterized by Developmental Delay and Corpus Callosum, Skeletal, and Renal Abnormalities

“…Other disorders linked to genes/proteins involved in GAG sulfation are CHST3-related skeletal dysplasia (spondyloepiphyseal dysplasia with congenital joint dislocations [MIM: 143095]), Ehlers-Danlos syndrome, musculocontractural type 1 (EDSMC1 [MIM: 601776]), and osteochondrodysplasia, brachydactyly, and overlapping malformed digits (OCBMD [MIM: 618167]). 62,63 CHST3related skeletal dysplasia is typically characterized by short stature, joint dislocations, clubfeet, restricted movement, kyphosis, and minor heart valve dysplasia (see Superti-Furga and Unger in GeneReviews in Web Resources). Bi-allelic variants in CHST3 encoding carbohydrate sulfo-transferase 3 or chondroitin 6-O-sulfotransferase 1 lead to functional impairment of the enzyme.…”