The GUSB gene encodes β-glucuronidase, a lysosomal hydrolase responsible for the stepwise degradation of glycosaminoglycans (GAGs) such as heparan sulfate, dermatan sulfate, and chondroitin-4,6-sulfate. The enzyme is active as a lysosomal homotetramer, and its proper function is essential for cellular recycling of GAGs.
Biallelic pathogenic variants in GUSB lead to deficient or absent β-glucuronidase activity, resulting in lysosomal accumulation of undegraded GAGs. This accumulation disrupts cellular and tissue homeostasis, particularly in connective tissue, bone, the CNS, and visceral organs, leading to the multisystemic manifestations of Mucopolysaccharidosis type VII (Sly syndrome).
The GUSB gene exhibits a spectrum of pathogenic variants, including:
• Missense variants that result in amino acid substitutions, potentially destabilizing the enzyme’s structure or impairing catalytic function.
• Nonsense variants introducing premature stop codons, often leading to truncated, nonfunctional proteins.
• Small deletions, which can cause frameshifts or aberrant splicing.
• Splice-site and intronic variants that may alter mRNA processing or stability.
GUSB