Mutations in HYAL1, a member of a tandemly distributed multigene family encoding disparate hyaluronidase activities, cause a newly described lysosomal disorder, mucopolysaccharidosis IX

Hyaluronan (HA), a large glycosaminoglycan abundant in the extracellular ma trix, is important in cell migration during embryonic development, cellular proliferation, and differentiation and has a structural role in connective tissues. The turnover of HA requires endoglycosidic breakdown by lysosomal hyaluronidase, and a congenital deficiency of hyaluronidase has been thoug ht to be incompatible with life. However, a patient with a deficiency of se rum hyaluronidase, now designated as mucopolysaccharidosis IX, was recently described. This patient had a surprisingly mild clinical phenotype, includ ing notable periarticular soft tissue masses, mild short stature, an absenc e of neurological or visceral involvement, and histological and ultrastruct ural evidence of a lysosomal storage disease. To determine the molecular ba sis of mucopolysaccharidosis IX, we analyzed two candidate genes tandemly d istributed on human chromosome 3p21.3 and encoding proteins with homology t o a sperm protein with hyaluronidase activity. These genes, HYAL1 and HYAL2 , encode two distinct lysosomal hyaluronidases with different substrate spe cificities. We identified two mutations in the HYAL1 alleles of the patient , a 1412G --> A mutation that introduces a nonconservative amino acid subst itution (Glu268Lys) in a putative active site residue and a complex intrage nic rearrangement, 1361de137ins14, that results in a premature termination codon. We further show that these two hyaluronidase genes, as well as a thi rd recently discovered adjacent hyaluronidase gene, HYAL3, have markedly di fferent tissue expression patterns, consistent with differing roles in HA m etabolism. These data provide an explanation for the unexpectedly mild phen otype in mucopolysaccharidosis IX and predict the existence of other hyalur onidase deficiency disorders.