PMID- 10339581
OWN - NLM
STAT- MEDLINE
DCOM- 19990624
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 96
IP  - 11
DP  - 1999 May 25
TI  - Mutations in HYAL1, a member of a tandemly distributed multigene family encoding 
      disparate hyaluronidase activities, cause a newly described lysosomal disorder,
      mucopolysaccharidosis IX.
PG  - 6296-300
AB  - Hyaluronan (HA), a large glycosaminoglycan abundant in the extracellular matrix, 
      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 thought to
      be incompatible with life. However, a patient with a deficiency of serum
      hyaluronidase, now designated as mucopolysaccharidosis IX, was recently
      described. This patient had a surprisingly mild clinical phenotype, including
      notable periarticular soft tissue masses, mild short stature, an absence of
      neurological or visceral involvement, and histological and ultrastructural
      evidence of a lysosomal storage disease. To determine the molecular basis of
      mucopolysaccharidosis IX, we analyzed two candidate genes tandemly distributed on
      human chromosome 3p21.3 and encoding proteins with homology to a sperm protein
      with hyaluronidase activity. These genes, HYAL1 and HYAL2, encode two distinct
      lysosomal hyaluronidases with different substrate specificities. We identified
      two mutations in the HYAL1 alleles of the patient, a 1412G --> A mutation that
      introduces a nonconservative amino acid substitution (Glu268Lys) in a putative
      active site residue and a complex intragenic rearrangement, 1361del37ins14, that 
      results in a premature termination codon. We further show that these two
      hyaluronidase genes, as well as a third recently discovered adjacent
      hyaluronidase gene, HYAL3, have markedly different tissue expression patterns,
      consistent with differing roles in HA metabolism. These data provide an
      explanation for the unexpectedly mild phenotype in mucopolysaccharidosis IX and
      predict the existence of other hyaluronidase deficiency disorders.
FAU - Triggs-Raine, B
AU  - Triggs-Raine B
AD  - Department of Biochemistry and Molecular Biology, University of Manitoba,
      Winnipeg, MB R3E OW3, Canada. traine@ms.umanitoba.ca
FAU - Salo, T J
AU  - Salo TJ
FAU - Zhang, H
AU  - Zhang H
FAU - Wicklow, B A
AU  - Wicklow BA
FAU - Natowicz, M R
AU  - Natowicz MR
LA  - eng
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (DNA Transposable Elements)
RN  - EC 3.2.1.35 (Hyaluronoglucosaminidase)
SB  - IM
MH  - Amino Acid Sequence
MH  - Amino Acid Substitution
MH  - Animals
MH  - Base Sequence
MH  - Binding Sites
MH  - Chromosome Mapping
MH  - *Chromosomes, Human, Pair 3
MH  - DNA Transposable Elements
MH  - Female
MH  - Fibroblasts/enzymology
MH  - Humans
MH  - Hyaluronoglucosaminidase/chemistry/deficiency/*genetics
MH  - Leukocytes/enzymology
MH  - Lysosomes/enzymology
MH  - Male
MH  - Molecular Sequence Data
MH  - Mucopolysaccharidoses/blood/enzymology/*genetics
MH  - *Multigene Family
MH  - Pedigree
MH  - *Point Mutation
MH  - *Polymorphism, Single-Stranded Conformational
MH  - Sequence Alignment
MH  - *Sequence Deletion
MH  - Sequence Homology, Nucleic Acid
MH  - Spermatozoa/enzymology
PMC - PMC26875
EDAT- 1999/05/26 00:00
MHDA- 1999/05/26 00:01
CRDT- 1999/05/26 00:00
PHST- 1999/05/26 00:00 [pubmed]
PHST- 1999/05/26 00:01 [medline]
PHST- 1999/05/26 00:00 [entrez]
AID - 10.1073/pnas.96.11.6296 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1999 May 25;96(11):6296-300. doi:
      10.1073/pnas.96.11.6296.