Abstract
Gout is a highly prevalent disease manifesting most commonly as acute, episodic synovitis that
characteristically is excruciatingly painful. Gout continues to grow as a public health problem. The disorder is
promoted by elevated body stores of uric acid, and the clinical phenotypes of arthritis are caused by
inflammatory responses associated with articular deposits of urate crystals. However, gout develops in only a
minority subset of hyperuricemic subjects. Moreover, clinical responses to deposited urate crystals are highly
variable, including the frequency and extent of acute arthritis, and progression to palpable subcutaneous tophi,
chronic arthritis, and erosive joint damage. There is unmet need to define new therapy targets and biomarkers
for incident gout and progression to erosive joint disease. The rationale for this high risk/high reward
application is that by clarifying major gaps in knowledge in these areas, the work will be paradigm-shifting, and
potentially identify new targets to help prevent and limit gout-associated morbidity. Emerging findings, including
from certain arthropathies other than gout, suggest that altered extracellular matrix O-linked glycoprotein
components such as the mucin-type boundary lubricant lubricin, and active urate pumping into the joint by an
unidentified transport mechanism play a role in development of gout. Our scientific premise is that, in synovial
fibroblast lining cells (FLS), mechanistically linked alterations in lubricin and other mucin-type extracellular
matrix O-glycoproteins and increased urate secretion are in a mechanistic lop that promotes “common gout”,
and progression to chronic, destructive synovitis. We will use primarily a combined candidate gene and reverse
genetics approach to analyze a highly unusual observation, specifically a case of gout as an “experiment of
nature”. The proband, an otherwise healthy female without hyperuricemia, at age 22 had onset of destructive
hip synovitis, and asymmetric acute gouty arthritis flares of small and intermediate joints with classic toe joint
gout erosions, and gout definitively confirmed. Collective preliminary data for proband whole genomic DNA,
and serum glycomics, proteomics, and glycoproteomics suggest dysregulation in biosynthesis of lubricin and
other mucin-type O-glycoproteins that normally serve as constitutive inhibitors of inflammation. Gene
candidates are highly enriched in the “reactome” of TMEM171, an incompletely characterized transmembrane
molecule implicated in urate transport and recently defined as a gout susceptibility gene. Specifically, the
TMEM171 reactome comprises over 20 molecules involved in glycoprotein biosynthesis, more than 10
mucintype. O-glycoproteins, and over 20 ADAMTS protease superfamily members. The work aims to illuminate
novel intersections between synovial extracellular matrix biology, urate metabolism and transport, tophus
formation, and synovitis. Positive impact includes building a new disease paradigm for “common gout”,
potential new biomarkers, and possible gout therapeutics from the novel class of O-glycoprotein agents.