Consequences of Disease-causing Mutations on Lubricin Protein Synthesis, Secretion, and Post-translational Processing

Rhee, David K.; Marcelino, José Roberto; Al‐Mayouf, Sulaiman M.; Schelling, Deborah K.; Bartels, Cynthia F.; Cui, Yang; Laxer, Ronald M.; Goldbach‐Mansky, Raphaela; Warman, Matthew L.

doi:10.1074/jbc.m505401200

Cited by 65 publications

(64 citation statements)

References 31 publications

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“…1). The clinical findings for this patient do not differ from those of our other patients, however, and this is consistent with PRG4 monitoring via nonsense mediated mRNA decay as has been recently suggested (Rhee et al, 2005a). Figure 1.…”

Section: Resultssupporting

confidence: 90%

Novel PRG4 mutations underlie CACP in Saudi families

et al. 2006

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The camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome is an autosomal recessive disorder caused by mutations in the PRG4 (Proteoglycan 4) gene. Manifestations vary across families as well as between affected individuals from the same family, with camptodactyly and arthropathy of the knees the most ubiquitous, while pericarditis is evident in only one-fifth of all reported cases. Thus far only eight pathogenic mutations have been described in this gene. We examined seven newly diagnosed childhood patients of this syndrome, hailing from four unrelated families of Saudi origin. Five novel mutations were uncovered, including four frameshift deletions and one nonsense mutation (c.923_924delAA, c.3125_3128delGAGT, c.3139_3140delAA, c.3276_3277delAA, c.4078A>T). No genotype/phenotype association was observed. Because all mutations reported in CACP patients thus far predict premature truncation, we hypothesize that missense mutations are either not physiologically relevant, or that they trigger a clinical phenotype that is distinct from classical CACP. This is only the second published communication on PRG4 mutations, and increases the number of reported mutations for all ethnicities from 8 to 13, and for the Arab population specifically from one to six.

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Section: Resultssupporting

confidence: 90%

Novel PRG4 mutations underlie CACP in Saudi families

et al. 2006

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“…SF is composed of HA ranging from 2,000 kd to 10,000 kd (30,44), PRG4 proteins ranging from ϳ14 kd to ϳ345 kd (4,45), and SAPL of different types with DPPC being a major form (33). HA has been shown to lubricate at a cartilage-cartilage interface on a joint scale equally well at 1,030 kd and 1,930 kd (14), and certain other properties of HA do not depend on molecular weight either (in the range of 500-6,000 kd) (46).…”

Section: Discussionmentioning

confidence: 99%

Boundary lubrication of articular cartilage: Role of synovial fluid constituents

Schmidt

Gastelum

Nguyen

et al. 2007

Arthritis & Rheumatism

480

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Objective. To determine whether the synovial fluid (SF) constituents hyaluronan (HA), proteoglycan 4 (PRG4), and surface-active phospholipids (SAPL) contribute to boundary lubrication, either independently or additively, at an articular cartilage-cartilage interface.Methods. Cartilage boundary lubrication tests were performed with fresh bovine osteochondral samples. Tests were performed using graded concentrations of SF, HA, and PRG4 alone, a physiologic concentration of SAPL, and various combinations of HA, PRG4, and SAPL at physiologic concentrations. Static ( static, Neq ) and kinetic (< kinetic, Neq >) friction coefficients were calculated.Results. Normal SF functioned as an effective boundary lubricant both at a concentration of 100% (< kinetic, Neq > ‫؍‬ 0.025) and at a 3-fold dilution (< kinetic, Neq > ‫؍‬ 0.029). Both HA and PRG4 contributed independently to a low in a dose-dependent manner. Values of < kinetic, Neq > decreased from ϳ0.24 in phosphate buffered saline to 0.12 in 3,300 g/ml HA and 0.11 in 450 g/ml PRG4. HA and PRG4 in combination lowered further at the high concentrations, attaining a < kinetic, Neq > value of 0.066. SAPL at 200 g/ml did not significantly lower , either independently or in combination with HA and PRG4. Conclusion. The results described here indicate that SF constituents contribute, individually and in combination, both at physiologic and pathophysiologic concentrations, to the boundary lubrication of apposing articular cartilage surfaces. These results provide insight into the nature of the boundary lubrication of articular cartilage by SF and its constituents. They therefore provide insight regarding both the homeostatic maintenance of healthy joints and pathogenic processes in arthritic disease.

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“…The latter possibility has been previously proved for some nonsense/frameshift PRG4 mutations as a consequence of nonsense-mediated mRNA decay. 20 Unfortunately, due to the unavailability of synovial fluid from the patients, the structure of the protein could not be investigated.…”

Section: Resultsmentioning

confidence: 99%