Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: Chondrocalcinosis is characterized by calcium pyrophosphate dihydrate (CPPD) deposition in articular cartilage. It can occur as a rare autosomal dominant disorder with florid early-onset osteoarthritis (OA). Two observed gene mutations are: ANKH 1 (progressive ankylosis; on chromosome 5p) and TNFRSF11B 2 (coding for osteoprotegerin (OPG), on chromosome 8q). ANKH mutations apparently affect extracellular pyrophosphate (PPi) levels by altering its transporter function. OPG, a decoy receptor, regulates bone remodeling by binding receptor activator nuclear factor Kappa beta ligand (RANKL), preventing osteoclast bone resorption. Any alteration in the bone remodeling process, may alter bone mineral density. We report a US family with gain-of-function mutation in TNFRSF11B coding for OPG that is potentially related to this family’s severe OPG-CPPD phenotype. Previously, only 1 family with the same OPG gene mutation has been described in the literature (Ramos et al, 2015). The purpose of this study is to screen 3 generations of affected members of a US family of Italian/German ancestry with early-onset autosomal dominant OA and radiographic chondrocalcinosis for mutations in ANKH or TNFRSF11B.
Methods: Subjects were identified by proband’s rheumatologist. Clinical presentations, similar to the proband were noted in 6 out of 10 male family members over 3 consecutive generations. Genetic testing was performed on peripheral blood and buccal swab samples from proband and 2 other affected family members, in accordance with institutional guidelines for human subjects with written informed consent and IRB approval. DNA isolated from samples was amplified for ANKH and TNRSF11B by PCR using gene-specific primers and subjected to dideoxy sequencing of PCR products. Patient sequences were compared to control samples and sequence anomalies were confirmed by antisense sequencing of the PCR products.
Results: The proband, a 43 year old male patient, presented at age 31, with progressive polyarticular crippling arthritis resulting in pain and disability. His knee X-rays showed advanced loss of joint space. X-rays of his wrists, elbows and ankles also revealed severe arthropathy and extensive chondrocalcinosis, strongly suggestive of CPPD disease. Arthrocentesis and synovial fluid analysis was deferred due to absence of significant joint effusions. Diagnostic work up for primary metabolic disorders associated with CPPD was negative. Genetic testing of proband and 2 affected family members identified a read-through mutation of the termination codon (A=>T; Stop402Leu) in TNFRSF11B. Studies performed by Ramos et al show that the mutant-OPG has enhanced capacity to inhibit osteoclastogenesis. Hence, this mutation is potentially linked to this family’s severe OA-CPPD phenotype.
Conclusion: We have identified a second family with a read-through, gain of function mutation (Stop402Leu) in TNFRSF11B gene coding for OPG that is likely related to their OA/CPPD phenotype. While it is not yet clear how mutations in OPG may give rise to the CPPD phenotype, targeted inhibition of OPG binding to RANKL may become a therapeutic approach to prevent and/or treat pathological joint chondrocalcinosis.
To cite this abstract in AMA style:Qazi U, Williams CJ, Bernstein ML, Charniak A, Ortiz A, Rosenthal AK, Cardinal L, Kaell AT. Mutation in Osteoprotegerin Gene: Early-Onset Osteoarthritis and Chondrocalcinosis in a US Family of Italian/German Ancestry [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/mutation-in-osteoprotegerin-gene-early-onset-osteoarthritis-and-chondrocalcinosis-in-a-us-family-of-italiangerman-ancestry/. Accessed June 2, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mutation-in-osteoprotegerin-gene-early-onset-osteoarthritis-and-chondrocalcinosis-in-a-us-family-of-italiangerman-ancestry/