<i>WISP3</i> mutation associated with pseudorheumatoid dysplasia

Sailani, M. Reza; Chappell, James; Inlora, Jingga; Narasimha, Anil; Zia, Amin; Lynch, Janet Linnea; Mazrouei, Safoura; Bernstein, Jonathan A.; Aryani, Omid; Snyder, M

doi:10.1101/mcs.a001990

Cited by 20 publications

(30 citation statements)

References 36 publications

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“…Cellular communication network factor 6 mutations have been linked to a debilitating skeletal disorder termed PPRD, which is characterized by loss of normal chondrocyte clusters in the cartilage growth plate 10 . In light of the fact that CCN6 (variant 3) exon 5 truncation mutation Trp 349 stop (equivalent to Trp 331 stop mutation in variant 1) is linked to PPRD 14,37 we used CRISPR‐Cas9 NHEJ methodology 30 to generate truncation mutations similar to Trp 349 stop in CCN6 for investigating if such mutations have any deleterious effects on mitochondrial respiratory complex assembly/activity, and thus cell viability. We focused on CCN6 variant 3 because the chondrocyte line used in this study expresses this variant predominantly (Supporting Figure S2).…”

Section: Resultsmentioning

confidence: 99%

CCN6 regulates mitochondrial respiratory complex assembly and activity

et al. 2020

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Cellular communication network factor 6 (CCN6) mutations are linked with Progressive Pseudo Rheumatoid Dysplasia (PPRD) a debilitating musculoskeletal disorder. The function of CCN6 and the mechanism of PPRD pathogenesis remain unclear. Accordingly, we focused on the functional characterization of CCN6 and CCN6 mutants. Using size exclusion chromatography and native polyacrylamide gel electrophoresis we demonstrated that CCN6 is present as a component of the mitochondrial respiratory complex in human chondrocyte lines. By means of siRNA‐mediated transfection and electron microscopy we showed that moderate reduction in CCN6 expression decreases the RER– mitochondria inter‐membrane distance. Parallel native PAGE, immunoblotting and Complex I activity assays furthermore revealed increase in both mitochondrial distribution of CCN6 and mitochondrial respiratory complex assembly/activity in CCN6 depleted cells. CCN6 mutants resembling those linked with PPRD, which were generated by CRISPR‐Cas9 technology displayed low level of expression of mutant CCN6 protein and inhibited respiratory complex assembly/activity. Electron microscopy and MTT assay of the mutants revealed abnormal mitochondria and poor cell viability. Taken together, our results indicate that CCN6 regulates mitochondrial respiratory complex assembly/activity as part of the mitochondrial respiratory complex by controlling the proximity of RER with the mitochondria, and CCN6 mutations disrupt mitochondrial respiratory complex assembly/activity resulting in mitochondrial defects and poor cell viability.

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Section: Resultsmentioning

confidence: 99%

CCN6 regulates mitochondrial respiratory complex assembly and activity

et al. 2020

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“…It is caused by mutations in the WISP3 gene, which encodes for a protein expressed in synoviocytes and chondrocytes that plays a major role in bone and cartilage development. 2 …”

Section: Discussionmentioning

confidence: 99%

Progressive pseudorheumatoid dysplasia: A rare entity mimicking juvenile idiopathic arthritis

Maatallah

Boussaa

Ferjani

et al. 2021

Clinical Case Reports

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“…Case5 had the homozygous missense mutation c.667T>G, p.C223G in the WISP3 gene. Three of our patients had WISP3 mutations involving c.589+2T>C, showing a homozygous mutation or compound heterozygous mutation with c.667T>G. The c.667T>G mutation, located in exon 4 of the WISP3 gene has beenreported before in Chinese and other ethnic origins' children affected with PPRD8,22 .…”

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confidence: 48%

“…PPRD is caused by mutations in the WISP3 gene which maps to chromosome 6q22, and encodes a protein in the connective tissue growth factor that is expressed in synoviocytes and chondrocytes involved in bone and cartilage growth and development 8 . Homozygous or compound heterozygous WISP3 mutations cause the loss of articular cartilage, which leads to the progressive narrowing of all articular spaces and reduced joint mobility 9 .…”

Section: Introductionmentioning

confidence: 99%

Systematical analysis of nine Chinese patients with progressive pseudorheumatoid dysplasia and assessment of calcitriol treatment

Li¹,

Mao²,

Zhou³

et al. 2020

Preprint

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Background: Progressive pseudorheumatoid dysplasia (PPRD) (MIM 208230) is a rare genetic disease characterized by progressive noninflammatory arthropathy affecting primarily the articular cartilage. Most patients are initially misdiagnosed because of the rarity of the disease and lack of awareness by most clinicians. Therefore, the purpose of the present study was to provide further diagnostic options to help clinicians make early precise diagnosis, and to investigate a new potential treatment for patients with PPRD. Methods: Clinical manifestations, radiographic features, Sanger Sequencing to determine WISP3 gene mutation and follow-up records were collected in 9 Chinese patients with PPRD. The time until diagnosis, relationship between clinical phenotypes and genotypes, and treatment effects were analyzed. Results: The clinical history and characteristics, mutations in the WISP3 gene, radiological data, treatment and outcome of 9 PPRD children were collected and reviewed. There were 3 pairs of siblings in this group and one patient had parental consanguinity. Five patients were misdiagnosed with juvenile idiopathic arthritis (JIA). The onset of disease in most patients (8/9) was between 3 and 6 years of age. The interval between onset of symptoms and obtaining the diagnosis for 8 of the patients varied between 3.6 years to 20 years. The onset of symptoms included enlarged and stiff interphalangeal joints of the fingers, gait disturbance or joint pain. Blood analysis revealed normal range of inflammatory parameters (erythrocyte sedimentation rate, C-reactive protein). Serum levels of 25-hydroxyvitamin D3 were analyzed in six patients and ranged from 6.16 to 22.1ng/ml, all lower than the normal range. Radiographic findings included different degree of abnormal vertebral bodies, epiphyseal enlargement of the interphalangeal joints with juxta-articular osteopenia, or reduction in hip articular space and cyst-like structures femoral head. A total of 7 variants in the WISP3 gene were identified in the 9 cases, presenting with three homozygous variants (c.397_404delCAAGTGTT, c.667T>G, and c.589+2T>C) and three compound heterozygous variants (c.589+2T>C/c.667T>G, c.624dupA/c.756C>A, and c.646T>C/c.1000T>C). After the treatment of calcitriol in the 6 patients with low level of 25-hydroxyvitamin D3 for 1.25 years to 1.75 years, two cases showed stable clinical disease activity and the other four patients joints’ pain and abnormal gait had improved. Conclusions: Combining the patient’s family history, clinical features presenting with abnormal gait or enlarged and stiff interphalangeal joints of the fingers, normal inflammatory markers, and the characteristic radiographic findings, we can obtain the clinical diagnosis of PPRD for the patients at a very early stage of the disease. The patients with PPRD having c.624dupA mutation in WISP3 may have delayed onset. Calcitriol showed treatment benefit by improving symptoms and decelerating progression of PPRD disease.

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WISP3 mutation associated with pseudorheumatoid dysplasia

Cited by 20 publications

References 36 publications

CCN6 regulates mitochondrial respiratory complex assembly and activity

CCN6 regulates mitochondrial respiratory complex assembly and activity

Progressive pseudorheumatoid dysplasia: A rare entity mimicking juvenile idiopathic arthritis

Systematical analysis of nine Chinese patients with progressive pseudorheumatoid dysplasia and assessment of calcitriol treatment

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