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Orthopaedic Proceedings
Vol. 93-B, Issue SUPP_II | Pages 108 - 109
1 May 2011
Shyy W Wang K Sheffield V Morcuende J
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Purpose: Congenital idiopathic clubfoot is the most common musculoskeletal birth defect developing during the fetal period, but with no known etiology. MYH 2, 3, 7, and 8 are expressed embryonically or perinatally, the period during which congenital idiopathic clubfoot develops; are all components of Type II muscle, which is consistently decreased in clubfoot patients; and are associated with several muscle contracture syndromes that have associated clubfoot deformities. In this study, we hypothesized that mutations in embryonic and perinatal myosin genes could be associated with congenital idiopathic clubfoot.

Methods: We screened the exons, splice sites, and predicted promoters of 24 bilateral congenital idiopathic clubfoot patients and 24 matched controls in MYH 1, 2, 3, and 8 via sequence-based analysis, and screened an additional 76 patients in each discovered SNP.

Results: While many SNPs were found, none proved to be significantly associated with the phenotype of congenital idiopathic clubfoot. Also, no known mutations that cause distal arthrogryposis syndromes were found in the congenital idiopathic clubfoot patients.

Conclusion: These findings demonstrate that congenital idiopathic clubfoot has a different pathophysiology than the clubfoot seen in distal arthrogryposis syndromes, and defects in myosin are most likely not directly responsible for the development of congenital clubfoot. Given the complexity of early myogenesis, many regulatory candidate genes remain that could cause defects in the hypaxial musculature that is invariably observed in congenital idiopathic clubfoot.

Significance: This study further differentiates congenital idiopathic clubfoot as distinct from other complex genetic syndromes that can present with similar deformities, and thus facilitates further research to improve the clinical diagnosis and treatment of congenital idiopathic clubfoot.


Orthopaedic Proceedings
Vol. 93-B, Issue SUPP_II | Pages 206 - 206
1 May 2011
Morcuende J Kaushik A Martin J Zhang Q Sheffield V
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Introduction: Primary cilia are found on virtually every mammalian cell; however, functions of primary cilia have not been extensively studied in chondrocytes. Interestingly, defects in the primary cilium result in skeletal defects such as polydactyly in Bardet-Biedl Syndrome (Bbs), a ciliary disorder that also results in obesity and retinopathy.

Wild-type mice and mutant mice of the ciliary proteins Bbs1, Bbs2, and Bbs6 were evaluated for histological and biochemical differences in chondrocytes from articular cartilage. The aim was to examine cartilage abnormalities related to ciliary defects in Bbs mutant mice.

Methods: Using immunofluorescence microscopy, chondrocytic cilia were visualized from load-bearing joints. Knee joints were then embedded in paraffin, stained, and serially sectioned. Articular cartilage was analyzed microscopically to evaluate histological differences between wild-type and mutant mice. Separately, chondrocytes were expanded in cell culture and implanted in solid agarose plugs that were sectioned over two weeks to quantify differences between mouse strains.

Results: Significant differences in ciliary morphology were not identified between mouse strains. However, histological analysis revealed that Bbs mutant mice had significantly lower articular joint thickness (p< .05) and lower proteogly-can content saturation (p< .05) than wild-type. Moreover, there were significant cell distribution differences between mouse strains (p< .05), indicating that mutant cartilage had changes consistent with early osteoarthritis. In cell culture, the fraction of ciliated cells in Bbs mutant cultures was significantly lower than in wild-type cultures (p< .05).

Discussion/Conclusion: These data indicate that Bbs gene function plays a role in normal cartilage maintenance and suggest that the chondrocytic primary cilium contributes significantly to articular cartilage biochemistry.