10 research outputs found
Glucosamine reduces the inhibition of proteoglycan metabolism caused by local anaesthetic solution in human articular cartilage: an in vitro study
Recent advances in the aetiology of adolescent idiopathic scoliosis
The aetiology of adolescent idiopathic scoliosis (AIS) is still unknown despite many years of research effort. Theories on AIS’s aetiology have included mechanical, hormonal, metabolic, neuromuscular, growth, and genetic abnormalities. Amongst these, some factors may be epiphenomena rather than the cause itself. Other factors may even contribute to curve progression, rather than curve initiation. Current views maintain that AIS is a multifactorial disease with genetic predisposing factors [Lowe et al. in J Bone Joint Surg [Am] 82:1157–1168, 2000]. With improvements in diagnostic methods, imaging and genomics, there has been considerable recent work on aetiology. This review aims to bring readers up-to-date with the latest developments in scoliosis research
Structural and Ultrastructural Characteristics of Bone-Tendon Junction of the Calcaneal Tendon of Adult and Elderly Wistar Rats
Syndapin promotes pseudocleavage furrow formation by actin organization in the syncytial Drosophila
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Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling
The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.
We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.
Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory.
Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor β signaling and hippocampal function