Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome.

The homologous genes GTPBP1 and GTPBP2 encode GTP-binding proteins 1 and 2, which are involved in ribosomal homeostasis. Pathogenic variants in GTPBP2 were recently shown to be an ultra-rare cause of neurodegenerative or neurodevelopmental disorders (NDDs). Until now, no human phenotype has been linked to GTPBP1. Here, we describe individuals carrying bi-allelic GTPBP1 variants that display an identical phenotype with GTPBP2 and characterize the overall spectrum of GTP-binding protein (1/2)-related disorders. In this study, 20 individuals from 16 families with distinct NDDs and syndromic facial features were investigated by whole-exome (WES) or whole-genome (WGS) sequencing. To assess the functional impact of the identified genetic variants, semi-quantitative PCR, western blot, and ribosome profiling assays were performed in fibroblasts from affected individuals. We also investigated the effect of reducing expression of CG2017, an ortholog of human GTPBP1/2, in the fruit fly Drosophila melanogaster. Individuals with bi-allelic GTPBP1 or GTPBP2 variants presented with microcephaly, profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. Abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Cell line studies identified a loss-of-function (LoF) impact of the disease-associated variants but no significant abnormalities on ribosome profiling. Reduced expression of CG2017 isoforms was associated with locomotor impairment in Drosophila. In conclusion, bi-allelic GTPBP1 and GTPBP2 LoF variants cause an identical, distinct neurodevelopmental syndrome. Mutant CG2017 knockout flies display motor impairment, highlighting the conserved role for GTP-binding proteins in CNS development across species

Effects of computer keyboarding on ultrasonographic measures of the median nerve

Background: Keyboarding is a highly repetitive daily task and has been linked to musculoskeletal disorders of the upper extremity. However, the effect of keyboarding on median nerve injuries is not well understood. The purpose of this study was to use ultrasonographic measurements to determine whether continuous keyboarding can cause acute changes in the median nerve. Methods: Ultrasound images of the median nerve from 21 volunteers were captured at the levels of the pisiform and distal radius prior to and following a prolonged keyboarding task (i.e., 1hr of continuous keyboarding). Images were analyzed by a blinded investigator to quantify the median nerve characteristics. Changes in the median nerve ultrasonographic measures as a result of continuous keyboarding task were evaluated. Results: Cross-sectional areas at the pisiform level were significantly larger in both dominant (P=0.004) and non-dominant (P=0.001) hands following the keyboarding task. Swelling ratio was significantly greater in the dominant hand (P=0.020) after 60min of keyboarding when compared to the baseline measures. Flattening ratios were not significantly different in either hand as a result of keyboarding. Conclusion: We were able to detect an acute increase in the area of the median nerve following 1hr of keyboarding with a computer keyboard. This suggests that keyboarding has an impact on the median nerve. Further studies are required to understand this relationship, which would provide insight into the pathophysiology of median neuropathies such as carpal tunnel syndrome. © 2011 Wiley Periodicals, Inc

The effects of long-term spinal cord injury on mechanical properties of the rat urinary bladder

We have demonstrated that bladder wall tissue in spinal cord injury (SCI) rats at 10 days post-injury is more compliant and accompanied by changes in material class from orthotropic to isotropic as compared to normal tissue. The present study examined the long-term effects (3-, 6-, and 10-weeks) post-SCI on the mechanical properties of bladder wall tissues, along with quantitative changes in smooth muscle orientation and collagen and elastin content. Bladder wall compliance (defined as det(F) - 1 under an equi-biaxial stress state of 100 kPa, where F is the deformation gradient tensor) was found to be significantly greater at 3- and 6-weeks (0.873 ± 0.092 and 0.864 ± 0.112, respectively) when compared to the normal bladders (0.260 ± 0.028), but at 10 weeks the compliance reduced (0.389 ± 0.061) to near that of normal bladders. This trend in mechanical compliance closely paralleled the collagen/elastin ratio. Moreover, changes in material class, assessed using a graphical technique, correlated closely with quantitative changes in smooth muscle fiber orientation. The results of the present study provide the first evidence that, while similarities exist between acute and chronic responses of the urinary bladder wall tissue to SCI, the overall alterations are distinct, result in profound and complex time dependent changes in bladder wall structure, and will lay the basis for simulations of the bladder wall disease process. © 2008 Biomedical Engineering Society

Quantification of bladder smooth muscle orientation in normal and spinal cord injured rats

Spinal cord injuries (SCI) often lead to severe bladder dysfunctions. Our previous studies have demonstrated that following SCI, rat bladder wall tissue became hypertrophied, significantly more compliant, and changed its mechanical behavior from orthotropic to isotropic. In order to elucidate the link between the tissue microstructure and mechanical properties of the wall, we have developed a novel semi-automated image analysis method to quantify smooth muscle bundle orientation and mass fraction in the bladder wall tissues from normal and 10 day-post-SCI rats. Results of the present study revealed that there were significant (p < 0.05) increases in smooth muscle area fractions as well as significantly (p < 0.001) fewer cell nuclei per muscle area in the SCI groups compared to the normal groups. Furthermore, while the normal rat bladders exhibited predominant smooth muscle orientation only in the longitudinal direction, the SCI rat bladders exhibited smooth muscles oriented in both the circumferential and longitudinal directions. These results provide first evidence that bladder smooth muscle cells exhibit hypertrophy rather than hyperplasia and developed a second, orthogonal orientation of smooth muscle bundles following SCI. The results of the present study corroborate our previous mechanical anisotropy data and provide the basis for development of structure-based constitutive models for urinary bladder wall tissue. © 2005 Biomedical Engineering Society