Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.

BACKGROUND: Bone dysplasias are a large group of disorders affecting the growth and structure of the skeletal system. METHODS: In the present study, we report the clinical and molecular delineation of a new form of syndromic autosomal recessive spondylometaphyseal dysplasia (SMD) in two Emirati first cousins. They displayed postnatal growth deficiency causing profound limb shortening with proximal and distal segments involvement, narrow chest, radiological abnormalities involving the spine, pelvis and metaphyses, corneal clouding and intellectual disability. Whole genome homozygosity mapping localised the genetic cause to 11q12.1-q13.1, a region spanning 19.32 Mb with ~490 genes. Using whole exome sequencing, we identified four novel homozygous variants within the shared block of homozygosity. Pathogenic variants in genes involved in phospholipid metabolism, such as PLCB4 and PCYT1A, are known to cause bone dysplasia with or without eye anomalies, which led us to select PLCB3 as a strong candidate. This gene encodes phospholipase C ß 3, an enzyme that converts phosphatidylinositol 4,5 bisphosphate (PIP2) to inositol 1,4,5 triphosphate (IP3) and diacylglycerol. RESULTS: The identified variant (c.2632G>T) substitutes a serine for a highly conserved alanine within the Ha2' element of the proximal C-terminal domain. This disrupts binding of the Ha2' element to the catalytic core and destabilises PLCB3. Here we show that this hypomorphic variant leads to elevated levels of PIP2 in patient fibroblasts, causing disorganisation of the F-actin cytoskeleton. CONCLUSIONS: Our results connect a homozygous loss of function variant in PLCB3 with a new SMD associated with corneal dystrophy and developmental delay (SMDCD).

Lipid profile, inflammatory biomarkers, endothelial dysfunction, and heart rate variability in adolescents with type 1 diabetes. A case-control study among UAE population.

Background: Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by the chronic inflammation and cause of endothelial dysfunction (ED). Heart rate variability (HRV) is a marker of sympathetic and parasympathetic autonomic nervous system dysfunction. We investigated the association of lipid profile, inflammatory biomarkers, endothelial dysfunction, and heart rate variability in adolescents with T1DM among UAE population. Method: In this case-control study we recruited 126 adolescents (13-22 years) from Abu Dhabi, UAE (United Arab Emirates). Demographic, anthropometric, blood and urine samples were collected after an overnight fasting. HRV measurements were determined per Task Force recommendations. Independent t-test or Mann-Whitney U test and Pearson's Chi-squared test were used to compare groups. Adjusted conditional logistic regression model was used to identify the determinants independently associated with T1DM. Results: The mean ages in control (n = 47) and patient (n = 79) groups were 17.5 ± 4.6 and 18.6 ± 4.8 years, respectively. A family history of diabetes and waist and hip circumferences significantly differed between the groups (p = 0.030 and 0.010). The patients with T1DM exhibited significantly higher levels of atherogenic markers than control. Endothelial dysfunction biomarkers such as levels of sICAM-1 (p < 0.001), adiponectin (p < 0.001) and 25-hydroxyvitamin D (p < 0.001) were significantly different in the control group compared with those in the T1DM group. There was a significant difference in SDNN intervals, NN50, pNN50, and SD1/SD2 among the two groups. In adjusted analysis, total cholesterol (adjusted Odds Ratio (aOR): 2.78, 95 % CI:1.37-5.64; p = 0.005), LDL (2.66, 95%CI:1.19-5.92; p = 0.017), and triglycerides (5.51, 95%CI:1.57-19.41; p = 0.008) were significantly associated with developing T1DM. The HRV indicators were significantly associated with decrease odds of T1DM after controlling for SBP, BMI, and family history of DM. Conclusion: In this study, adolescents with T1DM showed a significant association with lipid profile, ED, and HRV compared with controls. Thus, an early attention to diabetes control is required to reduce the risk of cardiac autonomic neuropathy leading to various cardiovascular diseases.

Cross-Sectional Association Between Body Fat Composition and Biomarkers of Inflammation and Endothelial Dysfunction in Children with Overweight/Obesity.

Background: Childhood obesity is most prevalent nutritional disorder worldwide. Studies on clinical correlations between body fat (BF) composition, lipid profile, inflammatory biomarkers, and endothelial dysfunction (ED) parameters in children from United Arab Emirates (UAE) are limited. Therefore, we aimed to study obesity pattern in children and determine clinical correlations with biomarkers. Methods: Children (6-13 years) from different schools were divided into obese, overweight, and normal groups based upon Centers for Disease Control and Prevention weight-for-age centiles study (n=166). Anthropometric, BF composition, lipid profile, inflammatory, and ED biomarkers were determined and analyzed using SPSS software. Results: The mean age and weight ± SD of participants were 10.6 ± 2.6 years and 48.2 ± 19.5 kg with 65% as overweight or obese. In normal, overweight, and obese group male were 40 (70.2%), 35 (67.3%), and 40 (70.2%) and female were 17 (29.8%), 17 (32.7%) and 17 (29.8%). There was significant difference in age (p<0.01), height (p< 0.01), weight (p< 0.01) among groups. Obesity markers (MCP-1, leptin, adiponectin) showed positive correlation with age, height, weight, WC, BF%, body fat mass (BFM), body muscle mass (BMM). A significant correlation (all p<0.01) of BMM with SBP (r=0.412), DBP (r=0.255), MCP-1 (r=0.558), adiponectin (r=0.635), hs-CRP (r=0.263), IL-6 (r=0.348), TNF-alpha (r=0.370), ICAM-1 (r=0.237), and VCAM-1 (r=0.343). The inflammatory markers (ICAM-1, VCAM-1) showed significant correlations with age, height, weight, WC, BF%, BFM, BMM. Leptin significantly (all p<0.01) correlated with age (r=0.470), height (r=0.423), weight (r=0.677), WC (r=0.606), BF (r=0.700), BFM (r=0.752), and BMM (r=0.524) and negatively correlated with TBW (r=-0.701). Adiponectin also showed a significant (all p<0.01) positive correlation with age, height, weight, WC, BF, BFM, and BMM. Conclusion: A strong association between BF composition, lipid profile, and inflammatory and ED biomarkers was observed in the study. Thus, immediate measures should be implemented to reduce risk of obesity and associated diseases.