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Background SHROOM4 is thought to play an important role in cytoskeletal modification and development of the early nervous system. Previously, single-nucleotide variants (SNVs) or copy number variations (CNVs) in SHROOM4 have been associated with the neurodevelopmental disorder Stocco dos Santos syndrome, but not with congenital anomalies of the urinary tract and the visceral or the cardiovascular system.MethodsHere, exome sequencing and CNV analyses besides expression studies in zebrafish and mouse and knockdown (KD) experiments using a splice blocking morpholino in zebrafish were performed to study the role of SHROOM4 during embryonic development.ResultsIn this study, we identified putative disease-causing SNVs and CNVs in SHROOM4 in six individuals from four families with congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems (CNS). Embryonic mouse and zebrafish expression studies showed Shroom4 expression in the upper and lower urinary tract, the developing cloaca, the heart and the cerebral CNS. KD studies in zebrafish larvae revealed pronephric cysts, anomalies of the cloaca and the heart, decreased eye-to-head ratio and higher mortality compared with controls. These phenotypes could be rescued by co-injection of human wild-type SHROOM4 mRNA and morpholino.ConclusionThe identified SNVs and CNVs in affected individuals with congenital anomalies of the urinary tract, the anorectal, the cardiovascular and the central nervous systems, and subsequent embryonic mouse and zebrafish studies suggest SHROOM4 as a developmental gene for different organ systems.

Monogenic diabetes is a rare disease caused by single gene mutations. Maturity onset diabetes of the young (MODY) is one of the major forms of monogenic diabetes recognised in the paediatric population. To date, 13 genes have been related to MODY development. The aim of the study was to analyse the sequence of the BCL2-associated agonist of cell death (BAD) gene in patients with clinical suspicion of GCK-MODY, but who were negative for glucokinase (GCK) gene mutations. A group of 122 diabetic patients were recruited from the \"Polish Registry for Paediatric and Adolescent Diabetes - nationwide genetic screening for monogenic diabetes\" project. The molecular testing was performed by Sanger sequencing. A total of 10 sequence variants of the BAD gene were identified in 122 analysed diabetic patients. Among the analysed patients suspected of MODY, one possible pathogenic variant was identified in one patient; however, further confirmation is required for a certain identification.

Wolfram syndrome (WFS) is inherited as an autosomal recessive disease with main clinical features of diabetes mellitus, optic atrophy, diabetes insipidus and deafness. However, various neurological defects may also be detected. The aim of this study was to evaluate aspects of brain structure and function using PET-CT (positron emission tomography and computed tomography) and MRI (magnetic resonance imaging) in pediatric patients with WFS. Regional changes in brain glucose metabolism were measured using standardized uptake values (SUVs) based on images of (18F) fluorodeoxyglucose (FDG) uptake in 7 WFS patients aged 10.1-16.0 years (mean 12.9±2.4) and in 20 healthy children aged 3-17.9 years (mean 12.8±4.1). In all patients the diagnosis of WFS was confirmed by DNA sequencing of the WFS1 gene. Hierarchical clustering showed remarkable similarities of glucose uptake patterns among WFS patients and their differences from the control group. SUV data were subsequently standardized for age groups <13 years old and>13 years old to account for developmental differences. Reduced SUVs in WFS patients as compared to the control group for the bilateral brain regions such as occipital lobe (-1.24±1.20 vs. -0.13±1.05; p = 0.028) and cerebellum (-1.11±0.69 vs. -0.204±1.00; p = 0.036) were observed and the same tendency for cingulate (-1.13±1.05 vs. -0.15±1.12; p = 0.056), temporal lobe (-1.10±0.98 vs. -0.15±1.10; p = 0.057), parietal lobe (-1.06±1.20 vs. -0.08±1.08; p = 0.058), central region (-1.01±1.04 vs. -0.09±1.06; p = 0.060), basal ganglia (-1.05±0.74 vs. -0.20±1.07; p = 0.066) and mesial temporal lobe (-1.06±0.82 vs. -0.26±1.08; p = 0.087) was also noticed. After adjusting for multiple hypothesis testing, the differences in glucose uptake were non-significant. For the first time, regional differences in brain glucose metabolism among patients with WFS were shown using PET-CT imaging.

Background Tuberous sclerosis (TSC) is a monogenic disease resulting from defects of the TSC1 or TSC2 genes, which encode the proteins forming hamartin-tuberin tumor suppressor complex, the mammalian target of rapamycin complex (mTOR). The mTOR pathway is constitutively activated in response to tuberin or hamartin defects. The mTOR pathway is also regulated by a multitude of epigenetic mechanisms, one of which is regulation by microRNA (miRNA) inhibition. This leads us to hypothesize that organ-level abnormalities of miRNA expression patterns are widespread in TSC. The aim of the study was to evaluate the serum profiles of miRNAs in patients with TSC and subependymal giant cell astrocytoma (SEGA) treated with mTOR inhibitor (everolimus). Methods Serum microRNA profiling was performed in 10 TSC-patients before and three months after everolimus treatment, as well as in 10 sex- and age-matched healthy controls. MicroRNAs were profiled using qPCR panels (Exiqon). Results Of 752 tested miRNAs, 11 showed statistically significant dysregulation in patients with TSC in comparison to controls. The following miRNAs were downregulated in TSC: miR-142-3p, miR-199a-5p, miR-142-5p and miR-136-5p; while miR-130a-3p, miR-378a-3p, miR-130b-3p, miR-192-5p, miR-25-3p, miR-215-5p and miR-222-3p were upregulated in TSC in comparison to the control group. After three months of everolimus treatment, mean dose 5.1 (2.6-9.7) mg/m 2 , seven miRNAs reached expression levels similar to healthy controls, with miR-142-3p and miR-136 showed significant increase over baseline levels in TSC patients. Moreover, miR-222-3p normalization due to treatment differed between patients with mutation in TSC1 and TSC2 gene. Conclusions Activation of the mTOR pathway in TSC patients alters serum miRNA levels, which may be partially reversed by an mTOR inhibitor. This indicates the involvement of miRNA dysregulation in the pathogenesis of TSC, linking miRNA profiles with treatment efficiency.