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Rationale: Noonan syndrome (NS) is one of the most frequent genetic disorders. Bleeding problems are among the most common, yet poorly defined complications associated with NS. A lack of consensus on the management of bleeding complications in patients with NS indicates an urgent need for new therapeutic approaches.
Objective: Bleeding disorders have recently been described in patients with NS harboring mutations of LZTR1 (leucine zipper-like transcription regulator 1), an adaptor for CUL3 (CULLIN3) ubiquitin ligase complex. Here, we assessed the pathobiology of LZTR1-mediated bleeding disorders.
Methods And Results: Whole-body and vascular specific knockout of results in perinatal lethality due to cardiovascular dysfunction. deletion in blood vessels of adult mice leads to abnormal vascular leakage. We found that defective adherent and tight junctions in -depleted endothelial cells are caused by dysregulation of vesicular trafficking. LZTR1 affects the dynamics of fusion and fission of recycling endosomes by controlling ubiquitination of the ESCRT-III (endosomal sorting complex required for transport III) component CHMP1B (charged multivesicular protein 1B), whereas NS-associated mutations diminish CHMP1B ubiquitination. LZTR1-mediated dysregulation of CHMP1B ubiquitination triggers endosomal accumulation and subsequent activation of VEGFR2 (vascular endothelial growth factor receptor 2) and decreases blood levels of soluble VEGFR2 in haploinsufficient mice. Inhibition of VEGFR2 activity by cediranib rescues vascular abnormalities observed in knockout mice Conclusions: deletion phenotypically overlaps with bleeding diathesis observed in patients with NS. ELISA screening of soluble VEGFR2 in the blood of -mutated patients with NS may predict both the severity of NS phenotypes and potential responders to anti-VEGF therapy. VEGFR inhibitors could be beneficial for the treatment of bleeding disorders in patients with NS.
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http://dx.doi.org/10.1161/CIRCRESAHA.119.315730 | DOI Listing |
Eur J Pediatr
December 2024
Dept. of Research and Development, SeysCentra, Malden, The Netherlands.
Unlabelled: Children with Noonan syndrome-like RASopathies are at increased risk for developing feeding problems due to comorbid organic impairments at an early age, such as gastrointestinal problems or other organicity. Their feeding problems can ultimately often be classified as avoidant/restrictive food intake disorder, for which behavioral therapy is the first-choice treatment. The research question in this study is whether this treatment leads to similar results as in children without these RASopathies.
View Article and Find Full Text PDFHum Brain Mapp
December 2024
Division of Interdisciplinary Brain Sciences, Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, California, USA.
Neurodevelopmental disorders (NDDs) can severely impact functioning yet effective treatments are limited. Greater insight into the neurobiology underlying NDDs is critical to the development of successful treatments. Using a genetics-first approach, we investigated the potential of advanced diffusion-weighted imaging (DWI) techniques to characterize the neural microstructure unique to neurofibromatosis type 1 (NF1) and Noonan syndrome (NS).
View Article and Find Full Text PDFInt J Dev Neurosci
December 2024
Department of Pediatric Neurology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
Background: According to previous literature reports, PTPN11 gene variants account for approximately 50% of Noonan syndrome (NS) cases and 85% of Leopard syndrome (LS) cases. Several patients who were diagnosed with NS or LS complicated with Chiari I malformation (CIM) and/or syringomyelia have been reported to have a PTPN11 variant. However, it is not always clear whether the association between CIM and/or syringomyelia and PTPN11 variants is real or random.
View Article and Find Full Text PDFZhonghua Yi Xue Yi Chuan Xue Za Zhi
December 2024
Center for Obstetrics and Gynecology, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China.
Objective: To report on the phenotype of an adult patient with 2p23.2p22.1 duplication and explore its genotype-phenotype correlation.
View Article and Find Full Text PDFBackground And Aims: Neurofibromatosis-Noonan syndrome (NFNS) is an extremely rare genetic entity combining the clinical phenotype of two conditions: neurofibromatosis type 1 syndrome (NF1) and Noonan syndrome (NS). Nevertheless, many inconsistencies reside in our understanding of this condition, mainly its clinical features and genetic background. Through this systematic review, we aim to shed light on the epidemiological features, the broad clinical spectrum, the underlying genetic defects and the associated comorbidities of NFNS.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!