Guillaume Jouret | Search PubMed

PubMed2025

Pathogenic XPO1 variants cause a dominant neurodevelopmental disorder.

PURPOSE: XPO1 functions in key cellular processes, including nucleo-cytoplasmic export and mitosis. The gene is deleted in a subset of patients with the 2p15p16.1 microdeletion syndrome; however, no monogenic XPO1-related disorder has been described to date. METHODS: We collected clinical data of individuals with de novo XPO1 variants through online matchmaking. We used Drosophila to study XPO1 function in development and habituation learning. RESULTS: A total of 22 individuals met the criteria to be included in the main study cohort. Of these, half have putative loss-of-function variants, and half have coding variants (10 missense and 1 in-frame deletion variant). We found an overlapping phenotype, consistent with a monogenic neurodevelopmental disorder. We demonstrate XPO1 functions in development by ubiquitous and neuron-specific knockdown in Drosophila. GABAergic neuron specific knockdown flies demonstrated impaired habituation. CONCLUSION: Our results establish XPO1 as a novel dominant monogenic neurodevelopmental disorder gene and demonstrate a central role for XPO1 in development.

Exportin 1 Protein↗

PubMed2024

Upregulation versus loss of function of NTRK2 in 44 affected individuals leads to 2 distinct neurodevelopmental disorders.

PURPOSE: Heterozygous pathogenic variants in NTRK2 (HGNC: 8032) have been associated with global developmental delay. However, only scattered cases have been described in small or general studies. The aim of our work was to consolidate our understanding of NTRK2-related disorders and to delineate the clinical presentation. METHODS: We reported an extended cohort of 44 affected individuals, of whom 19 are from the literature and 25 were previously unreported. RESULTS: Our analysis led to splitting the cohort into 2 entities. CONCLUSION: One group had variants in the cholesterol-binding motif of the transmembrane domain, with most of these being the recurrent variant c.1301A>G p.(Tyr434Cys). These variants probably lead to upregulation of tropomyosin receptor kinase B activity and to a severe phenotype of developmental delay/intellectual disability, muscular hypotonia, therapy-refractory epilepsy, visual impairment and blindness, and feeding difficulties. The second group had truncating variants or variants that presumably disturb the 3D structure of the protein leading to loss of function. These individuals had a remarkably milder phenotype of developmental delay, obesity, and hyperphagia.

Humans↗