Phosphatidylinositol 4-kinase IIIα (PI4KIIIα/PI4KA/OMIM:600286) is a lipid kinase generating phosphatidylinositol 4-phosphate (PI4P), a membrane phospholipid with critical roles in the physiology of multiple cell types. PI4KIIIα’s role in PI4P generation requires its assembly into a heterotetrameric complex with EFR3, TTC7 and FAM126. Sequence alterations in two of these molecular partners, TTC7 (encoded by TTC7A or TCC7B) and FAM126, have been associated with a heterogeneous group of either neurological (FAM126A) or intestinal and immunological (TTC7A) conditions.Here we show that biallelic PI4KA sequence alterations in humans are associated with neurological disease, in particular hypomyelinating leukodystrophy. In addition, affected individuals may present with inflammatory bowel disease, multiple intestinal atresia and combined immunodeficiency. Our cellular, biochemical and structural modelling studies indicate that PI4KA-associated phenotypical outcomes probably stem from impairment of PI4KIIIα-TTC7-FAM126's organ-specific functions, due to defective catalytic activity or altered intra-complex functional interactions.Together, these data define PI4KA gene alteration as a cause of a variable phenotypical spectrum and provide fundamental new insight into the combinatorial biology of the PI4KIIIα-FAM126-TTC7-EFR3 molecular complex.
Infektiologische Präventivmaßnahmen bei Praktikantinnen und Praktikanten im Gesundheitsdienst und der Wohlfahrtspflege : aktualisierte Stellungnahme der Kommission für Infektionskrankheiten und Impffragen der DAKJ (April 2021) = Infectious disease-related preventive measures for trainees in healthcare service and welfare : updated statement of the Committee for Infectious Diseases and Vaccination Questions of the German Academy for Pediatric and Adolescent Medicine (April 2021)
von Jan Henje Driedger ; Julian Schröter ; Jerome Jüngling ; Saskia Biskup ; Kerstin A. Klotz ; Thomas Bast ; Tobias Dietel ; Christoph Korenke ; Sophie Christoph ; Heiko Brennenstuhl ; Guido Rubboli ; Rikke S. Møller ; Gaetan Lesca ; Yves Chaix ; Stefan Kölker ; Georg F. Hoffmann ; Johannes R. Lemke ; Steffen Syrbe
Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)-valine(406)-proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype-phenotype correlation, variability, and predicted functional impact of KCNA2 variants.
International journal of molecular sciences Basel : Molecular Diversity Preservation International, 2000 22(2021), 6, Artikel-ID 2824, Seite 1-16 Online-Ressource
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