AMFR dysfunction causes autosomal recessive spastic paraplegia in human that is amenable to statin treatment in a preclinical model.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Deng Ruizhi, Medico-Salsench Eva, Nikoncuk Anita, Ramakrishnan Reshmi, Lanko Kristina, Kühn Nikolas A, van der Linde Herma C, Lor-Zade Sarah, Albuainain Fatimah, Shi Yuwei, Yousefi Soheil, Capo Ivan, van den Herik Evita Medici, van Slegtenhorst Marjon, van Minkelen Rick, Geeven Geert, Mulder Monique T, Ruijter George J G, Lütjohann Dieter, Jacobs Edwin H, Houlden Henry, Pagnamenta Alistair T, Metcalfe Kay, Jackson Adam, Banka Siddharth, De Simone Lenika, Schwaede Abigail, Kuntz Nancy, Palculict Timothy Blake, Abbas Safdar, Umair Muhammad, AlMuhaizea Mohammed, Colak Dilek, AlQudairy Hanan, Alsagob Maysoon, Pereira Catarina, Trunzo Roberta, Karageorgou Vasiliki, Bertoli-Avella Aida M, Bauer Peter, Bouman Arjan, Hoefsloot Lies H, van Ham Tjakko J, Issa Mahmoud, Zaki Maha S, Gleeson Joseph G, Willemsen Rob, Kaya Namik, Arold Stefan T, Maroofian Reza, Sanderson Leslie E, Barakat Tahsin Stefan
Аннотация
Hereditary spastic paraplegias (HSP) are rare, inherited neurodegenerative or neurodevelopmental disorders that mainly present with lower limb spasticity and muscle weakness due to motor neuron dysfunction. Whole genome sequencing identified bi-allelic truncating variants in AMFR, encoding a RING-H2 finger E3 ubiquitin ligase anchored at the membrane of the endoplasmic reticulum (ER), in two previously genetically unexplained HSP-affected siblings. Subsequently, international collaboration recognized additional HSP-affected individuals with similar bi-allelic truncating AMFR variants, resulting in a cohort of 20 individuals from 8 unrelated, consanguineous families. Variants segregated with a phenotype of mainly pure but also complex HSP consisting of global developmental delay, mild intellectual disability, motor dysfunction, and progressive spasticity. Patient-derived fibroblasts, neural stem cells (NSCs), and in vivo zebrafish modeling were used to investigate pathomechanisms, including initial preclinical therapy assessment. The absence of AMFR disturbs lipid homeostasis, causing lipid droplet accumulation in NSCs and patient-derived fibroblasts which is rescued upon AMFR re-expression. Electron microscopy indicates ER morphology alterations in the absence of AMFR. Similar findings are seen in amfra-/- zebrafish larvae, in addition to altered touch-evoked escape response and defects in motor neuron branching, phenocopying the HSP observed in patients. Interestingly, administration of FDA-approved statins improves touch-evoked escape response and motor neuron branching defects in amfra-/- zebrafish larvae, suggesting potential therapeutic implications. Our genetic and functional studies identify bi-allelic truncating variants in AMFR as a cause of a novel autosomal recessive HSP by altering lipid metabolism, which may potentially be therapeutically modulated using precision medicine with statins.