Details

Autor(en) / Beteiligte

• Brugger, Melanie
• Lauri, Antonella
• Zhen, Yan
• Gramegna, Laura L.
• Zott, Benedikt
• Sekulić, Nikolina
• Fasano, Giulia
• Kopajtich, Robert
• Cordeddu, Viviana
• Radio, Francesca Clementina
• Mancini, Cecilia
• Pizzi, Simone
• Paradisi, Graziamaria
• Zanni, Ginevra
• Vasco, Gessica
• Carrozzo, Rosalba
• Palombo, Flavia
• Tonon, Caterina
• Lodi, Raffaele
• La Morgia, Chiara
• Arelin, Maria
• Blechschmidt, Cristiane
• Finck, Tom
• Sørensen, Vigdis
• Kreiser, Kornelia
• Strobl-Wildemann, Gertrud
• Daum, Hagit
• Michaelson-Cohen, Rachel
• Ziccardi, Lucia
• Zampino, Giuseppe
• Prokisch, Holger
• Abou Jamra, Rami
• Fiorini, Claudio
• Arzberger, Thomas
• Winkelmann, Juliane
• Caporali, Leonardo
• Carelli, Valerio
• Stenmark, Harald
• Tartaglia, Marco
• Wagner, Matias

Titel

Bi-allelic variants in SNF8 cause a disease spectrum ranging from severe developmental and epileptic encephalopathy to syndromic optic atrophy

Ist Teil von

• American journal of human genetics, 2024-03, Vol.111 (3), p.594-613

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2024

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• The endosomal sorting complex required for transport (ESCRT) machinery is essential for membrane remodeling and autophagy and it comprises three multi-subunit complexes (ESCRT I-III). We report nine individuals from six families presenting with a spectrum of neurodevelopmental/neurodegenerative features caused by bi-allelic variants in SNF8 (GenBank: NM_007241.4), encoding the ESCRT-II subunit SNF8. The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy, massive reduction of white matter, hypo-/aplasia of the corpus callosum, neurodevelopmental arrest, and early death. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile). In patient-derived fibroblasts, bi-allelic SNF8 variants cause loss of ESCRT-II subunits. Snf8 loss of function in zebrafish results in global developmental delay and altered embryo morphology, impaired optic nerve development, and reduced forebrain size. In vivo experiments corroborated the pathogenicity of the tested SNF8 variants and their variable impact on embryo development, validating the observed clinical heterogeneity. Taken together, we conclude that loss of ESCRT-II due to bi-allelic SNF8 variants is associated with a spectrum of neurodevelopmental/neurodegenerative phenotypes mediated likely via impairment of the autophagic flux. We identified bi-allelic variants in SNF8, encoding a subunit of the ESCRT-II complex, in individuals presenting with a disease spectrum ranging from epileptic encephalopathy to syndromic optic atrophy—findings also present in a zebrafish model. Functional experiments suggest impaired autophagic flux as the disease mechanism.