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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Molecular and cellular basis of hyperassembly and protein aggregation driven by a rare pathogenic mutation in DDX3X

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Fonseca, Matheus de Castro [1] ; de Oliveira, Juliana Ferreira [1] ; Silva Araujo, Bruno Henrique [1] ; Canateli, Camila [1] ; Vital do Prado, Paula Favoretti [1] ; Amorim Neto, Dionisio Pedro [2, 1] ; Bosque, Beatriz Pelegrini [2, 1] ; Rodrigues, Paulla Vieira [2, 1] ; Pereira de Godoy, Joao Vitor [2, 1] ; Tostes, Katiane [1] ; Ribeiro Filho, Helder Veras [1] ; Ziem Nascimento, Andrey Fabricio [3] ; Saito, Angela [1] ; Costa Tonoli, Celisa Caldana [1] ; Heleno Batista, Fernanda Aparecida [1] ; Lopes de Oliveira, Paulo Sergio [1] ; Figueira, Ana Carolina [1] ; da Costa, Silvia Souza [4] ; Victorino Krepischi, Ana Cristina [4] ; Rosenberg, Carla [4] ; Westfahl, Jr., Harry [3] ; Roque da Silva, Antonio Jose [3] ; Franchini, Kleber Gomes [1, 5]
Total Authors: 23
[1] Brazilian Ctr Res Energy & Mat CNPEM, Brazilian Biosci Natl Lab LNBio, 10000 Giuseppe Maximo Scolfaro St, BR-13083100 Campinas, SP - Brazil
[2] Univ Estadual Campinas, Dept Struct & Funct Biol, Campinas - Brazil
[3] Brazilian Ctr Res Energy & Mat CNPEM, Brazilian Synchrotron Light Natl Lab LNLS, Campinas - Brazil
[4] Univ Sao Paulo, Inst Biosci, Dept Genet & Evolutionary Biol, Sao Paulo, SP - Brazil
[5] Univ Estadual Campinas, Sch Med, Dept Internal Med, Campinas - Brazil
Total Affiliations: 5
Document type: Journal article
Source: ISCIENCE; v. 24, n. 8 AUG 20 2021.
Web of Science Citations: 0

Current studies estimate that 1-3% of females with unexplained intellectual disability ( ID) present de novo splice site, nonsense, frameshift, or missense mutations in the DDX3X protein (DEAD-Box Helicase 3 X-Linked). However, the cellular and molecular mechanisms by which DDX3X mutations impair brain development are not fully comprehended. Here, we show that the ID-linked missense mutation L556S renders DDX3X prone to aggregation. By using a combination of biophysical assays and imaging approaches, we demonstrate that this mutant assembles solid-like condensates and amyloid-like fibrils. Although we observed greatly reduced expression of the mutant allele in a patient who exhibits skewed X inactivation, this appears to be enough to sequestrate healthy proteins into solid-like ectopic granules, compromising cell function. Therefore, our data suggest ID-linked DDX3X L556S mutation as a disorder arising from protein misfolding and aggregation. (AU)

FAPESP's process: 18/20014-0 - The gut-brain connection: role of the gut microbioma in the outcome and development of the sporadic Parkinson's disease
Grantee:Matheus de Castro Fonseca
Support Opportunities: Regular Research Grants
FAPESP's process: 19/24511-0 - The role of LRRK2 and Rab GTPases in the neurodegeneration during sporadic Parkinson's Disease
Grantee:Beatriz Pelegrini Bosque
Support Opportunities: Scholarships in Brazil - Master
FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
Grantee:Mayana Zatz
Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC