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A Congenital hydrocephalus-causing mutation in Trim71 induces stem cell defects via inhibiting Lsd1 mRNA translation

ABSTRACT: Congenital hydrocephalus (CH) is a major cause of childhood morbidity. Mono-allelic mutations in Trim71, a conserved stem-cell-specific RNA-binding protein, cause CH, however, the molecular basis for pathogenesis mediated by these mutations remains unknown. Here, using mouse embryonic stem cells as a model we reveal that the mouse R783H mutation (R796H in human) alters Trim71's mRNA substrate specificity and leads to accelerated stem-cell differentiation and neural lineage commitment. Mutant Trim71, but not wild-type Trim71, binds Lsd1 (Kdm1a) mRNA and represses its translation. Specific inhibition of this repression or a slight increase of Lsd1 in the mutant cells alleviates the defects in stem cell differentiation and neural lineage commitment. These results determine a functionally relevant target of the CH-causing Trim71 mutant that can potentially be a therapeutic target and provide molecular mechanistic insights into the pathogenesis of this disease.

SUBMITTER: Qiuying Liu

PROVIDER: S-SCDT-10_15252-EMBR_202255843 | biostudies-other |

REPOSITORIES: biostudies-other

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Studies on a hydrocephalus-causing mutation on Trim71

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Inhibiting MARSs reduces hyperhomocysteinemia-associated neural tube and congenital heart defects.

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A novel GJA8 mutation (p.V44A) causing autosomal dominant congenital cataract.

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