TRIM71 – Congenital Hydrocephalus

This summary evaluates the association of TRIM71 (HGNC:32669) with congenital hydrocephalus (MONDO_0016349) based on multiple lines of evidence. Several independent studies have identified mono-allelic, de novo variants in TRIM71 as a strong genetic contributor to congenital hydrocephalus, with the clinical presentations including severe ventriculomegaly and other structural brain anomalies. The evidence spans detailed case reports, multi-patient cohort analyses, and robust functional studies, which together support the pathogenic role of TRIM71 disruptions in neurodevelopment.

Case report data have documented individual patients harboring TRIM71 mutations. For instance, the EMBO reports (2023) study demonstrated that a mutation, exemplified by the variant c.2337G>A (p.Arg783His), leads to altered mRNA substrate specificity causing accelerated stem cell differentiation and neural lineage commitment (PMID:36573342). Additional case-level studies noted that these mutations consistently occur in regions critical for RNA binding, implicating a gain-of-function mechanism that perturbs normal stem cell homeostasis.

The multi-patient study published in Brain : a journal of neurology (2024) provides compelling genetic evidence based on a cohort of 2697 parent–proband trios (PMID:38833623). In this study, 13 protein-altering, de novo TRIM71 variants were identified in unrelated patients. The recurrence of arginine substitutions, including variants akin to c.2337G>A (p.Arg783His), alongside segregating familial findings, strongly supports a definitive role for TRIM71 in the etiology of congenital hydrocephalus.

Complementary functional studies further substantiate this association. Experimental models have shown that mutant TRIM71 proteins lose specificity in binding to key mRNAs such as Lsd1 and fail to regulate downstream targets, leading to aberrant neural stem cell differentiation (PMID:36573342; PMID:31371437). These results are bolstered by in vitro rescue experiments and altered subcellular localization patterns noted in patient-derived cell models, which are consistent with the clinical manifestations observed. Although the mechanistic details vary slightly between different mutations, the overall disruptive effect on normal neurodevelopment is clear.

Integrating the genetic and experimental data, the evidence for the association of TRIM71 with congenital hydrocephalus is strong. The recurrent detection of de novo variants, corroborative segregation data in large cohorts, and consistent functional abnormalities collectively underscore the gene’s pathogenic role. While alternative gain-of-function mechanisms have been proposed, no studies have definitively refuted this link. In summary, the converging lines of evidence not only support the clinical utility of TRIM71 as a diagnostic biomarker but also pave the way for targeted therapeutic strategies.

Key Take‑home: The robust genetic and functional evidence for TRIM71 mutations in congenital hydrocephalus substantiates its role as a critical driver of neurodevelopmental disease, providing a reliable basis for diagnostic decision‑making and potential precision therapies.

References

• EMBO reports • 2023 • A congenital hydrocephalus-causing mutation in Trim71 induces stem cell defects via inhibiting Lsd1 mRNA translation PMID:36573342
• PLoS biology • 2023 • Different congenital hydrocephalus-associated mutations in Trim71 impair stem cell differentiation via distinct gain-of-function mechanisms PMID:36757932
• Brain : a journal of neurology • 2024 • TRIM71 mutations cause a neurodevelopmental syndrome featuring ventriculomegaly and hydrocephalus PMID:38833623

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