Mis-spliced FMR1 transcripts in human fragile X syndrome neural progenitors and neurons.

Overview

1. Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Djavad Mowafaghian Centre for Brain Health, Edwin S. H. Leong Centre for Healthy Aging, Faculty of Medicine, British Columbia Children’s Hospital Research Institute, University of British Columbia, 950 West 28th Avenue, Vancouver, BC V5Z 4H4 Canada
2. Duke NUS Medical School, Singapore, Singapore
3. Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland

Abstract

Background: Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by loss of fragile X messenger ribonucleoprotein (FMRP). In most cases, this results from a CGG expansion exceeding 200 repeats in the 5’ untranslated region of the fragile X messenger ribonucleoprotein 1 (FMR1) gene, known as the “full mutation”. While the trinucleotide expansion has long been thought to induce epigenetic silencing of this locus, studies have shown that many males with a full mutation still express FMR1 mRNA. However, these individuals produce little to no FMRP protein, due to mechanisms that remain unclear. Mis-splicing of FMR1 transcripts with an expanded CGG tract has recently been proposed as a potential mechanism underlying the absence of FMRP in FXS tissues despite the presence of gene transcripts.

Methods: We used human neural progenitors and neurons differentiated from FXS human pluripotent stem cells and RNA-seq to examine splicing patterns of expanded FMR1 transcripts. We analyzed transcript structure and protein expression to validate mis-splicing mechanisms.

Results: We demonstrate an enrichment in levels of mis-spliced transcripts in human neural progenitors and neurons differentiated from FXS human pluripotent stem cells. Our findings confirm that expanded transcripts undergo aberrant splicing, which may contribute to the absence of FMRP despite transcriptional activity. We further show that pharmacological reactivation of the FMR1 locus results in expression of mis-spliced transcripts and that FMRP loss alone, in the absence of an expanded CGG tract, causes only a modest increase in splicing defect.

Conclusions: These results suggest that mis-splicing may represent one of several mechanisms contributing to the absence of FMRP in FXS, specifically in cases where transcriptional silencing of the FMR1 locus is incomplete and expanded transcripts are still produced. In these cases, expanded FMR1 transcripts are produced but undergo aberrant processing that prevents functional protein production. These findings have important implications for understanding FXS pathogenesis and developing therapeutic strategies targeting the expanded locus.

Supplementary Information: The online version contains supplementary material available at 10.1186/s11689-026-09686-0.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper links to its data, not to its authors' code: see the Data section.

Tracing map

A tracing map links a paper to the code its authors published: this paper has none, so it has no map.

Data

Datasets cited

• geo:GSE117248, at NCBI GEO; found in “Data availability”

Data availability

All data generated or analyzed during this study have been deposited in the GEO (GSE117248 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE117248) and GSE307114). Any additional information related to the current study is available from the corresponding author on reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 5 authors, 8 keywords, 9 MeSH terms, 3 funders, 35 references.

Cite

This paper

Hourani, S. M., Utami, K. H., Oh, S. L., Castrén, M. L., & Pouladi, M. A. (2026). Mis-spliced FMR1 transcripts in human fragile X syndrome neural progenitors and neurons. Journal of neurodevelopmental disorders, 18(1), 26. https://doi.org/10.1186/s11689-026-09686-0

Similar papers

The papers with a page that share the most with this one: the tools found in their code, their categories, datasets, cited references and authors, the rarest counting most.

[1] doi:10.1038/s41467-026-76976-5

Acoustic cell patterning reveals geometry- and substrate-dependent vasculogenesis and human embryo model development.

Journal: Nature communications

In common: developmental, 1 reference

[2] doi:10.1093/narmme/ugag028 [code]

MCVAE-based multi-omic anomaly detection in Fragile X Syndrome.

Journal: NAR molecular medicine

In common: genetics / omics, other condition, 1 reference

[3] doi:10.1371/journal.pone.0352693

Loss of Fmr1 reorganizes the multi-elemental composition across tissues in Fragile X Syndrome mice.

Journal: PloS one

In common: genetics / omics, other condition, 1 reference

[4] doi:10.1038/s41467-026-71919-6 [code]

Suppression of astrocyte BMP signaling improves molecular signatures and functional deficits in a fragile X syndrome mouse model.

Journal: Nature communications

In common: genetics / omics, other condition, 1 reference

[5] doi:10.1172/jci.insight.200106

HDAC6 inhibition alleviates mitochondrial trafficking in models of Charcot-Marie-Tooth disease type 2A.

Journal: JCI insight

In common: other condition, 1 reference

[6] doi:10.1002/aur.70312 [code]

Aberrant Neural Entrainment to Word-Level Speech Patterns in Fragile X Syndrome: Evidence for a Statistical Learning Deficit.

Journal: Autism research : official journal of the International Society for Autism Research

In common: other condition, 1 reference

[7] doi:10.1016/j.isci.2026.115267

Regulatory BC200 RNA promotes breast carcinogenesis by repressing BRCA1 gene expression.

Journal: iScience

In common: other condition, 1 reference

[8] doi:10.1002/cns.71074

Bard1-Mediated Regulation of Hnrnpa2b1 Ubiquitination and Protein Stability Contributes to Neuronal Ferroptosis and Cognitive Dysfunction Following Ischemic Stroke.

Journal: CNS neuroscience & therapeutics

In common: 1 reference

[9] doi:10.1016/j.ebiom.2026.106408 [code]

Microcephaly-like phenotype triggered by novel reassortant and prototypic Oropouche virus strains in brain organoids.

Journal: EBioMedicine

In common: developmental, genetics / omics, other condition

[10] doi:10.1016/j.mocell.2026.100387

USP15 mutation associated with autism spectrum disorder alters progenitor fate and neuronal maturation in human brain organoids.

Journal: Molecules and cells

In common: developmental, genetics / omics, other condition

Contribute

The authors of this paper can claim it, correct its record and validate its tracing map, and the maintainers of its code (its owner, or a public member of its organization) correct what it says of their repository; anyone signed in can ask for its removal. Every request goes to OSCR's own machine, which answers it; your account page follows them.

Request its removal

To ask OSCR to remove this record, the copies of its authors' scripts or its tracing map, use the removal request page: signed in, you say who you are, what to remove and why, then review and confirm the request. Published rules decide every request (how).

Discussion: questions and error reports about this paper and its code, from signed-in readers and its authors. It opens with sign-in.

Reproductions: reports from readers who ran the authors' code: what they reproduced, with which environment, commit and data. It opens with sign-in.

Activity: what happens around this paper: new versions of its record, its map's validation, discussions and reproductions. It opens with sign-in.