Research shows actin mutations result in reduced brain organoid size in Baraitser-Winter syndrome — Evidence Review

A new study finds that a single mutation in actin genes can permanently reduce brain growth by disrupting the division of early brain progenitor cells. Related research broadly supports these findings, highlighting the crucial role of cytoskeletal proteins in neurodevelopment and brain structure, as seen in other genetic syndromes and models (2, 3, 6).

• Mutations in other cytoskeletal or chromatin-remodeling genes, such as ACTB and ACTL6B, are also linked to abnormal neurodevelopment, supporting the new study's focus on actin's pivotal role in brain growth (2, 3).
• Abnormalities in cell division, migration, and the balance of neuronal cell types are recurring mechanisms in studies of neurodevelopmental disorders, aligning with this study's findings about altered progenitor cell division orientation (1, 2, 6).
• Broader genetic research into brain structure demonstrates that both rare and common variants affecting cytoskeletal and signaling pathways can influence brain growth trajectories, reinforcing the relevance of actin mutations in human neurodevelopment (4, 6).

Study Overview and Key Findings

Understanding the genetic and cellular mechanisms behind microcephaly is a major challenge in neurodevelopmental research. This study is particularly significant as it uses patient-derived brain organoids to directly model the effects of actin mutations observed in Baraitser-Winter syndrome, allowing unprecedented insights into the early developmental events that determine brain size. The research bridges molecular genetics and organoid technology, illustrating how subtle defects at the cellular level can have lifelong consequences for brain structure.

Property	Value
Study Year	2025
Organization	German Primate Center – Leibniz Institute for Primate Research, Hannover Medical School, Max Planck Institute of Molecular Cell Biology and Genetics
Journal Name	EMBO Reports
Authors	Indra Niehaus, Michaela Wilsch-Bräuninger, Felipe Mora-Bermúdez, Fabian Rost, Mihaela Bobic-Rasonja, Velena Radosevic, Marija Milkovic-Perisa, Pauline Wimberger, Mariasavina Severino, Alexandra Haase, Ulrich Martin, Karolina Kuenzel, Kaomei Guan, Katrin Neumann, Noreen Walker, Evelin Schröck, Natasa Jovanov-Milosevic, Wieland B Huttner, Nataliya Di Donato, Michael Heide
Population	Patients with Baraitser-Winter syndrome
Methods	In Vitro Study
Outcome	Effects of actin mutations on brain organoid development
Results	Organoids with actin mutations were 25% smaller than controls.

Literature Review: Related Studies

To contextualize these findings, we searched the Consensus paper database, which includes over 200 million research papers. We used the following search queries to identify relevant related studies:

1. actin mutation brain growth effects
2. organoid size comparison actin mutations
3. long-term impact brain growth mutations

Topic	Key Findings
How do actin and other cytoskeletal gene mutations impact neurodevelopment?	- Mutations in actin-related genes (e.g., ACTB, ACTL6B) cause developmental syndromes with intellectual disability, brain malformations, and altered cell proliferation and migration (2, 3). - Mouse and human cell studies show that cytoskeletal disruptions affect neuronal morphology, proliferation, and gene expression, sometimes leading to microcephaly or other brain growth abnormalities (2, 3, 6).
What mechanisms link genetic mutations to abnormal brain growth and cell allocation?	- Altered orientation and balance of neuronal progenitor cell division—often due to cytoskeletal or signaling pathway mutations—can drive abnormal brain size, as seen in PTEN and β-catenin pathway disruptions (6, 7). - Changes in the timing and type of neuronal cell differentiation are tied to brain size abnormalities, with similar patterns observed in both rare genetic syndromes and common variants affecting brain development (4, 6).
Are the effects of brain growth mutations specific or do they affect other organs?	- ACTB mutations impact not only the brain but also heart and kidney development, highlighting the systemic effects of some cytoskeletal gene mutations (2). - Other chromatin-remodeling and cytoskeletal gene disorders show overlapping patterns of multiorgan malformations, suggesting that disrupted cytoskeletal functions can have pleiotropic consequences (2, 3).
How do cell-level changes translate to clinical or anatomical outcomes?	- Mutations that disrupt actin or related pathways can reduce brain size or alter neuronal connectivity, correlating with clinical features such as intellectual disability, epilepsy, or autism spectrum disorders (1, 2, 3, 5). - Both rare and common variants may influence brain growth trajectories, with downstream impacts on cognition and neurological health across the lifespan (4, 5, 6).

How do actin and other cytoskeletal gene mutations impact neurodevelopment?

The current study's findings are consistent with prior research indicating that mutations in actin or actin-associated genes can have widespread effects on brain development. Both ACTB and ACTL6B mutations have been shown to cause intellectual disability and brain malformations, with cellular changes including reduced proliferation, altered morphology, and impaired migration (2, 3). These results reinforce the importance of actin and related cytoskeletal proteins in neural progenitor cell function and brain growth.

• ACTB loss-of-function mutations decrease cell proliferation and alter cell shape and migration, leading to multi-organ developmental defects (2).
• ACTL6B mutations result in dendritic loss, neurodevelopmental deficits, and epilepsy through altered regulation of cytoskeletal genes (3).
• The new study's focus on division orientation and progenitor cell renewal echoes cellular mechanisms observed in earlier work on cytoskeletal gene mutations (2, 3).
• Disruption of the cytoskeleton, whether in actin or associated complexes, appears to be a convergent mechanism for several neurodevelopmental disorders (2, 3).

What mechanisms link genetic mutations to abnormal brain growth and cell allocation?

Research has established that abnormal orientation of progenitor cell division and imbalances in cell differentiation can result from various genetic mutations, leading to changes in brain size. The new study adds to this by showing that actin mutations cause a shift in division orientation and a reduction in apical progenitor cell renewal, producing smaller brain organoids—a mechanism also implicated in PTEN and β-catenin pathway models (6, 7).

• Mutations in PTEN and β-catenin signaling balance are known to disrupt brain growth trajectories through effects on neuronal and glial cell production (6).
• mTOR pathway mutations can induce self-reinforcing effects on dendritic growth, affecting overall brain morphology (7).
• The altered balance between apical and basal progenitor cells seen in the new study parallels findings in other models of disrupted brain development (6).
• Both rare mutations (e.g., in actin genes) and more common genetic variants can affect the cellular mechanisms guiding brain growth (4, 6).

Are the effects of brain growth mutations specific or do they affect other organs?

While the present study focuses on brain organoids, related research shows that cytoskeletal gene mutations often have effects beyond the brain. For example, ACTB mutations result in malformations in the heart and kidneys as well as the brain, underscoring the pleiotropic roles of cytoskeletal proteins (2). This suggests that interventions targeting these pathways may need to consider systemic as well as neurological effects.

• ACTB haploinsufficiency leads to a distinct syndrome with brain, heart, and kidney malformations (2).
• Some chromatin-remodeling disorders with cytoskeletal involvement display multiorgan developmental anomalies (2, 3).
• The non-neural impacts of cytoskeletal gene mutations highlight shared developmental mechanisms across organ systems (2, 3).
• Understanding the tissue specificity of these effects remains a critical area for future study (2).

How do cell-level changes translate to clinical or anatomical outcomes?

Clinical manifestations such as microcephaly, intellectual disability, and epilepsy can be traced back to disruptions in the cytoskeleton and related pathways at the cellular level. The current study connects altered cell division in organoids to reduced brain size, paralleling findings in both rare syndromes and broader population studies of brain structure (1, 2, 3, 4, 5).

• SHANK3 mutations modify dendritic spine morphology and synaptic function, contributing to autism spectrum disorder risk (1).
• ACTB and ACTL6B mutations are associated with cognitive and neurological deficits due to altered brain development (2, 3).
• Longitudinal studies demonstrate that genetic variants, including those outside the cytoskeleton, can alter brain growth and aging trajectories (4, 5).
• The translation from molecular defects to clinical outcomes remains complex but is increasingly understood through integrative genetic and cellular studies (1, 2, 3, 4, 5).

Future Research Questions

While this study advances our understanding of how actin mutations can alter brain development, several important questions remain. Future research is needed to address the broader implications for other organ systems, the potential for therapeutic intervention, and the generalizability of these findings to more common forms of microcephaly or other brain disorders.

Research Question	Relevance
How do actin mutations affect brain development in vivo?	Organoid models closely mimic early brain development, but in vivo studies are needed to confirm these findings and assess potential compensatory mechanisms or additional effects in the whole organism (2, 3).
Can pharmacological modulation of the cytoskeleton rescue brain growth deficits caused by actin mutations?	Investigating whether drugs targeting actin-microtubule interactions can restore normal progenitor cell division could inform new therapies for microcephaly and related disorders (2, 6).
Do actin gene mutations impact the development of other organs in humans?	Given the pleiotropic effects observed in ACTB-related syndromes, it is important to determine whether similar mechanisms underlie heart, kidney, or other organ defects (2).
Are there common genetic variants in the actin pathway that influence brain growth in the general population?	Identifying whether common variants in actin or cytoskeletal genes contribute to brain size variation could improve understanding of neurodevelopmental diversity and disease risk (4, 6).
How do cytoskeletal mutations interact with other neurodevelopmental risk factors?	Elucidating gene-gene and gene-environment interactions could help explain the variability in clinical presentation among individuals with cytoskeletal mutations (1, 4).