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Patricia L Musolino

Publications and source records attributed to Patricia L Musolino.

6 recordsLinked to original sources
PubMed2026

Microglial GRB2 is essential for brain ventriculogenesis and CSF homeostasis.

Microglia play essential yet poorly understood roles in brain development, including axon guidance, regulation of neurogenesis, and pruning of neuronal projections. Congenital hydrocephalus (CH), characterized by enlarged cerebrospinal fluid (CSF)-filled ventricles, is a leading cause of pediatric brain surgery, but its molecular mechanisms remain unclear. We have identified what we believe to be novel, recurrent, damaging missense variants in the SH3-binding domain of the adaptor protein Growth Factor Receptor-Bound Protein 2 (GRB2) in unrelated patients with CH. GRB2 is significantly co-expressed with one of its known upstream receptor tyrosine kinase partners, CSF1R, in the developing human brain, particularly in a microglial subtype associated with regulation of neural stem cells. Immunoprecipitation validated GRB2-CSF1R binding in mouse microglial cells and human monocyte cell line. Cx3cr1-Grb2fl/fl mice engineered with conditional deletion of Grb2 in microglia exhibit congenital absence of microglia and early postnatal severe communicating (non-obstructive) hydrocephalus, mimicking GRB2-mutant patients. The severe ventriculomegaly of Cx3cr1-Grb2fl/fl mice is associated with both depletion of cerebral cortical neurons and impairment of glia-lymphatic-mediated CSF flow. Together, these findings implicate a role of GRB2 in microglia that could be essential for brain development and CSF homeostasis.

Genetics↗
PubMed2026

Towards precision medicine for brain arteriovenous malformations.

Recent advances in cerebrovascular genomics, single-cell biology, pharmacology, and gene editing technology are transforming our understanding of brain arteriovenous malformations (bAVMs) - a leading cause of pediatric hemorrhagic stroke. Once considered static anatomical defects, bAVMs are now recognized as dynamic, genetically driven lesions resulting from somatic mutations in KRAS, BRAF, and pathways involved in arteriovenous specification, angiogenesis, and vascular remodeling. By integrating human genetics, animal models, and endovascular innovations, researchers have uncovered convergent mechanisms that link endothelial Ras/MAPK hyperactivation to abnormal vessel growth and higher rupture risk. These insights provide a foundation for precision medicine approaches that combine molecular diagnostics - such as liquid or endoluminal biopsies - with mutation-specific pharmacotherapies and emerging CRISPR-based gene editing strategies. We suggest that genotype-guided interventions, tailored by spatial and developmental cerebrovascular context, could ultimately reclassify bAVMs from surgically incurable malformations to treatable molecular conditions.

Humans↗
PubMed2026

Structural and functional gastrointestinal abnormalities in ACTA2 R179H mice modeling multisystemic smooth muscle dysfunction syndrome.

Multisystemic smooth muscle dysfunction syndrome (MSMDS) is a rare disorder caused by ACTA2 mutations, including the R179H variant, which alters actin filament stability and dynamics and smooth muscle contractility. Cardiovascular complications dominate its clinical presentation, but gastrointestinal (GI) dysfunction significantly affects quality of life. To investigate the structural, functional, and cellular basis of gut dysmotility in MSMDS, we reviewed clinical data from 24 patients with MSMDS and studied the ACTA2 R179H mouse model. Patients exhibited severe gut dysmotility, with 75% requiring medication for chronic constipation. ACTA2 mutant mice displayed cecal and colonic dilatation, reduced intestinal length, and disrupted colonic migrating motor complexes. Delayed whole-gut transit and impaired contractile responses to electrical and pharmacological stimulation were observed. Transcriptomic analysis revealed significant actin cytoskeleton-related gene changes in smooth muscle cells, and immune profiling identified increased lymphocytic infiltration. Despite functional abnormalities, there were no obvious changes in the enteric nervous system. These findings establish ACTA2 mice as a robust model for studying GI pathology in MSMDS, elucidating the role of smooth muscle dysfunction in gut dysmotility. This model provides a foundation for developing targeted therapies aimed at restoring intestinal motility by directly addressing actin cytoskeletal disruptions in smooth muscle cells.

Animals↗
PubMed2025

Treatment of a severe vascular disease using a bespoke CRISPR-Cas9 base editor in mice.

Pathogenic missense mutations in the alpha actin isotype 2 (ACTA2) gene cause multisystemic smooth muscle dysfunction syndrome (MSMDS), a genetic vasculopathy that is associated with stroke, aortic dissection and death in childhood. Here we perform mutation-specific protein engineering to develop a bespoke CRISPR-Cas9 enzyme with enhanced on-target activity against the most common MSMDS-causative mutation ACTA2 R179H. To directly correct the R179H mutation, we screened dozens of configurations of base editors to develop a highly precise corrective A-to-G edit with minimal deleterious bystander editing that is otherwise prevalent when using wild-type SpCas9 base editors. We create a murine model of MSMDS that shows phenotypes consistent with human patients, including vasculopathy and premature death, to explore the in vivo therapeutic potential of this strategy. Delivery of the customized base editor via an engineered smooth muscle-tropic adeno-associated virus (AAV-PR) vector substantially prolongs survival and rescues systemic phenotypes across the lifespan of MSMDS mice, including in the vasculature, aorta and brain. Our results highlight how bespoke mutant-specific CRISPR-Cas9 enzymes can improve mutation correction with base editors.

Animals↗
PubMed2025

COL4A1 and COL4A2-related disorders: Clinical features, diagnostic guidelines, and management.

PURPOSE: Collagen type 4 alpha 1 (COL4A1) and alpha 2 (COL4A2) chains, encoded by COL4A1 and COL4A2, are essential for basement membrane integrity, contributing to structural stability and cell regulation. Pathogenic variants in these genes cause a spectrum of autosomal dominant and, more rarely, autosomal recessive disorders, which are collectively known as COL4A1/A2-related disorders. These multisystem disorders can include neurologic, ophthalmologic, renal, and other organ system pathology and vary widely in symptoms, complicating diagnosis and management. METHODS: Using a modified eDelphi method, we obtained consensus from international experts across medical subspecialties on the evaluation and management of COL4A1/A2-related disorders, with consensus set at ≥70% agreement. RESULTS: Consensus was achieved on recommendations for evaluating and managing these conditions. CONCLUSION: Genetic testing and counseling are advised for individuals showing symptoms of COL4A1/A2-related disorders and for at-risk relatives. Given the complexity and rarity of these disorders, management requires a multidisciplinary approach informed by current understanding of disease mechanisms. Recommended care includes neurological and ophthalmological imaging and monitoring of cardiovascular and renal function. Ongoing research is critical to uncover genotype-phenotype links and potential modifiers, with clinical research participation encouraged to advance knowledge and treatments.

Humans↗