Research & Initiatives

Mitochondrial Aminoacyl-tRNA Synthetase (mt-ARS) Disorders

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Mitochondrial aminoacyl-tRNA synthetases (mt-ARSs) are nuclear-encoded enzymes essential for mitochondrial protein translation and oxidative phosphorylation. Pathogenic variants in mt-ARS genes cause a growing class of rare mitochondrial disorders, frequently presenting with neurodevelopmental delay, neuromuscular disease, and multi-system involvement. A major focus of the Webb Lab is defining the genetic basis and molecular mechanisms of mt-ARS–related disease.

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MARS2-related disorders.
Dr. Bryn Webb was among the first to identify pathogenic variants in MARS2, encoding the mitochondrial methionyl-tRNA synthetase, as a disease-causing gene. This discovery arose through genomic sequencing of children who presented with unexplained neurodevelopmental and mitochondrial phenotypes. Following this gene discovery, the Webb Lab established a comprehensive disease-modeling framework, including genetically engineered mouse models of Mars2 deficiency and patient-derived induced pluripotent stem cell (iPSC) models, to investigate how impaired methionyl-tRNA charging disrupts mitochondrial translation, oxidative phosphorylation, and downstream cellular networks.

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WARS2-related disorders.
Building on this foundation, the lab also studies WARS2, which encodes the mitochondrial tryptophanyl-tRNA synthetase and is associated with neurodevelopmental delay, movement disorders, and mitochondrial dysfunction. Using patient-derived iPSCs, neuronal differentiation systems, and mouse models carrying disease-relevant WARS2 variants, we examine how defects in mitochondrial translation impact early neural development, mitochondrial bioenergetics, and stress responses in disease-relevant cell types.

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Elijah’s Project for Hope Partnership
The Webb Lab partners closely with Elijah’s Project for Hope, a family-led nonprofit organization dedicated to advancing research, awareness, and support for individuals affected by WARS2-related disease. This collaboration ensures that our research remains patient-centered and translational, connecting families directly with scientists and clinicians. Through this partnership, we align disease modeling and mechanistic studies with the priorities of the WARS2 community, accelerating progress toward improved understanding, diagnosis, and future therapeutic development.

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Across both MARS2 and WARS2 projects, we integrate transcriptomic profiling, mitochondrial functional assays, and cross-species comparisons to identify convergent pathogenic mechanisms shared among mt-ARS disorders, as well as gene-specific vulnerabilities. These studies aim to move from variant discovery to mechanism, informing diagnostic interpretation and highlighting potential therapeutic entry points for mitochondrial disease.

 

POU4F1-Related Neurodevelopmental Disorder

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Discovery of POU4F1 as a disease gene.
The gene POU4F1 (also known as BRN3A) encodes a class IV POU domain transcription factor that plays a critical role in neuronal development and the formation of motor control circuits. In 2021, Dr. Bryn Webb and colleagues used whole-exome sequencing to identify heterozygous loss-of-function variants in POU4F1 in multiple unrelated individuals presenting with strikingly similar neurodevelopmental symptoms including childhood-onset ataxia (balance and coordination problems), intention tremor, and hypotonia (reduced muscle tone), as well as developmental delays and cerebellar abnormalities on neuroimaging. This marked the first report linking POU4F1 haploinsufficiency to a novel hereditary neurological syndrome. 

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Clinical features and research focus.
Individuals with POU4F1-related disorder typically present in early childhood with motor delay, impaired balance and coordination, mild cognitive delays, and characteristic movement abnormalities. The condition is ultra-rare, with fewer than 30 cases described worldwide, and the full phenotypic spectrum is still being defined as more individuals enter research registries and clinical studies. 

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The Webb Lab’s research aims to characterize the molecular and cellular consequences of POU4F1 deficiency, leveraging patient-derived cellular models and deep clinical phenotyping to understand how disruptions in this transcription factor affect neural development and motor circuit formation.

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Partnership with the POU4F1 Foundation.
To accelerate discovery and support affected families, the Webb Lab partners closely with the POU4F1 Foundation, Inc., a parent-led 501(c)(3) organization dedicated to raising awareness, connecting families, and driving collaborative research into POU4F1-related conditions. The Foundation sponsors a comprehensive patient registry and natural history efforts that are essential for defining disease progression, enabling data sharing across research groups, and laying the groundwork for future therapeutic development. 

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Together, these efforts aim to transform an ultra-rare genetic diagnosis into mechanistic insight and, ultimately, clinical action for families affected by POU4F1-related neurodevelopmental disorders.

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Moebius Syndrome and Congenital Facial Weakness Disorders​​

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Approximately 1 in 33 infants in the United States is born with a congenital birth defect, including a subset of children affected by congenital facial weakness (CFW). CFW can profoundly affect facial expression, communication, and social interaction, with lasting consequences for psychosocial development and quality of life.

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Moebius syndrome (MBS) is a rare neurodevelopmental condition defined by non-progressive congenital facial weakness and limited eye abduction, reflecting impaired function of cranial nerves involved in facial movement and ocular motility. In addition to facial paralysis, MBS and related CFW disorders can be associated with a broad range of medical and neurodevelopmental features, including hearing loss, difficulties with swallowing and breathing, peripheral neuropathy, muscle hypotonia, congenital heart defects, chest wall abnormalities, limb malformations, and increased risk of intellectual disability and autism spectrum disorders.

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Despite their clinical significance, the phenotypic spectrum and the genetic and environmental factors underlying CFW disorders remain poorly understood. The overarching goal of the Webb Lab is to define phenotypic distinctions and identify causative gene mutations across the spectrum of CFW conditions, including but not limited to Moebius syndrome, hereditary congenital facial paresis, and oculoauriculovertebral dysplasia.

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Genetic Discovery in Congenital Facial Weakness

Our group has played a leading role in defining several genetically distinct syndromes characterized by congenital facial weakness, including:

• A syndrome featuring CFW, horizontal gaze palsy, deafness, and absent internal carotid arteries caused by mutations in HOXA1

• Bilateral CFW with hearing loss and strabismus associated with mutations in HOXB1

• CFW accompanied by congenital ophthalmoplegia, Kallmann syndrome, intellectual and social disabilities, peripheral neuropathy, and cyclic vomiting linked to mutations in TUBB3

• Generalized muscle hypoplasia with mild axial and appendicular weakness resulting from mutations in TMEM8C

These discoveries have expanded the molecular and developmental framework underlying facial nerve, muscle, and craniofacial development.

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Mechanistic Modeling and Translational Impact

To move from gene discovery to biological mechanism, the Webb Lab uses functional studies in mouse model systems to investigate how pathogenic variants disrupt cranial nerve development, muscle formation, and skeletal patterning. These models provide critical insight into the developmental pathways that underlie not only congenital facial weakness, but also broader neurodevelopmental conditions such as intellectual disability and autism.

By integrating genomic discovery with developmental biology and model systems, our work aims to transform congenital facial weakness from a primarily descriptive diagnosis into a mechanistically defined group of neurodevelopmental disorders, improving diagnosis, counseling, and future therapeutic strategies for affected individuals and families.

 

Undiagnosed Disease Program (UDP)

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A central mission of the Webb Lab is to shorten the diagnostic odyssey for individuals and families affected by rare and unexplained conditions. Through leadership in the University of Wisconsin Undiagnosed Disease Program (UW-UDP), the lab integrates clinical evaluation, genomic sequencing, and functional research to identify the causes of complex and previously unsolved diseases.

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Patients referred to the UW-UDP often present with atypical or severe phenotypes that remain unexplained despite extensive prior testing. Using whole-exome and whole-genome sequencing, deep phenotyping, and multidisciplinary case review, we work to identify pathogenic variants in known disease genes as well as discover novel gene–disease associations. 

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As a Diagnostic Center of Excellence within the NIH Undiagnosed Diseases Network (UDN), the UW-UDP contributes to national efforts to improve rare disease diagnosis, share data and expertise across institutions, and accelerate gene discovery. Insights gained through the UDP directly inform the lab’s research programs, creating a bidirectional pipeline in which patient care drives discovery and discovery advances patient care.

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Through this integrated clinical–research framework, the Webb Lab aims to transform unsolved cases into actionable diagnoses, advance understanding of rare disease biology, and improve outcomes for patients and families living with undiagnosed conditions.