Research & Initiatives

Mitochondria tRNA Synthetases

The first compound, heterozygous variants of MARS2 were found in in one family in 2015 by Dr. Webb and since then Dr. Webb has developed cellular models and animals of MARS2 to study the pathophysiology and molecular mechanisms behind the disease. Her discovery of of these variants led her down the path of studying mitochondrial aminoacyl-tRNA synthetases (mt-ARS) disorders. mt-ARS are nuclear encoded genes that function in the mitochondria to catalyze the charging of an individual tRNA molecule to its cognate amino acid. There are 19 mt-ARS genes and each leads to a different disorder and have varying etiologies.

Mitochondrial aminoacyl-tRNA synthetases (mt-ARSs) are essential for protein synthesis in the mitochondria and generation of oxidative phosphorylation (OXPHOS) system components. These proteins are nuclear-encoded and function to charge the mitochondrial tRNA molecules with their cognate amino acids. Recently, pathogenic variants in multiple mt-ARSs have been identified and the associated conditions represent a new class of Mendelian disorders. The Webb lab focuses on methionyl aminoacyl-tRNA synthetase (MARS2) as well as tryptophanyl aminoacyl-tRNA (WARS2) synthetase. Though the use of cellular models and mice models, we aim to understand the pathophysiology of MARS2 and WARS2.

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Moebius Syndrome and Related Facial Paralysis Syndromes

One in 33 infants in the United States is born with a birth defect. Among them are those with congenital facial weakness (CFW) that can have profound effects on social interactions and psychosocial development. Moebius syndrome (MBS) is defined by non- progressive CFW and limited eye abduction (ability to move the eye in an outward direction). Although rare, this syndrome, and other CFW syndromes, causes significant impairment and can be associated with hearing loss, difficulty in swallowing and breathing, peripheral neuropathy, muscle hypotonia, heart defects, chest wall abnormalities, limb malformations, and associated intellectual disabilities and autism. The phenotypic (visible clinical signs) spectrum and the genetic and environmental factors underlying CFW disorders are poorly understood. Our goal is to identify phenotypic distinctions and causative gene mutations for CFW, including but not limited to MBS, hereditary congenital facial paresis, and oculoauriculovertebral dysplasia.

We had previously defined syndromes with CFW, horizontal gaze palsy, deafness, and absent internal carotid arteries resulting from mutations in the gene HOXA1; with bilateral CFW, hearing loss, and strabismus (crossed eyes) resulting from mutations in HOXB1; with CFW, congenital ophthalmoplegia (weakness of eye muscles), Kallmann syndrome, intellectual and social disabilities, peripheral neuropathy, and cyclic vomiting resulting from mutations in gene TUBB3 mutations; and generalized muscle hypoplasia with mild axial and appendicular weakness with mutations in the gene TMEM8C. Functional studies of these novel mutations using mouse model systems will have a significant impact on our understanding of the pathogenesis underlying facial nerve, muscle, and bone development, and common disorders such as intellectual impairment and autism.

 

Undiagnosed Disease Program

Congenital anomalies or birth defects are a significant cause of pediatric morbidity and mortality. About 2 to 3% of infants worldwide are born with a birth defect. Birth defects may be caused by genetic and/or environmental factors. The purpose of this study is to better define the genetic etiologies of a wide variety of congenital anomalies.

The goal of the UW-Undiagnosed Disease Program (UW-UDP) is to improve the health and well-being of individuals with undiagnosed disorders. The program’s objectives are to shorten the diagnostic odyssey for patients with rare diseases, discover new disease genes, develop novel diagnostic techniques, improve our understanding of the relationships between genomic variants and disease, and share our discoveries with the global genomic medicine community. The UW-UDP has both clinical service and research components. Patients first are seen in the UW-UDP clinic. Patients who cannot be diagnosed by conventional means then are invited to enroll in the UW-UDP research study where they will undergo a comprehensive ‘omics analysis, starting with trio whole genome sequencing.