Candidate: The proposed career development award is designed to support the transition of Dr. Russell Butterfield to an independent physician-scientist and leader in study of the congenital muscular dystrophies. Dr. Butterfield's PhD work in genetic analysis of complex traits to identify susceptibility loci for autoimmune disease gave him a solid foundation in genetics and computational biology. His clinical training in child neurology and neuromuscular disorders has given him a firm foundation in clinical research. His recent work cataloging genotype-phenotype correlations in collagen VI related muscular dystrophies (COL6-RD) and storing patient samples will provide the necessary patient resource to pursue further studies. He has developed computational skills in the analysis of next-generation sequencing data, including RNA-Seq and exome sequencing. Dr. Butterfield has assembled a strong mentoring team with Dr. Gabrielle Kardon as Primary mentor, and Drs. Robert Weiss and Carsten Bonnemann as co-mentors. With the guidance of his mentors, Dr. Butterfield has designed a career development plan to encompass a 5-year period that will build on his previous experience in genetic analysis and develop new skills in gene-targeting, mouse model development, and cellular and molecular biology techniques, and proteomics. During the award period he will receive formal training in gene targeting, microscopy, mass spectroscopy and proteomics, mouse phenotyping, research administration, and leadership. His mentors provide expertise and experience that is both distinct and complementary. They are internationally recognized experts with long and successful track records of funding and trainee mentorship. The work proposed here will fill the gaps in his training in cellular and molecular biology and genetic manipulation of model organisms. In addition, this research will allow him to position himself as a leader in the congenital muscular dystrophies and as a successful independent investigator Research: COL6-RD are inherited disorders of collagen VI characterized by progressive muscle weakness and a combination of distal joint laxity and proximal joint contractures. COL6-RD are increasingly recognized disorders accounting for up to 30% of patients with congenital muscular dystrophy (CMD). Children with COL6-RD have life-long neurologic, orthopedic, and pulmonary complications necessitating complex, multispecialty care. There are no treatments. Phenotypic heterogeneity is the hallmark of COL6-RD with a spectrum of severity in patients from the very severe Ullrich congenital muscular dystrophy (UCMD) to the milder Bethlem myopathy (BM). Factors controlling severity in COL6-RD patients are largely unknown. Dr. Butterfield's research plan incorporates 3 related aims with a goal to identify factors that control phenotypic heterogeneity in COL6-RD and develop a mouse model that reflects the heterogeneity seen in human COL6- RD. In the first aim, Dr. Butterfield will identify factors intrinsic to the collagen VI genes such as allele specific expression that control severity of human COL6-RD. In the second aim, he will foucs on the genetic modifiers outside the collagen VI genes with a particular focus on LTBP4, a regulator of TGF-? signaling in the extracellular matrix (ECM). LTBP4 has been shown to be a regulator of severity in Duchenne muscular dystrophy and it has been suggested that it may be a modifier of muscular dystrophies common to all muscular dystrophies.
In Aim 3, Dr. Butterfield will characterize a novel mouse model for COL-RD. We have designed this mouse model with a dominant negative glycine substitution in the triple helix of Col6a1 flanked by loxP sites, allowing conditional conversion of the dominant negative allele to a null allele. This unique design will allow identification of factors controlling phenotypic heterogeneity in COL6-RD by comparison of dominant negative, null, and haploinsufficient mice in the same model and allows testing of genetic modifiers in a model that more closely reflects human COL6-RD. These studies will provide critical insights into the phenotypic heterogeneity seen in patients with COL6-RD, identify targets for the development of therapies, and provide an important model for future studies of the molecular pathogenesis.
/RELEVANCE TO PUBLIC HEALTH The collagen VI myopathies, Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) are the most common congenital muscular dystrophies. There are no treatments. Phenotypic heterogeneity is the hallmark of COL6-RD with a spectrum of severity in patients from the very severe UCMD to the milder BM. The factors controlling this variability are largely unknown. In this study, we will identify factors controlling phenotypic heterogeneity in COL6-RD in humans and in a novel mouse model, with the goal of identifying targets for the development of new treatments.
| Cornwall, Kylie M; Butterfield, Russell J; Hernandez, Antonio et al. (2018) A Qualitative Approach to Health Related Quality-of-Life in Congenital Muscular Dystrophy. J Neuromuscul Dis 5:251-255 |
| Butterfield, Russell J; Dunn, Diane M; Hu, Ying et al. (2017) Transcriptome profiling identifies regulators of pathogenesis in collagen VI related muscular dystrophy. PLoS One 12:e0189664 |
