Our research focuses on three inherited human diseases:

Schimke immuno-osseous dysplasia

Spinocerebellar ataxia with neuropathy type 1

a disorder of sterol metabolism regulating behavior and neural development

We have identified the genetic causes of these diseases. Schimke immuno-osseous dysplasia is caused by a defect of organizing DNA within the nucleus. Spinocerebellar ataxia with neuropathy type 1 is caused by a defect in the ability to repair damaged DNA. The disorder of sterol metabolism, which is X-linked, causes brain neuron migration defects and intellectual disability in males but only aggressive behaviour in females.

To understand how these genetic defects cause disease, we are using multiple approaches including biochemistry, cell biology, fruit fly genetics and mouse genetics. Because these disorders cause alterations observed in other human diseases, we are also developing them as models for dissecting the pathophysiology of those diseases.


Pan-cancer RNA-seq data stratifies tumours by some hallmarks of cancer
Journal of Cellular and Molecular Medicine
F. Graeme Frost and Praveen F. Cherukuri and Samuel Milanovich and Cornelius F. Boerkoel
DOI: 10.1111/jcmm.14746

FOXP1 haploinsufficiency: Phenotypes beyond behavior and intellectual disability?
American Journal of Medical Genetics Part A
Angela Myers and Christèle du Souich and Connie L. Yang and Lior Borovik and Jill Mwenifumbo and Rosemarie Rupps and CAUSES Study and Anna Lehman and Cornelius F. Boerkoel
DOI: 10.1002/ajmg.a.38462

Pharmacogenomic incidental findings in 308 families: The NIH Undiagnosed Diseases Program experience
Genetics in Medicine
Elizabeth M.J. Lee and Karen Xu and Emma Mosbrook and Amanda Links and Jessica Guzman and David R. Adams and Elise Flynn and Elise Valkanas and Camillo Toro and Cynthia J. Tifft and Cornelius F. Boerkoel and William A. Gahl and Murat Sincan
DOI: 10.1038/gim.2016.47


Disorders of cognition and behaviour
Many families and patients presenting to the Psychiatric and Medical Genetics Clinics have strong family histories of cognition and behaviour. We have been using multiple tools to map the molecular bases of their disease. Through these studies of individuals and families, we are identifying novel pathways that not only regulate neural development and maintenance, but also regulate human behaviour. Currently we are studying inherited causes of aggressive behaviour, obsessive compulsive disorder and intellectual disability. We have identified a studied pathway of sterol metabolism as a regulator of neural development and aggressive behaviour. To define the function of this pathway and the molecular pathology underlying the disease, we are employing a combination of yeast and murine genetics, cell culture systems and biochemical analyses.

Spinocerebellar ataxia with neuropathy: a developmental role for DNA repair
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) repairs covalent topoisomerase IB-DNA complexes. In yeast, Tdp1 mutations cause double strand breaks through interference of the stalled topoisomerase IB complexes with DNA replication. This would suggest that mutations of Tdp1 predispose mammals to neoplasia or dysfunction of rapidly replicating tissues; however, we have found that deficiency of Tdp1 in humans causes spinocerebeller ataxia with axonal neuropathy (SCAN1), a disease of large terminally differentiated essentially non-dividing neuronal cells. We hypothesize that loss-of-function mutations in TDP1 cause SCAN1 either by interfering with DNA transcription or by inducing apoptosis in post-mitotic neurons rather than by interfering with DNA replication. To define the function of TDP1 and the molecular pathology underlying SCAN1, we are using a combination of Drosophila and murine genetics, and cell culture systems; these studies are being done in collaboration with Dr. Hiroshi Takashima. To date, our analyses suggest a novel biological process that is distinct from the previously described function of Tdp1. Our challenge is to use this process to gain insight into a new pathway for neural development and maintenance.

Schimke immuno-osseous dysplasia: exploration of a novel chromatin remodeling pathway
Presently the research in my laboratory focuses on defining the biologic and biochemical function of SMARCAL1 (swi/snf related, matrix associated, actin dependent regulator of chromatin, subfamily a-like 1), a protein homologous to helicases and the SNF2 family of chromatin remodeling proteins. Mutations in the SMARCAL1 gene cause Schimke immuno-osseous dysplasia (SIOD), an autosomal recessive fatal multisystem human disease. The SMARCAL1 protein has not been studied previously in any organism; therefore, its function and the underlying mechanism by which mutations cause SIOD are unknown. To define the function of SMARCAL1 and the molecular pathology underlying SIOD, we are employing a combination of Drosophila and murine genetics, cell culture systems and biochemical analyses to obtain insight into this novel pathway regulating tissue growth and maintenance.

SIOD is characterized by skeletal dysplasia, progressive renal failure and immunodeficiency. Additional but more variable disease features include atherosclerosis, hypothyroidism, and tooth and pigmentary abnormalities. SIOD is usually fatal within the first two decades of life because of renal failure, systemic infection, bone marrow failure, or cerebral ischemia. Our challenge is to explain molecularly how mutations of SMARCAL1 cause this severe pleiotropic disease, identify potential therapies to treat or ameliorate the disease, and derive insights into general principles of developmental biology and pathophysiology.

Honours & Awards

Clinical Investigator Award, Child & Family Research Institute - 2008

Michael Smith Foundation for Health Research Scholar Award in the Biomedical Sciences - 2008

Chairman’s Prize, United Mitochondrial Disease Foundation - 2010