• Boerkoel, Cornelius F.

    Investigator, BC Children's Hospital

    Clinical Associate Professor, Department of Medical Genetics, University of British Columbia

    Degrees / Designations
    MD, PhD
    Primary Area of Research
    Childhood Diseases
    Secondary Area(s) of Research
    Lab Phone
    Mailing Address
    BC Children's Hospital
    Room C234

    4500 Oak Street
    Vancouver, BC V6H 3V4

    Affiliate Websites
    Research Areas

    Our research focuses on defining the cause of and potential therapies for inherited human diseases. Currently we are studying a disorder of chromatin remodelling, a disorder of DNA repair, and disorders of cognition and behavior.


    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.

    Current Projects

    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.

    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.

    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.

    Selected Publications

    Chou, A., Boerkoel, C.F., du Souich, C., Rupps, R. 2009. Phenotypic and molecular characterization of a novel DCX deletion. Clinical Genetics. 76:214:218.

    Cunningham D., Spychala K., McLarren K. W., Garza L. A., Boerkoel C. F., Herman G. E. 2009. Developmental expression pattern of the cholesterogenic enzyme NSDHL and negative selection of NSDHL-deficient cells in the heterozygous Bpa(1H)/+ mouse. Mol Genet Metab. 98: 356-366

    du Souich, C., Chou, A., Yin, J., Oh, T., Nelson, T., Hurlburt, J., Friedlander, R., McGillivray, B., Tyshchenko, N., Rump, A., Poskitt, K.J., Demos, M., Van Allen, M.I., Boerkoel, C.F. 2009. Characterisation of a New X-Linked Mental Retardation Syndrome with Microcephaly, Pachygyria, and a Marfanoid habitus. Am. J. Med Genet 149A: 2469-2478.

    Hunter, K. B., Lücke, T., Spranger, J., Smithson, S. F., Alpay, H., André, J.-L., Yumi Asakura, Y., Bogdanovic, R., Bonneau, D., Cairns, R., Cransberg, K., Fründ, S., Fryssira, H., Goodman, D., Helmke, K., Hinkelmann, B., Lama, G., Lamfers, P., Loirat, C., Majore, S., Mayfield, C., Pontz, B. F., Rusu, C., Saraiva, J. M., Schmidt, B., Shoemaker, L., Sigaudy, S., Stajic, N., Taha, D., Boerkoel, C. F. 2010. Schimke immuno-osseous dysplasia: defining skeletal features. Eur. J. Pediatr. 169: 801-11.

    Vassel, J. L., Rupps, R., Krakow, D., Puvanachandra, N., Gardiner, J. A., Lazeo, S. R., Boerkoel C.F. 2010. Fetal Alcohol Syndrome: A Phenocopy of Spondylocarpotarsal Synostosis Syndrome. Clin. Dysmorphol. 9: 175-80.

    Bansbach, C. E., Boerkoel, C. F., Cortez, D. 2010. SMARCAL1 and Replication Stress: An explanation for SIOD? Nucleus. 1: 245-248.

    McLarren, K. W., Severson, T. M., du Souich, C., Friedlander, R., Larstone, R., Stockton, D. W., Limbos, M., Kratz, L. E., Cunningham, D., Hendson, G., Morin, R. D., Wu, D., Paul, J. E., An, J., Nelson, T. N., Chou, A., DeBarber, A. E., Merkens, L. S., Steiner, R. D., Kuzeljevic, B., Michaud, J. L., Grzeschik, K.-H., Waters, P., Bard, M., Lopez, E., Yin, J., McGillivray, B., Demos, M., Rouleau, G. A., Smith, R., Tarpey, P. S., Kini, U., Schwartz, C. E., Gecz, J., Stratton, M. R., Arbour, L., Hurlburt, J., Van Allen, M. I., Herman, G. E., Zhao, Y., Moore, R., Kelley, R. I., Jones, S. J. M., Raymond, F. L., Livesley, J., Marra, M. A., Boerkoel, C. F. 2010. Hypomorphic Temperature-Sensitive Alleles of NSDHL Cause CK Syndrome. Am. J. Hum. Genet. 87:905-14.

    AM Lehman, A. M., du Souich, C., Chai, D., Eydoux, P., Huang, J. L., Fok, A. K., Avila, L., Swingland, J., Delaney, A. D., McGillivray, B., Goldowitz, D., Agiropolous, R., Kobor, M. S., Boerkoel, C. F. 2010. 19p13.2 microduplication causes a Sotos syndrome-like phenotype and alters gene expression. Clin. Genet.

    du Souich C, Raymond FL, Grzeschik K-H, Konig A, Boerkoel CF: NSDHL-Related Disorders (February 2011) in: GeneReviews at GeneTests: Medical Genetics Information Resource [database online]. Copyright, University of Washington, Seattle, 1997-2010. Available at www.genetests.org

    Boerkoel CF.: Schimke Immuno-osseous Dyslpasia. In: Lang F, ed. Encyclopedia of Molecular Mechanisms of Diseases. Springer. Mar 2009.

    Elizondo LI, Jafar-Nejad P, Clewing J M, Boerkoel CF.: Gene clusters, molecular evolution and disease: a speculation. Current Genomics. 2009 Mar;10(1): 64-75.

    du Souich C, Austin JC, Friedlander R, Boerkoel CF.: A novel syndrome with psychiatric features and review of malformation syndromes with psychiatric disorders. Am J Med Genet A. 2009 Feb 15;149A(4):713-21.

    Honours & Awards

    Chairman’s Prize, United Mitochondrial Disease Foundation - 2010

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

    Clinical Investigator Award, Child & Family Research Institute - 2008

    MRDDRC New Project Development Award, funded by National Institutes of Health - 2004

    MRDDRC New Project Development Award, funded by the National Institutes of Health - 2003

    Baylor College of Medicine Junior Faculty Seed Funding Award, funded by the Gillson Longenbaugh Foundation - 2003

    Burroughs Wellcome Fund Career Award in the Biomedical Sciences, Baylor College of Medicine, Houston, TX - 2002

    Mentored Clinical Scientist Development Award (K08), Baylor College of Medicine, Houston, TX - 1999

    HHMI Physician Postdoctoral Fellowship (awarded but declined), Baylor College of Medicine, Houston, TX - 1998

    Child Health Research Award, Baylor College of Medicine, Houston, TX - 1998

    Trainee Research Start Up Award, The Hospital for Sick Children, Toronto - 1998

    Henry F. Saunders Award in Paediatrics, Case Western Reserve University, Cleveland, Ohio - 1983-1993

    Medical Scientist Training Program Award, Case Western Reserve University, Cleveland, Ohio - 1983-1992

    Trustee Research Grant and Dirkse Health Care Scholarship, Calvin College, Grand Rapids, MI - 1982-83

    Research Group Members

    Alireza Baradaran-Heravi
    Kunho Choi
    Miraj Chowdhury
    Andrew Fam
    Marie Morimoto