SIOD Research Summary

Dr. Neil Schimke first described Schimke immuno-osseous dysplasia in 1971. In the ensuing two decades, a few physicians reported other individuals with SIOD. Among them, Drs. Jochen H. H. Ehrich and Jürgen Spranger and their colleagues made particularly seminal contributions to defining the features, course and outcome of the disease. In particular, Dr. Ehrich and Thomas Lücke and their colleagues have contributed much to our understanding of the renal and the neurovascular disease and our knowledge about the efficacy of various interventions. In the late 1990s they, numerous physicians from around the world and Dr. Cornelius Boerkoel combined their efforts: 1) to define better the clinical course and features of SIOD, 2) to identify effective and ineffective empiric therapies, and 3) to collect DNA samples for genetic studies. As a result of this study, they published the first comprehensive clinical study of SIOD patients, highlighted several additional features of the disease, and assembled the first international database of SIOD patients.

Subsequently, they identified the genetic cause of SIOD as inheritance of alterations (mutations) in both copies of a gene named SMARCAL1. This finding is of great significance to families and physicians because for the first time, this provides a test for confirmation of the clinical diagnosis.

As a next step to understanding SIOD, they turned our attention to determining what the SMARCAL1 gene coded for. SMARCAL1 codes for a protein (SMARCAL1) that had not been studied before, although some features are similar to those identified in other proteins. Based on these similarities, they predicted that the SMARCAL1 protein would modify DNA and that such DNA modifications would control genes modulating the ability of cells either to multiply or to grow. Indeed, SMARCAL1 is involved in a previously undescribed aspect of regulating DNA structure. DNA structure affects the expression of genes and the replication and the repair of DNA. By studying cells from SIOD patients and mouse and fruit fly models, the laboratory of Drs. Boerkoel, Jaspers, and Cortez have that SMARCAL1 plays a role in each of these processes.

These findings raise the question as to why SIOD has specific features if SMARCAL1 has a role in such fundamental biological processes. Dr. Boerkoel’s laboratory has now shown that despite global alterations in DNA structure, some regions are more affected and thus the expression of certain genes is more susceptible to SMARCAL1 deficiency than are others. This differential susceptibility likely explains why SIOD has specific features and some tissues are more affected than others.

This current understanding of SIOD suggests two approaches for treatment in addition to the current symptomatic management. First, based on the differential sensitivity of tissues, targeting of the affected pathway(s) in the affected tissue could correct the disease in that tissue. Supporting this hypothesis, Dr. Lewis has found that pharmacologic doses of some growth factors can correct the poor proliferation characteristic of the immune problem in SIOD. Second, rather than reacting to the consequences of SMARCAL1 deficiency, treatment might try to reactivate SMARCAL1. Recent progress in identifying compounds that allow synthesis of a protein past a premature stop codon suggests that these compounds might be useful for reactivating SMARCAL1 in some patients. Premature stop codons are the most common type of mutation found in SMARCAL1 among SIOD patients. Testing of these drugs for reactivating SMARCAL1 is currently in progress.

Bio for Cornelius (Neal) Boerkoel, MD, PhD

Dr. Boerkoel grew up in Michigan and earned his BA from Calvin College. He received a scholarship to the Medical Scientist Training Program at Case Western Reserve University in Cleveland, Ohio, where he earned his MD and PhD.

Following a brief stint in translational medical research at the National Institutes of Health, he pursued training in Pediatrics at the University of Washington, and Clinical Genetics at the University of Toronto. After completing his clinical training, he entered clinical practice in genetics at Baylor College of Medicine and its associated hospitals in Houston, Texas, where he simultaneously returned to translational medical research.

Over the last six years, Dr. Boerkoel has spearheaded identification of the genetic basis for three different inherited disorders and characterized the molecular pathophysiology of three disorders. He joined the Department of Medical Genetics at the University of British Columbia in 2006.

Meet the physicians dedicated to research for some of the rarest dwarfisms known, including Schimke.

  1. Cornelius F. Boerkoel, M.D., Ph.D.: - Clinical Professor, University of British Columbia
  2. Dr. David Lewis: Head of Pediatric Immunology, Stanford University, USA
  3. Dr. Nicholaas Jaspers: DNA repair biology, Erasmus Medical Centre, Netherlands
  4. Dr. David Cortez: DNA replication biology, Vanderbilt University, USA
  5. Dr. Dekker: physical-biochemistry of DNA strucure, Delf Technical University, Netherlands
  6. Dr. Jürgen Spranger, retired Chair of Pediatrics, Mainz, Germany
  7. Drs. J. H. H. Ehrich & Thomas Lücke, Dept of Pediatrics, Hannover, Germany
  8. Dr. Norman Rosenblum, Kidney biology, Hospital for Sick Children, Toronto, Canada

photos of Mitchell Cupps