Genetic predisposition to leprosy: A major gene reveals novel pathways of immunity to Mycobacterium leprae |
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Authors: | Erwin Schurr Alexandre Alcaïs Louis de Lsleuc Laurent Abel |
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Institution: | aMcGill Centre for the Study of Host Resistance, Departments of Human Genetics and Medicine, McGill University, Montreal, PQ, Canada;bLaboratoire de Génétique Humaine des Maladies Infectieuses, Université de Paris René Descartes-INSERM U550, Faculté de Médecine Necker, 156 rue de Vaugirard, 75015 Paris, France, EU |
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Abstract: | The elucidation of the genetic control of susceptibility to common infectious diseases is expected to provide new and more effective tools for prevention and control of some of the most pressings health needs on a global scale. A major advantage of whole genome based genetic approaches is that no a priori assumptions about mechanisms of pathogenesis need to be made in these studies. Hence, genetic studies can identify previously unrecognized pathways of disease susceptibility and tag critical pathogenic events for further biochemical, immunological or physiological analysis. We have applied this strategy to leprosy, a disease that still claims 400,000 new cases each year. We identified genetic variants in the shared promoter region of the PARK2 and PACRG genes as major risk factors of leprosy susceptibility. Both encoded proteins are part of the cellular ubiquitination system. Specifically, PARK2, the cause of early onset Parkinson's disease, is an E3 ligase that likely is involved in controlled proteolysis, the cellular anti-oxidants response and the regulation of innate immune responsiveness. In addition, numerous E3 ligases have recently been shown to be critical regulators of immunity. While the specific role of PARK2/PACRG in leprosy pathogenesis remains unknown, a number of experimentally testable scenarios can be developed to further explore the role of these proteins in anti-Mycobacterium leprae host responsiveness. |
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Keywords: | Leprosy Parkin Complex trait Susceptibility genes Ubiquitination |
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