Friday, July 11, 2014

Disease Causality: Unexpected Complexity from Simple Gene Defects

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

One of the points discussed in the book is disease causation, and how we often fool ourselves into thinking that we understand how a disease develops, simply because we can name the gene or agent that precipitates the disease.

A gene may code for a single protein, but complex genetic and epigenetic conditions will effect the individual's response to a specific gene defect. Hence, different individuals, each with their own unique genome and epigenome, will respond differently to the same genetic aberration. Here is an excerpt from Chapter 9:
If a disease were truly caused by an aberration of a single gene, then all of the consequences of the genetic aberration would be identical in every person with the gene. In fact, some monogenic diseases have remarkably uniform clinical phenotypes in affected populations (e.g., sickle cell disease). What would happen if the same genetic aberration were recapitulated in a mouse? If the mouse homologue served the same purpose as the human gene, and if the gene were the sole cause of the disease, then you might expect the disease to be the same in man and mouse.

Lesch–Nyhan disease is a rare syndrome caused by a deficiency of HGPRT (hypoxanthine-guanine phosphoribosyl transferase), an enzyme involved in purine metabolism. In humans, HGPRT deficiency results in high levels of uric acid, with resultant renal disease and gout. A vast array of neurologic and psychologic signs accompanies the syndrome, including self-mutilation. Neurologic features tend to increase as the affected child ages. The same HGPRT deficiency of humans can be produced in mice. Mice with HGPRT deficiency do not have disease. As far as anyone can tell, mice with HGPRT deficiency are totally normal [18]. How can this be?

A single gene cannot cause a disease all by itself. Every monogenic disease is expressed in a complex system wherein the defective gene is a participant in various pathways that eventually lead to a disease. The mouse, evidently, has a set of pathways that compensates for the deficiency in HGPRT.

Diabetes is usually a common polygenic disease. There are rare subtypes of type 2 diabetes that have a monogenic origin. As you would expect, these rare subtypes arise in children, and have a Mendelian pattern of inheritance. One such monogenic form of diabetes is MODY-8 (maturity-onset diabetes of the young), caused by a mutation in the carboxyl-ester lipase gene. This same mutation was delivered to a transgenic mouse, intended as an animal model for MODY (see Glossary item, Transgenic). Mice carrying the same altered gene as the human failed to develop any signs of diabetes, or pancreatic damage, or any dysfunction caused by the mutated gene [19].

I urge you to read more about my book. There's a good preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D. tags: rare disease, common disease, orphan disease, orphan drugs, monogenic disease, complex disease, causality, disease causation, cause of disease, pathogenesis