Monday, December 7, 2009

“All of the easy experiments have been done”*


I am attending a great meeting right now. About 110 participants are gathered in a nondescript conference room in the DC area. The morning session provided valuable background information for my next proposal. Multiple speakers reviewed the embryology and gene expression of genitourinary development. I am amazed at how many things must go right for the urinary tract to form correctly. Yet, most of the time, it works out!

My brain is really, really full right now.

Overlapping phenotype (clinical presentation) seems to be a huge problem within this field. Very few identified mutations consistently produce the same clinical picture, even within members of the same kindred. This is true for some mouse models also! Trying to find genes of interest with a variable phenotype  will be problematic. Throw in environmental influences, like intrauterine exposures or post-natal infections, and you have a real mess to sort out. Like most diseases, what we identify as a single diagnosis likely results from numerous different causes. A single causative factor or gene may produce multiple diagnoses as well.

For example, we know the genetic defect in branchio-oto-renal syndrome (BOR), an autosomal dominant mutation in the gene EYA1. I know of an affected family where one member was born with a single kidney (unilateral renal agenesis). The other kidney is normal, and the patient’s renal function remains normal at adulthood. This patient had no extrarenal manifestations of the syndrome. Another child was born with only one kidney, and it showed dysplasia (small with cysts and areas that appear abnormal on ultrasound). Eventually this child required a kidney transplant. Other children in the family failed to form kidneys at all and died in utero. These variable phenotypes all resulted from the exact same genetic mutation. What modifies this mutation to make it milder in some cases and more severe in others? If only one of the living children had been born, and there had been no family history, how would we have classified them for gene association studies?

Part of the meeting is devoted to discussing strategies to scan large populations for gene associations. Lucky for me that part occurs tomorrow; I will have a chance to empty a bit of my brain by then!

Congenital renal anomalies cause ~40% of end-stage kidney failure in children throughout the world. Clearly, we need a better understanding of this spectrum of disorders. Small, intense meetings such as this one are a great way to focus parties of interest on a common goal and make things happen.

I’m glad I’m here. And I hope I can help!

*The title of this post is the first of “Carmines Laws of Science.” Credit must go to Pamela Carmines, PhD, a colleague in Cellular and Integrative Physiology at the University of Nebraska Medical Center.

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