More than a decade has passed since President Clinton first announced that the human genome project was successfully completed:

We are here to celebrate the completion of the first survey of the entire human genome.  Without a doubt, this is the most important, most wondrous map ever produced by human kind.

Although the $3 billion dollar project has yet to definitely identify the genetic causes of cancer and Alzheimer’s disease, whole genome sequencing case studies reveal revolutionary advances in pinpointing specific disease-related genes.

In a recent report in Science Translational Medicine, we meet fraternal twins Noah and Alexis Beery.  Initially diagnosed with cerebral palsy, the twins struggled with tremors and finding the strength even to sit for extended periods of time.  Their condition deteriorated, and by age six they were re-diagnosed with the movement disorder dopa (3,4-dihydroxyphnylalanine)-responsive dystonia (DRD).  This movement disorder is challenging to diagnose and is often mistaken for other disorders that involve the loss of the neurotransmitter dopamine.  Treatment for DRD parallels the therapeutic treatment of Parkinson’s disease and involves replacing dopamine by providing its precursor L-dopa.

Despite being treated with L-dopa, not all of the twin’s symptoms were alleviated.  Most seriously, Alexis struggled to breathe on multiple occasions.  This prompted the twin’s parents to seek full genome sequencing at Baylor College of Medicine by the same group that sequenced Dr. Watson’s genome (of Watson and Crick DNA structure fame).  The scientists were surprised to find that there were no mutations in the two genes commonly mutated in DRD.  Performing full genome sequencing on the twins, their parents, and a healthy older brother enabled the researchers to identify a mutation in the SPR gene.  SPR encodes sepiapterin reductase, an enzyme that is required for the synthesis of a cofactor that is necessary to activate a class of enzymes that produce dopamine (congruent with the DRD diagnosis) and serotonin (an unforeseen contributor to the twins’ troubles).  These neurotransmitters are important for synaptic transmission and neuronal communication.

Identifying this novel gene mutation enabled the twins’ physicians to alter the course of their treatment to account for their serotonin deficiency.  The children inherited two mutant forms of the gene.  From their mother, they received a nonsense mutation wherein the reading of the messenger RNA was stopped prematurely, resulting in a truncated protein.  From their father, they received a missense mutation that resulted in a change in the amino acid sequence encoding the protein associated with the SPR gene.  Remarkably, when the twins were giving 5-hydroxytryptophan (5-HTP) in combination with L-dopa, after only two weeks they exhibited better motion and coordination, reduced tremors, and better attention.

It is important to recognize that this study describes only one set of twins.  Still, it is a compelling example of how whole-genome sequencing can identify gene mutations that give rise to a specific deficit that can be corrected with personalized therapeutics.

Bainbridge M.N., Wiszniewski W., Murdock D.R., Friedman J., Gonzaga-Jauregui C., Newsham I., Reid J.G., Fink J.K., Morgan M.B. & Gingras M.C. & (2011). Whole-Genome Sequencing for Optimized Patient Management, Science Translational Medicine, 3 (87) 87re3-87re3. DOI: 
Image adapted from William Whitehurst/CORBIS.

Written by Jillian Shaw

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Jillian L. Shaw

Jillian decided to dedicate herself to a life of exploring the mysteries of the brain after reading neurological case studies by Oliver Sachs and Ramachandran as a student at Vassar College.After completing a B.A. in Neuroscience with honors in 2009, Jillian headed to USC to pursue a Ph.D. in Neuroscience where she is now in her 5th year.A research stint in Belgium exposed Jillian to the complexities of cell signaling pathways, and her interests shifted from cognitive neuroscience to cellular and molecular neuroscience.Her current research focuses on the link between Down syndrome and Alzheimer’s disease using Drosophila as a genetic model to explore axonal transport, mitochondria dysfunction, synaptic defects, and neurodegeneration.When she is not in the lab, Jillian is forming new synapses by rock climbing throughout Southern California.
Profile photo of Jillian L. Shaw

Jillian L. Shaw

View posts by Jillian L. Shaw
Jillian decided to dedicate herself to a life of exploring the mysteries of the brain after reading neurological case studies by Oliver Sachs and Ramachandran as a student at Vassar College. After completing a B.A. in Neuroscience with honors in 2009, Jillian headed to USC to pursue a Ph.D. in Neuroscience where she is now in her 5th year. A research stint in Belgium exposed Jillian to the complexities of cell signaling pathways, and her interests shifted from cognitive neuroscience to cellular and molecular neuroscience. Her current research focuses on the link between Down syndrome and Alzheimer’s disease using Drosophila as a genetic model to explore axonal transport, mitochondria dysfunction, synaptic defects, and neurodegeneration. When she is not in the lab, Jillian is forming new synapses by rock climbing throughout Southern California.

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