Our Scientists

Discovering the Genetic Basis of Pediatric Brain Disorders
Unlike adult disorders, which are frequently due to dominant genetic or multifactorial causes, many pediatric disorders, especially severe or life-threatening types, are due to recessive genetic mutations. In such families, in the absence of environmental influences, two healthy parents have one or more children with a severe disease. Having such a child frequently leads the parents to a genetic counselor, to ask how their genetic makeup could have led to their child's condition, and whether the condition could be repeated in future children.

Many pediatric brain diseases have no known causes. Most human genes are expressed in the developing brain but have no known function. These observations led us to the hypothesis that permeates our work: many of these connections between diseases and genes remain to be established. If we can establish these connections and understand how these mutations give rise to a specific disease, we hope to understand more about the assembly of the human brain. This work is the perfect synergy between clinical and basic science, allowing for advances in human health as well as advances in our understanding of fundamental mechanisms.

Focus on the Middle East, North Africa, and Asia
To understand the function of recessive disease genes, we must study populations where both copies of a gene are missing, because the presence of a single intact copy of any of these genes is sufficient to prevent disease symptoms. In most cases of recessive disease in the United States, physicians assume that two different mutations in the same gene were inherited. However, in practice, to identify the causes of such diseases, it is most useful to have a situation in which we know that the child inherited the same mutation from both parents. Such inheritance is typical in regions of the world with high rates of inbreeding, as when a grandparent passes the mutation to relatives who marry, and their child inherits the same mutation in a homozygous state.

To find these genes, and to connect them to specific neurological diseases, our lab works to identify families in which the parents are related to one another, and in which there are at least two children with the same condition. We use the powerful approach of homozygosity mapping to identify the chromosomal region that carries the mutation. By focusing on a particular chromosomal region for each condition, we hope to identify the cause of the disease.

For this reason, we have established collaborations with physician-scientists in major cities in many countries where the consanguinity rates are above 25–50 percent. Physicians from our group make regular trips to cities in Egypt, Lebanon, Kuwait, Jordon, Saudi Arabia, Pakistan, Turkey, Morocco, Qatar, Oman, and neighboring countries to evaluate patients, enroll then in studies, and link disease to gene. These discoveries can then be translated in a "bench-to-bedside" approach to develop new diagnostic tests, bring information to families, and help us understand basic mechanisms of brain development.

Molecular Mechanisms of Cerebellar Development
One focus of our research is the development of the cerebellum, the main brain region that controls balance. Surprisingly, we now know that the cerebellum is responsible for much more than just balance: it establishes much of our basic bodily rhythms and a lot of higher cognitive processing. In Joubert syndrome, the most common inherited cerebellar malformation, the midline, or vermis, is underdeveloped. We have contributed to the identification of more than six different genetic causes of this disease, and there appear to be many more causes yet to identify. We found that the gene products appear to localize to the region of the cell known as the primary cilium, an organelle that, until recently, was thought to be vestigial. It is now established, however, that the primary cilium plays critical roles in most regions of the body. We are exploring how dysfunction of Joubert syndrome genes can lead to cerebellar development, and whether defective signaling at the primary cilium is a major contributor.

Uncovering the Basis for Human Brain-Wiring Defects
We know from work in model organisms such as worm, fly, and mouse that extremely specific defects in brain wiring can be the result of single-gene interruptions. In these organisms, gene knockouts (many of which were pioneered by HHMI investigators) result in missing or misrouted axonal tracts within the central nervous system. Our hypothesis is that there must be a collection of human diseases, yet unclassified, that are due to defective brain wiring. One such well-known disease is hypogenesis of the corpus callosum, the major axonal tract that is visible on brain MRI (magnetic resonance imaging). We recently found that the doublecortin gene, when mutated in humans, gives rise to hypogenesis of the corpus callosum, likely as a result of a requirement for the protein in organizing the microtubule cytoskeleton within growing neurons. We are searching for families with recessive defects in corpus callosum development, with the idea that the underlying gene mutations will point to new mechanisms involved in brain wiring, and help define this category of disease.

Understanding Complex and Multifactorial Diseases
Homozygosity mapping, the main approach that we use to discover new disease genes, works extremely well in inbred families with single-gene recessive disorders. It should, however, be possible to use this same approach to study more complex disorders, such as epilepsy and mental retardation. These disorders, which are much more common than typical recessive diseases, display many forms of inheritance, as well as environmental influences that can negatively influence genetic studies. By ascertaining large families with a classical recessive mode of inheritance, we believe that it should be possible to make advances on these diseases as well. Our goal is to identify diseases that can be approached using this strategy.

As of May 30, 2012