Dr. Muenke's research program seeks to improve knowledge about the formation of the central nervous system and to elucidate the origin of developmental disabilities and mental retardation. Specifically, his laboratory investigates birth defects that affect normal embryonic development and lead to neurological impairment. His two major areas of focus involve holoprosencephaly (HPE) and attention deficit hyperactivity disorder. HPE, a common brain birth defect that occurs in one in 250 embryos, is characterized by the failure of the embryonic brain to divide properly into left and right hemispheres during early development. It frequently results in fetal demise; consequently, the live birth rate is low - approximately one in 10,000. Children born with the disorder show various degrees of developmental disabilities and mental retardation.
Dr. Muenke's laboratory has discovered over ten genes associated with HPE and, in doing so, illuminated a number of key molecular processes involved in early embryonic development. The first human HPE-related gene his group identified was Sonic Hedgehog (SHH), a gene initially found in fruit flies and named for the prickly appearance it gives them. Dr. Muenke and other investigators have since identified a number of additional genes in the Sonic Hedgehog and Nodal signaling pathways that are implicated in HPE. However, these genes together only account for 20 percent of documented HPE cases. Thus, Dr. Muenke and colleagues are continuing their hunt for additional genes and other causes contributing to HPE.
Dr. Muenke's group is also studying environmental factors that may affect the development of HPE, particularly cholesterol. It is well-known that cholesterol is necessary for the activation of SHH, and researchers have found an association in animal models between low maternal cholesterol during pregnancy and birth defects. There have also been reports of babies with various birth defects, including HPE, being born to women who took cholesterol-lowering statin drugs during pregnancy. One of Dr. Muenke's goals is to conduct a larger study to determine whether low maternal cholesterol can indeed adversely affect embryonic development. In related research, Dr. Muenke is studying laterality defects, or abnormal left-right positioning of body organs. In vertebrates, laterality defects occur very early in development, resulting in the growth of some organs on the wrong side of the body. Many people are unaware that they are affected by these disorders, but severe symptoms can and often do arise in their children.
Another major research area for Dr. Muenke's group involves understanding the genetic basis of attention deficit hyperactivity disorder (ADHD). ADHD is the most common behavioral disorder in children; it affects at least 4 to 6 percent of school-age children and five times as many boys as girls. Characterized by impulsiveness, hyperactivity, and attention problems, ADHD has been recognized as a distinct disorder for many years. Its cause has remained a mystery, although environmental factors were long considered the most likely culprits. Over the past decade, studies of twins, adopted children, and families with a high prevalence of this disorder have shown instead that genetic factors are the major underlying cause of ADHD.
Building on research by investigators in Colombia studying 18 large multigenerational families with a high incidence of ADHD, Dr. Muenke's laboratory conducted detailed phenotyping and genotyping of this population. His group found strong evidence for familial ADHD, including comorbidity with other behavioral disorders, such as nicotine dependence. By studying this population, Dr. Muenke's laboratory has now identified several candidate genomic regions for ADHD and is currently performing fine-mapping studies to identify specific contributing genes. His group is conducting a similar study of more than 1,000 families in the United States. Because of the typically smaller size of American families, this second arm of the study focuses on families with only two children, at least one of whom has ADHD.
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Last Updated: October 28, 2013