For the past two decades, the Human Development Section (HDS) has focused on the delineation and identification of the underlying causes of craniofacial anomalies in humans. Dr. Muenke's interest in this work was sparked during his fellowship training by a clinical encounter with two newborns: one had an unusual skull shape and the other had a severe brain anomaly. These two patients initiated the work on craniosynostosis and holoprosencephaly (HPE). By collecting samples from large families with Pfeiffer syndrome (PS) for linkage and candidate gene studies, the Muenke lab was able to identify causative gain-of-function mutations in FGFR1 and FGFR2. Further studies of mutation-negative families that were originally considered to have PS led to the discovery of a defining mutation in FGFR3 in all affected patients. This condition, now termed Muenke syndrome, is the most common craniosynostosis syndrome. Detailed clinical analyses at the NIH Clinical Center showed that virtually all mutation carriers have sensorineural hearing loss, leading to new patient care standards. Current studies of Muenke syndrome involve 1) natural history studies with special emphasis on behavior and cognition, and 2) determining multifactorial influences of disease severity using a variety of techniques.
A major focus of the Muenke lab is on holoprosencephaly (HPE), which is the most common anomaly of the developing forebrain (1 in 250 during early embryogenesis; 1 in 10,000 at birth; and an estimated 1 in 100, 000 at one year of life). Dr. Muenke's group has collected samples from over 1,000 unrelated kindreds to date. His work in HPE emphasizes the understanding of normal and abnormal brain development through gene identification and functional studies of disease-associated alleles in cell-based assays and animal models. Since the first HPE gene found in the lab - Sonic Hedgehog (SHH) - a dozen additional HPE genes have been discovered (ZIC2, SIX3, TGIF, PTCH1, TDGF1, GLI2, FOXH1, DISP1, FGF8, CDON, GAS1, BOC). Dr. Muenke's group identified the involvement of abnormal sterol metabolism in HPE, as well as the relatively common etiology of submicroscopic copy number variations.
This work on HPE stimulated gene identification in other early gastrulation midline defects such as heterotaxy (CFC1) and common types of cardiac anomalies (CFC1, FOXH1, NODAL, and GDF1). Current research goals include comprehensive targeted capture of both coding and non-coding conserved elements in key developmental pathways (e.g. Hedgehog and Nodal) using next-generation approaches. The lab has demonstrated that ultra-conserved NCE are targets for mutations in HPE (e.g. ZIC2 3'UTR) and has developed methods in the zebrafish to demonstrate enhancer activity. Finally, as a service to the community, Dr. Muenke's group organizes regular HPE conferences for families and health care professionals, runs a CLIA-certified diagnostic lab free of charge for HPE-associated gene testing, and is a worldwide HPE referral and consultation center.
Work in animal models from other labs demonstrated the importance of cholesterol modification for optimal SHH function. Dr. Muenke's work showed that cholesterol-lowering statin drugs taken in the first trimester are associated with specific brain and limb anomalies, in part influencing the Food and Drug Administration to disallow over-the-counter sale of statins. Further, in analyzing data from over 10,000 pregnant women, his group found that low maternal cholesterol is associated with prematurity and low birth weight. Recently, the observation by Dr. Muenke's group of the extremely high frequency of fatty liver in HPE gene mutation-positive individuals has led to collaborative mouse-based studies aimed to test the role of HPE-related genes in liver regeneration and idiopathic liver disease, as well as a new protocol designed to look for genetic contributions to idiopathic fatty liver in the general population.
Based on successes with syndrome delineation and gene identification in Mendelian disorders, the Muenke lab initiated a clinical, neuropsychological and molecular genetic study of the most common behavioral disorder in childhood, Attention-Deficit/Hyperactivity Disorder (ADHD). Initial work emphasized detailed phenotypic and linkage studies in large families from a genetic isolate, which led to the identification of ADHD and comorbid disorder (e.g., substance use disorders) susceptibility loci. The Muenke lab found and replicated the association between ADHD, including treatment response, and LPHN3 variants. They then demonstrated that an interaction between LPHN3 and a region on chromosome 11 (NCAM1, TTC12, ANKK1, and DRD2) doubles the risk for ADHD and predicts severity and long-term outcome. The Muenke lab is now generating genotypes on samples already available in the lab (over 5,000 patients and controls to date), as well as on samples from a cohort of individuals who have been followed for over 16 years as a part of the NIH Multicenter Treatment Assessment study, in order to define a genetics-symptoms-function-treatment predictive framework as a step towards personalized medicine in ADHD.
Human Development Section Members
Yu Abe, M.D., Ph.D., Postdoctoral Fellow
Yonit Addissie, B.A., Postbaccalaureate Fellow
Maria T. Acosta, M.D., Medical Director, ADHD Clinic
Nicole Banks, M.D., Clinical Fellow
Maria Guillen Sacoto, M.D., Clinical Fellow
Sung-Kook Hong, Ph.D., Staff Scientist
Ping Hu, M.S., Biologist
Paul Kruszka, M.D., Clinical Fellow
Ariel Martinez, M.S., Biologist
Erich Roessler, M.D., Ph.D., Staff Scientist and Associate Investigator
Colin Yarnell, B.S., Postbaccalaureate Fellow
Last Updated: July 31, 2015