Newswise — (New York, NY – May 15, 2012) Researchers at Mount Sinai School of Medicine in New York have found new clues in the pathogenesis of skull and skin birth defects associated with a rare genetic disorder, Beare-Stevenson cutis gyrata syndrome (BSS). Using a mouse model, investigators found that by inhibiting the protein p38, previously associated with cancer and certain autoimmune conditions, they were able to interrupt development of specific birth defects associated with it: craniosynostosis, or the premature fusion of certain bones of the skull, and acanthosis nigricans, a hyperpigmentation skin disorder that often makes the skin look dirty and rough.
“We urgently need to identify the molecular mechanisms underlying the development of these disorders so that we can design effective treatment and strategies,” said Ethylin Wang Jabs, MD, the study’s senior investigator and Professor of Genetics and Genomic Sciences, Developmental and Regenerative Biology, and Pediatrics at Mount Sinai School of Medicine. “What this opens up for the first time are potential targets for treatment.”
Results from the study are published in the June 2012 Journal of Clinical Investigation.
Using a mouse model of Beare-Stevenson cutis gyrata syndrome, researchers found that there was an increase in intracellular signaling through p38. When Yingli Wang, DMD, PhD, used intraperitoneal injections of an inhibitor of p38 into the mouse in utero, the skull and skin defect improved. In a separate experiment, topical application to the skin of a p38 inhibitor helped the skin defect.
The skull disorder, craniosynostosis, has devastating consequences if surgery is not performed within the first 6 months of life. Excessive intracranial pressure prevents normal growth of the head, impairing the brain, the eyes, the ears, and cognitive development. Approximately 1 in 2500 newborns across all groups are born with this birth defect, making it one of the top 10 birth defects. The disorder is listed in birth registries in the United States.
The skin disorder, acanthosis nigricans (AN), causes hyperpigmentation, and there are no standard treatments for it. AN is common. Certain conditions increase the risk for AN, including insulin resistance, obesity, diabetes, and polycystic ovary disease. Some series have shown that as many as 74 percent of obese individuals and 36 percent of people with type 2 diabetes are parents of newborns with AN. The skin disorder is especially common in Native Americans, followed by African-Americans, Hispanics, and Caucasians.
Other researchers involved in the study were Yingli Wang, Xueyan Zhou, Kurun Oberoi, Robert Phelps, Amelie Rezza, Greg Holmes, Jenna Friedenthal, Michael Rendl of Mount Sinai School of Medicine.
The research was funded in part by the National Institutes of Health in Bethesda, Maryland. Dr. Jabs is a world-class leader in the study of craniosynosis.
About the Mount Sinai Department of Genetics and Genomic SciencesThe Mount Sinai Department of Genetics and Genomic Sciences is one of the largest medical genetics centers in the United States, providing expert diagnostic, therapeutic, and counseling services for patients and families with genetic disorders, birth defects, and pregnancy loss. The Department offers diagnostic tests in state-of-the-art DNA, biochemical, and cytogenetics laboratories.
About The Mount Sinai Medical CenterThe Mount Sinai Medical Center encompasses both The Mount Sinai Hospital and Mount Sinai School of Medicine. Established in 1968, Mount Sinai School of Medicine is one of the leading medical schools in the United States. The Medical School is noted for innovation in education, biomedical research, clinical care delivery, and local and global community service. It has more than 3,400 faculty in 32 departments and 14 research institutes, and ranks among the top 20 medical schools both in National Institutes of Health (NIH) funding and by U.S. News & World Report.
The Mount Sinai Hospital, founded in 1852, is a 1,171-bed tertiary- and quaternary-care teaching facility and one of the nation’s oldest, largest and most-respected voluntary hospitals. In 2011, U.S. News & World Report ranked The Mount Sinai Hospital 16th on its elite Honor Roll of the nation’s top hospitals based on reputation, safety, and other patient-care factors. Of the top 20 hospitals in the United States, Mount Sinai is one of 12 integrated academic medical centers whose medical school ranks among the top 20 in NIH funding and U.S. News & World Report and whose hospital is on the U.S. News & World Report Honor Roll. Nearly 60,000 people were treated at Mount Sinai as inpatients last year, and approximately 560,000 outpatient visits took place.
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Journal of Clinical Investigation (June 2012)