Holoprosencephaly in RSH/Smith-Lemli-Opitz syndrome: Does abnormal cholesterol metabolism affect the function of sonic hedgehog?
Corresponding Author
Richard I. Kelley
The Kennedy Krieger Institute and Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland
Kennedy Krieger Institute, 707 North Broadway, Baltimore, MD 21205 or Dr. M. Muenke, Children's Hospital of Philadelphia, 34th and Civic Center Blvd, Philadelphia, PA 19104Search for more papers by this authorErich Roessler
The Children's Hospital of Philadelphia, Division of Human Genetics and Molecular Biology and Departments of Pediatrics and Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Search for more papers by this authorRaoul C. M. Hennekam
Department of Human Genetics, Academic Medical Center, Amsterdam, The Netherlands
Search for more papers by this authorGerald L. Feldman
Henry Ford Hospital, Medical Genetics and Birth Defects Center, Detroit, Michigan
Search for more papers by this authorKenjiro Kosaki
Department of Pediatrics, University of California, San Diego, California
Search for more papers by this authorMarilyn C. Jones
Department of Pediatrics, University of California, San Diego, California
Search for more papers by this authorJanice C. Palumbos
Division of Medical Genetics, Department of Pediatrics, University of Utah Medical Center, Salt Lake City, Utah
Search for more papers by this authorMaximilian Muenke
The Children's Hospital of Philadelphia, Division of Human Genetics and Molecular Biology and Departments of Pediatrics and Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Search for more papers by this authorCorresponding Author
Richard I. Kelley
The Kennedy Krieger Institute and Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland
Kennedy Krieger Institute, 707 North Broadway, Baltimore, MD 21205 or Dr. M. Muenke, Children's Hospital of Philadelphia, 34th and Civic Center Blvd, Philadelphia, PA 19104Search for more papers by this authorErich Roessler
The Children's Hospital of Philadelphia, Division of Human Genetics and Molecular Biology and Departments of Pediatrics and Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Search for more papers by this authorRaoul C. M. Hennekam
Department of Human Genetics, Academic Medical Center, Amsterdam, The Netherlands
Search for more papers by this authorGerald L. Feldman
Henry Ford Hospital, Medical Genetics and Birth Defects Center, Detroit, Michigan
Search for more papers by this authorKenjiro Kosaki
Department of Pediatrics, University of California, San Diego, California
Search for more papers by this authorMarilyn C. Jones
Department of Pediatrics, University of California, San Diego, California
Search for more papers by this authorJanice C. Palumbos
Division of Medical Genetics, Department of Pediatrics, University of Utah Medical Center, Salt Lake City, Utah
Search for more papers by this authorMaximilian Muenke
The Children's Hospital of Philadelphia, Division of Human Genetics and Molecular Biology and Departments of Pediatrics and Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Search for more papers by this authorAbstract
The RSH/Smith-Lemli-Opitz syndrome (RSH/SLOS) is an autosomal recessive malformation syndrome associated with increased levels of 7-dehydro-cholesterol (7-DHC) and a defect of cholesterol biosynthesis at the level of 3β-hydroxy-steroid-Δ7-reductase (7-DHC reductase). Because rats exposed to inhibitors of 7-DHC reductase during development have a high frequency of holoprosencephely (HPE) [Roux et al., 1979], we have undertaken a search for biochemical evidence of RSH/SLOS and other possible defects of sterol metabolism among patients with various forms of HPE. We describe 4 patients, one with semilobar HPE and three others with less complete forms of the HPE sequence, in whom we have made a biochemical diagnosis of RSH/SLOS. The clinical and biochemical spectrum of these and other patients with RSH/SLOS suggests a role of abnormal sterol metabolism in the pathogenesis of their malformations. The association of HPE and RSH/SLOS is discussed in light of the recent discoveries that mutations in the embryonic patterning gene, Sonic Hedgehog (SHH), can cause HPE in humans and that the sonic hedgehog protein product undergoes autoproteolysis to form a cholesterol-modified active product. These clinical, biochemical, and molecular studies suggest that HPE and other malformations in SLOS may be caused by incomplete or abnormal modification of the sonic hedgehog protein and, possibly, other patterning proteins of the hedgehog class, a hypothesis testable in somatic cell systems.
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