The interplay of genetic and environmental factors in craniofacial morphogenesis: holoprosencephaly and the role of cholesterol
- 1 March 2003
- journal article
- review article
- Published by Wiley in Congenital Anomalies
- Vol. 43 (1), 1-21
- https://doi.org/10.1111/j.1741-4520.2003.tb01022.x
Abstract
Cyclopia, the paradigmatic "face [that] predicts the brain" in severe holoprosencephaly (HPE) (DeMyer et al., 1964), has been recognized since ancient times. Descriptive embryologists and pathologists have noted the continuum of defective separation of the forebrain and loss of central nervous system (CNS) midline structures for more than a century. It has been recognized more recently that inhibitors of cholesterol biosynthesis, whether consumed in native plants by range sheep, or experimentally applied to early embryos, could phenocopy the natural malformation, as could a variety of other teratogens (maternal diabetes, alcohol). Yet it has been less than a decade that the genomic knowledge base and powerful analytic methods have brought the sciences of descriptive, molecular, and genetic embryology within range of each other. In this review, we discuss the clinical presentations and pathogenesis of HPE. We will outline various genetic and teratogenic mechanisms leading to HPE. Lastly, we will attempt to examine the pivotal role of cholesterol and the Sonic Hedgehog (Shh) pathway in this disorder and in normal embryonic forebrain development.Keywords
This publication has 140 references indexed in Scilit:
- Sonic Hedgehog Induces the Segregation of Patched and Smoothened in EndosomesCurrent Biology, 2002
- Inherited Disorders of Cholesterol BiosynthesisNeuropediatrics, 2001
- The sterol-sensing domain of Patched protein seems to control Smoothened activity through Patched vesicular traffickingCurrent Biology, 2001
- Interactions of the Low Density Lipoprotein Receptor Gene Family with Cytosolic Adaptor and Scaffold Proteins Suggest Diverse Biological Functions in Cellular Communication and Signal TransductionJournal of Biological Chemistry, 2000
- Mutations in the human Sonic Hedgehog gene cause holoprosencephalyNature Genetics, 1996
- Biochemical evidence that Patched is the Hedgehog receptorNature, 1996
- Endocrine Changes during Pregnancy in a Patient with Homozygous Familial HypobetalipoproteinemiaNew England Journal of Medicine, 1986
- Holoprosencephaly in infants of diabetic mothersThe Journal of Pediatrics, 1983
- Elevated Maternal Hemoglobin A1Cin Early Pregnancy and Major Congenital Anomalies in Infants of Diabetic MothersNew England Journal of Medicine, 1981
- Familial holoprosencephaly with endocrine dysgenesisThe Journal of Pediatrics, 1968