Nature Genetics
14, 357 - 360 (1996)
doi:10.1038/ng1196-357
Mutations in the human Sonic Hedgehog gene cause holoprosencephalyErich Roessler1, Elena Belloni2, Karin Gaudenz1, Philippe Jay3, Philippe Berta3, Stephen W. Scherer2, Lap-Chee Tsui2
& Maximilian Muenke1, 4
1The 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, 34th & Civic Center Boulevard, Pennsylvania 19104-4399, US
2The Hospital for Sick Children, Department of Genetics, 555 University Avenue, Toronto, Ontario M5G1X8, Canada
3Centre de Recherches de Biochimie Macromoléculaire, CNRS
ERS 155-INSERM U249, 34033 Montpellier cedex, France
4e-mail: muenke@mailmed.upenn.edu Holoprosencephaly (HPE) is a common developmental defect of the forebrain and frequently the midface in humans, with both genetic and environmental causes. HPE has a prevalence of 1:250 during embryogenesis and 1:16,000 newborn infants, and involves incomplete development and septation of midline structures in the central nervous system (CMS) with a broad spectrum of clinical severity1−3. Alobar HPE, the most severe form which is usually incompatible with postnatal life, involves complete failure of division of the forebrain into right and left hemispheres and is characteristically associated with facial anomalies including cyclopia, a primitive nasal structure (proboscis) and/or midfacial clefting. At the mild end of the spectrum, findings may include microcephaly, mild hypotelorism, single maxillary central incisor and other defects (Fig. 1). This phenotypic variability also occurs between affected members of the same family. The molecular basis underlying HPE is not known, although teratogens, non-random chromosomal anomalies, and familial forms with autosomal dominant and recessive inheritance have been described4. HPE3 on chromosome 7q36 is one of at least four different loci implicated in HPE5−9. Here, we report the identification of human Sonic Hedgehog (SHH) as HPE3 — the first known gene to cause HPE. Analyzing 30 autosomal dominant HPE (ADHPE) families, we found five families that segregate different heterozygous SHH mutations. Two of these mutations predict premature termination of the SHH protein, whereas the others alter highly conserved residues in the vicinity of the alpha-helix-1 motif or signal cleavage site.
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