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 (CNS) with a broad spectrum of clinical severity. 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 described. HPE3 on chromosome 7q36 is one of at least four different loci implicated in HPE. 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.

Holoprosencephaly (HPE) is a genetically and phenotypically heterogenous disorder involving the development of forebrain and midface, with an incidence of 1:16,000 live born and 1:250 induced abortions. This disorder is associated with several distinct facies and phenotypic variability: in the most extreme cases, anophthalmia or cyclopia is evident along with a congenital absence of the mature nose. The less severe form features facial dysmorphia characterized by ocular hypertelorism, defects of the upper lip and/or nose, and absence of the olfactory nerves or corpus callosum. Several intermediate phenotypes involving both the brain and face have been described. One of the gene loci, HPE3, maps to the terminal band of chromosome 7. We have performed extensive physical mapping studies and established a critical interval for HPE3, and subsequently identified the sonic hedgehog (SHH) gene as the prime candidate for the disorder. SHH lies within 15-250 kilobases (kb) of chromosomal rearrangements associated with HPE, suggesting that a 'position effect' has an important role in the aetiology of HPE. As detailed in the accompanying report, this role for SHH is confirmed by the detection of point mutations in hereditary HPE patients.

Diminished Sonic Hedgehog (Shh) signaling is associated with the most common forebrain defect in humans, holoprosencephaly (HPE), which includes cyclopia, a phenotype also seen in mice and other vertebrates with defective Shh signaling. The secreted protein Shh acts as a crucial factor that patterns the ventral forebrain and is required for the division of the primordial eye field and brain into two discrete halves. Gli2 is one of three vertebrate transcription factors implicated as obligatory mediators of Shh signal transduction. Here, we show that loss-of-function mutations in the human GLI2 gene are associated with a distinctive phenotype (within the HPE spectrum) whose primary features include defective anterior pituitary formation and pan-hypopituitarism, with or without overt forebrain cleavage abnormalities, and HPE-like midfacial hypoplasia. We also demonstrate that these mutations lack GLI2 activity. We report on a functional association between GLI2 and human disease and highlight the role of GLI2 in human head development.