Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly

Abstract

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.

Expression and functional analysis of Tgif during mouse midline development

“…For example, either loss of BMP inhibitors, Chordin and Noggin, from the axial mesendoderm region or ectopic expression of BMPs in the neural plate leads to defects in ventral specification of the forebrain (Golden et al, 1999;Anderson et al, 2002). In parallel with experimental embryology studies, studies of human genetics have also identified a number of genes whose mutations are associated with human HPE including SHH, ZIC2, and CRIPTO (TDGF) (Anderson et al, 2002;Belloni et al, 1996;Brown et al, 1998;de la Cruz et al, 2002;Roessler et al, 1996). Tgif encodes a homeodomain protein that was originally identified by its ability to bind a retinoid X receptor (RXR) responsive element and inhibit activation of transcription (Bertolino et al, 1995).…”

Isolated sacral agenesis in a fetus monosomic for 7q36.1-->qter.

“…Duplications of distal 19q have been reviewed by Boyd et al,9 but none of the clinical features described in the review was present in our case, presumably because the duplicated regions in the reviewed cases were more extensive than in the present case. By contrast, the association between terminal 7q deletions and developmental anomalies of the prosencephalon and the caudal region is well known and has been reviewed by Morichon-Delvallez et al6 Three of the 13 …”

Fetal alcohol exposure impairs hedgehog cholesterol modification and signaling

“…HPE is also one of the extreme manifestations of severe fetal alcohol spectrum defects (FASD) in human embryos and in animal models of FASD. [15][16][17][18][19][20] Similarly, production of Shh in the floor plate of the neural tube regulates the development of neural components in the overlying basal plate, including progenitors of motor neurons. 12,21 FASD patients display delayed motor development and impaired fine-and gross-motor skills.…”