Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired

Abstract

Holoprosencephaly (HPE) is the most common structural anomaly of the human brain and is one of the anomalies seen in patients with deletions and duplications of chromosome 13. On the basis of molecular analysis of a series of patients with hemizygous deletions of the long arm of chromosome 13, we have defined a discrete region in band 13q32 where deletion leads to major developmental anomalies (the 13q32 deletion syndrome). This approximately 1-Mb region lies between markers D135136 and D13S147. Patients in which this region is deleted usually have major congenital malformations, including brain anomalies such as HPE or exencephaly, and digital anomalies such as absent thumbs. We now report that human ZIC2 maps to this critical deletion region and that heterozygous mutations in ZIC2 are associated with HPE. Haploinsufficiency for ZIC2 is likely to cause the brain malformations seen in 13q deletion patients.

TGIF, a gene associated with human brain defects, regulates neuronal development

“…HPE is etiologically heterogeneous, and a number of both environmental and genetic causes have been identified (Muenke and Beachy, 2000;Ming and Muenke, 2002). Mutations in seven genes have been noted to cause human HPE: SHH (Roessler et al, 1996(Roessler et al, , 1997, ZIC2 (Brown et al, 1998), SIX3 (Wallis et al, 1999), TGIF (Gripp et al, 2000), PTCH (Ming et al, 2002b), TDGF1 (De La Cruz et al, 2002), and GLI2 (Roessler et al, 2003). Several other candidate genes for HPE also exist (Kamnasaran et al, 2005).…”

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).…”

Zic2 regulates the kinetics of neurulation

“…Recently, it was reported that mutations in human ZIC2 cause HPE (3). ZIC2 is a zinc finger protein homologous to Drosophila odd-paired (opa), which is required for the timely activation of a segment polarity gene, wingless, in the parasegment of the embryo (4,5).…”