Expression of the Sonic hedgehog (SHH) gene during early human developmentand phenotypic expression of new mutations causing holoprosencephaly

Holoprosencephaly (HPE), the most common developmental defect of the forebr ain and the face, is genetically heterogeneous. One of the genes involved, Sonic hedgehog (SHH), on 7q36, has been identified as the first HPE-causing gene both in mouse and humans, In order to delineate the phenotype of spec ific SHH mutations, we described the expression of the SHH gene during earl y human embryogenesis and investigated the phenotype of novel SHH mutations . In situ hybridization studies were performed on paraffin-embedded human e mbryo sections at three different development stages. These studies show th at SHH is expressed in the notochord, the floorplate, the brain, the zone o f polarizing activity and the gut. We also report on the phenotype of four novel mutations identified in 40 HPE families (two in isolated HPE and two in familial HPE), Expressivity ranged from alobar HPE to microcephaly and h ypoplasia of the pituitary gland in one family, and from HPE to an asymptom atic form in another family. No SHH mutation was found in six polymalformed cases combining HPE with other defects, such as skeletal, limb, cardiac, a nal and/or renal anomalies. This study confirms the genetic heterogeneity o f HPE, and further demonstrates that SHH mutations are associated with a br oad spectrum of cerebral midline defects.