This is a proposal to identify and characterize genes whose products are necessary for the development of the central nervous system. The strategy is to identify genes in which mutations cause holoprosencephaly (HPE) in humans. HPE is associated with abnormalities in midline development of the brain and face. Severe forms of HPE present with a single brain ventricle and cyclopia while milder cases have mental retardation and other developmental disabilities. Both familial and sporadic forms of HPE exist. Thus, the P.I. hypothesizes that HPE is caused by alterations in genes whose products are critical for proper early brain development. To address this hypothesis the P.I. has concerted molecular genetic analyses to those forms of HPA associated with cytogenetic deletions and translocations in 21q22.3 (HPE1), 2p21 (HPE2), 7q36 (HPE3), and 18p11.3 (HPE4). Recently, HPE3 was shown to be due to mutations in the human Sonic Hedgehog gene. Future efforts will be directed at five specific aims: 1) Map mutations in the human SHH gene in familial and sporadic HPE, 2) examine the biological consequences of the these mutations in SHH, 3) Determine whether other genes in the SHH signaling pathway are candidates for other forms of HPE, 4) Screen the critical chromosomal regions for HPE1 and HPE4 for candidate genes, and 5) Use positional cloning to identify and characterize HPE genes.
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