Molecular and Developmental Analysis of Holoprosencephaly

Icahn School Of Medicine At Mount Sinai, New York NY

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Abstract

DESCRIPTION (provided by applicant): Holoprosencephaly (HPE) is a common human developmental defect caused by failure to define the midline of the forebrain and/or midface. HPE is associated with heterozygous mutations in NODAL and Sonic hedgehog (SHH) pathway components, but clinical presentation is highly variable, and many mutation carriers are unaffected. It is therefore thought that such mutations must interact with more common modifiers, genetic and/or environmental. Furthermore, many distinct variant alleles are observed for individual HPE-associated genes. HPE is therefore characterized by a lack of clear genotype-phenotype correlation and by high genetic heterogeneity. These phenomena have prevented a deep understanding of HPE etiology and made it difficult to provide counseling to mutation carriers. Two significant issues need to be addressed to provide accurate information: 1) interactions between bona fide pathogenic mutations and the modifiers that grade penetrance and expressivity must be identified and understood mechanistically; and 2) specific HPE-associated genetic variants must be analyzed to prove that they are functionally deficient and identify the underlying mechanism. This proposal addresses both issues. We have modeled HPE in mice. CDON encodes a multifunctional coreceptor that promotes signaling by several pathways, including the SHH pathway. Mice with a mutation in Cdon have a largely subthreshold defect in SHH signaling. These mice are sensitive to induction of a spectrum of craniofacial and forebrain HPE phenotypes by genetic or environmental modifiers that are, themselves, insufficient to produce HPE. Among these modifiers is transient fetal alcohol exposure during gastrulation. New findings indicate that, in addition to its role in SHH signaling, CDON interacts with components of the NODAL receptor complex. Furthermore, transient inhibition of NODAL pathway activity appears to be the point of synergistic interaction between loss of CDON and fetal alcohol exposure. Regulation of NODAL signaling represents a new role for CDON, complementing its function in SHH signaling during midline patterning of the face and forebrain. We have also identified and characterized loss-of-function CDON mutations in human HPE. Other components of the SHH receptor complex are also mutated in human HPE, including PTCH1 and BOC, but there is little information on whether and how these receptor variants are defective in SHH signaling. The following Aims are proposed: 1) to determine genetic and mechanistic interactions between CDON and the NODAL pathway; and 2) to determine the functional and mechanistic consequences of HPE-associated variants in BOC and PTCH1. The successful completion of the proposed aims will provide important information about: 1) how environmental factors interact with predisposing mutations, thus providing a basis for preventive action; and 2) the pathogenic nature of specific patient mutations. Therefore, these studies are expected to aid in the counseling of individuals whose offspring may be genetically predisposed to HPE.