title: Truncating loss-of-function mutations of DISP1 contribute to holoprosencephaly-like microform features in humans.
abstract: Defective function of the Sonic Hedgehog (SHH) signaling pathway is the most frequent alteration underlying holoprosencephaly (HPE) or its various clinical microforms. We performed an extensive mutational analysis of the entire human DISP1 gene, required for secretion of all hedgehog ligand(s) and which maps to the HPE 10 locus of human chromosome 1q41, as a HPE candidate gene. Here, we describe two independent families with truncating mutations in human DISP1 that resemble the cardinal craniofacial and neuro-developmental features of a recently described microdeletion syndrome that includes this gene; therefore, we suggest that DISP1 function contributes substantially to both of these signs in humans. While these clinical features are consistent with common HPE microforms, especially those linked to defective signaling by Sonic Hedgehog, we have insufficient evidence so far that functionally abnormal DISP1 alleles will commonly contribute to the more severe features of typical HPE.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, 35 Convent Drive-MSC 3717, Building 35, Bethesda, MD 20892-3717, USA.
authors.forename: Erich
authors.initials: E
authors.lastname: Roessler
authors.forename: Yong
authors.initials: Y
authors.lastname: Ma
authors.forename: Maia V
authors.initials: MV
authors.lastname: Ouspenskaia
authors.forename: Felicitas
authors.initials: F
authors.lastname: Lacbawan
authors.forename: Claude
authors.initials: C
authors.lastname: Bendavid
authors.forename: Christèle
authors.initials: C
authors.lastname: Dubourg
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beachy
authors.forename: Maximilian
authors.initials: M
authors.lastname: Muenke
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D014644:Genetic Variation; D016142:Holoprosencephaly / Q000235:genetics*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D000072079:Patched Receptors; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; D014162:Transfection
chemical_list: D017931:DNA Primers; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins