title: The full spectrum of holoprosencephaly-associated mutations within the ZIC2 gene in humans predicts loss-of-function as the predominant disease mechanism.
abstract: Mutations of the ZIC2 transcription factor gene are among the most common heterozygous variations detected in holoprosencephaly (HPE) patients, a patient group who lack critical midline forebrain specification due to defective embryonic signaling during development. Recent studies indicate that complete deficiency of the related murine Zic2 transcription factor can also be a contributing factor to variable midline deficiencies, presenting during mid-gastrulation, that could explain similar forebrain anomalies in this model system. Here we collect and summarize all available mutations in the human ZIC2 gene detected in HPE patients (21 published and 62 novel). Our analysis corroborates this mechanism proposed in mice by predicting loss-of-function as the likely pathogenetic mechanism common to most, if not all, of these mutations in HPE.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-3717, USA.
authors.forename: Erich
authors.initials: E
authors.lastname: Roessler
authors.forename: Felicitas
authors.initials: F
authors.lastname: Lacbawan
authors.forename: Christèle
authors.initials: C
authors.lastname: Dubourg
authors.forename: Aimee
authors.initials: A
authors.lastname: Paulussen
authors.forename: Jos
authors.initials: J
authors.lastname: Herbergs
authors.forename: Ute
authors.initials: U
authors.lastname: Hehr
authors.forename: Claude
authors.initials: C
authors.lastname: Bendavid
authors.forename: Nan
authors.initials: N
authors.lastname: Zhou
authors.forename: Maia
authors.initials: M
authors.lastname: Ouspenskaia
authors.forename: Sherri
authors.initials: S
authors.lastname: Bale
authors.forename: Sylvie
authors.initials: S
authors.lastname: Odent
authors.forename: Vèronique
authors.initials: V
authors.lastname: David
authors.forename: Maximilian
authors.initials: M
authors.lastname: Muenke
mesh_terms: D000595:Amino Acid Sequence; D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis / Q000379:methods; D016142:Holoprosencephaly / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology
chemical_list: D009687:Nuclear Proteins; D014157:Transcription Factors; C491812:ZIC2 protein, human