The full spectrum of holoprosencephaly-associated mutations within the ZIC2 gene in humans predicts loss-of-function as the predominant disease mechanism.
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.
Roessler
Erich
E
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-3717, USA.
Lacbawan
Felicitas
F
Dubourg
Christèle
C
Paulussen
Aimee
A
Herbergs
Jos
J
Hehr
Ute
U
Bendavid
Claude
C
Zhou
Nan
N
Ouspenskaia
Maia
M
Bale
Sherri
S
Odent
Sylvie
S
David
Vèronique
V
Muenke
Maximilian
M
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
D009687:Nuclear Proteins; D014157:Transcription Factors; C491812:ZIC2 protein, human