title: Functional analysis of mutations in TGIF associated with holoprosencephaly.
abstract: Holoprosencephaly (HPE) is the most common structural malformation of the forebrain and face in humans. Our current understanding of the pathogenesis of HPE attempts to integrate genetic susceptibility, evidenced by mutations in the known HPE genes, with the epigenetic influence of environmental factors. Mutations or deletions of the human TGIF gene have been associated with HPE in multiple population cohorts. Here we examine the functional effects of all previously reported mutations, and describe four additional variants. Of the eleven sequence variations in TGIF, all but four can be demonstrated to be functionally abnormal. In contrast, no potentially pathogenic sequence alterations were detected in the related gene TGIF2. These results provide further evidence of a role for TGIF in HPE and demonstrate the importance of functional analysis of putative disease-associated alleles.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-3717, USA.
authors.forename: Kenia B
authors.initials: KB
authors.lastname: El-Jaick
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Powers
authors.forename: Laurent
authors.initials: L
authors.lastname: Bartholin
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Myers
authors.forename: Jin
authors.initials: J
authors.lastname: Hahn
authors.forename: Ieda M
authors.initials: IM
authors.lastname: Orioli
authors.forename: Maia
authors.initials: M
authors.lastname: Ouspenskaia
authors.forename: Felicitas
authors.initials: F
authors.lastname: Lacbawan
authors.forename: Erich
authors.initials: E
authors.lastname: Roessler
authors.forename: David
authors.initials: D
authors.lastname: Wotton
authors.forename: Maximilian
authors.initials: M
authors.lastname: Muenke
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D016142:Holoprosencephaly / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012097:Repressor Proteins / Q000235:genetics* / Q000502:physiology
chemical_list: D018398:Homeodomain Proteins; D012097:Repressor Proteins; C097504:TGIF1 protein, human