title: A SALL4 zinc finger missense mutation predicted to result in increased DNA binding affinity is associated with cranial midline defects and mild features of Okihiro syndrome.
abstract: Truncating mutations of the gene SALL4 on chromosome 20q13.13-13.2 cause Okihiro and acro-renal-ocular syndromes. Pathogenic missense mutations within the SALL4 or SALL1 genes have not yet been reported, raising the question which phenotypic features would be associated with them. Here we describe the first missense mutation within the SALL4 gene. The mutation results in an exchange of a highly conserved zinc-coordinating Histidine crucial for zinc finger (ZF) structure within a C2H2 double ZF domain to an Arginine. Molecular modeling predicts that this exchange does not result in a loss of zinc ion binding but leads to an increased DNA-binding affinity of the domain. The index patient shows mild features of Okihiro syndrome, but in addition cranial midline defects (pituitary hypoplasia and single central incisor). This finding illustrates that the phenotypic and functional effects of SALL4 missense mutations are difficult to predict, and that other SALL4 missense mutations might lead to phenotypes not overlapping with Okihiro syndrome.
authors.affiliation: International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34012 Trieste, Italy.
authors.forename: Jan
authors.initials: J
authors.lastname: Miertus
authors.forename: Wiktor
authors.initials: W
authors.lastname: Borozdin
authors.forename: Vladimir
authors.initials: V
authors.lastname: Frecer
authors.forename: Giorgio
authors.initials: G
authors.lastname: Tonini
authors.forename: Sara
authors.initials: S
authors.lastname: Bertok
authors.forename: Antonio
authors.initials: A
authors.lastname: Amoroso
authors.forename: Stanislav
authors.initials: S
authors.lastname: Miertus
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kohlhase
mesh_terms: D001483:Base Sequence; D001667:Binding, Competitive / Q000235:genetics; D019465:Craniofacial Abnormalities; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004370:Duane Retraction Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005192:Family Health; D005260:Female; D006801:Humans; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016335:Zinc Fingers
chemical_list: D004268:DNA-Binding Proteins; C472575:SALL4 protein, human; D014157:Transcription Factors; D004247:DNA