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

University of Freiburg, Freiburg, Baden-Württemberg, Germany
Human Genetics (Impact Factor: 4.82). 04/2006; 119(1-2):154-61. DOI: 10.1007/s00439-005-0124-7
Source: PubMed


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.

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    • "The phenotype of larger deletions (not extending into other genes) is not significantly different from that caused by almost all truncating point mutations [128], which are all expected to result in nonsense-mediated mRNA decay. One missense mutation, His888Arg, has been reported in a mild form of the syndrome [129]. Mutations in SALL4 have been also reported in patients with an initial diagnosis of VAC- TERL (Gln166*) and HOS (Lys175*, Arg617*, Val754Met, Glu889*), which was later revised to DDRS [126]. "
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    • "Several studies have proposed that heterozygous mutations in human SALL4 are the cause of Duane Radial Ray Syndrome (Okihiro syndrome), which is characterized by eye retraction in association with limb and multiple developmental defects in other organs (Al-Baradie et al., 2002; Kohlhase et al., 2002; Miertus et al., 2006). The murine Sall4 gene is expressed in oocytes (Su et al., 2002) and binds to the highly conserved regulatory region of the Pou5f1 (also known as Oct4) distal enhancer activating Pou5f1 expression in vivo and in vitro (Zhang et al., 2006). "
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    • "In human, mutations at the SALL4 locus cause an autosomal dominant disorder known as Okihiro syndrome, which is characterized by limb deformity, eye movement deficits and, less commonly, anorectal, ear, heart, cranial midline and kidney anomalies (Kohlhase et al. 2002b, 684 2005; Miertus et al. 2006). Similar phenotypes were reported in Sall4 heterozygous mutant mice (Koshiba- Takeuchi et al. 2006; Sakaki-Yumoto et al. 2006; Warren et al. 2007). "
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