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, GermanyHuman Genetics (Impact Factor: 4.82). 04/2006; 119(1-2):154-61. DOI: 10.1007/s00439-005-0124-7
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 , 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 . 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 . "
ABSTRACT: Radial deficiencies (RDs), defined as under/abnormal development or absence of any of the structures of the forearm, radial carpal bones and thumb, occur with a live birth incidence ranging from 1 out of 30,000 to 1 out 6,000 newborns and represent about one third/one fourth of all the con genital upper limb anomalies. About half of radial disorders have a mendelian cause and pattern of inheritance, whereas the remaining half appears sporadic with no known gene involved. In sporadic forms certain anomalies, such as thumb or radial hypoplasia, may occur either alone or in association with systemic conditions, like vertebral abnormalities or renal defects. All the cases with a mendelian inheritance are syndromic forms, which include cardiac defects (in Holt-Oram syndrome), bone marrow failure (in Fanconi anemia), platelet deficiency (in thrombocytopenia-absent-radius syndrome), ocular motility impairment (in Okihiro syndrome). The genetics of radial deficiencies is complex, characterized by genetic heterogeneity and high inter- and intra-familial clinical variability: this review will analyze the etiopathogenesis and the genotype/phenotype correlations of the main radial deficiency disorders in humans.Current Genomics 05/2015; 16(999):1-1. DOI:10.2174/1389202916666150528000412 · 2.34 Impact Factor
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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). "
ABSTRACT: Pluripotency associated transcription factor, SAL-Like 4 (SALL4), might play an important role in conferring totipotency on oocytes. In the present study, we screened SALL4 coding regions for mutations in 100 Han Chinese women with non-syndromic ovarian failure and discovered two novel non-synonymous variants in the SALL4 gene: c.541G>A (p.Val181Met) and c.2449A>G. (p.Thr817Ala). The former variant was located in an evolutionary conserved region of SALL4 protein and might affect its function. This is the first report to suggest that SALL4 might be a potential candidate gene of premature ovarian failure.Molecular Human Reproduction 08/2009; 15(9):557-62. DOI:10.1093/molehr/gap046 · 3.75 Impact Factor
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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). "
ABSTRACT: Pluripotency of embryonic stem (ES) cells is maintained by a network consisting of multiple transcription factors, including Oct3/4, Sox2, Nanog, Klf4 and Sall4. Among these factors, the forced expressions of Oct3/4, Sox2 and Klf4 are sufficient to reprogram fibroblasts into induced pluripotent stem (iPS) cells. The current study analyzed the role of Sall4 during the generation of ES cells and iPS cells. The mouse Sall4 gene was deleted by homologous recombination. Sall4-null embryos died shortly after implantation, as has been reported. ES-like cell lines can be established from Sall4-null blastocysts, albeit with a lower efficiency and a slower time course. The knockdown of Sall4 significantly decreased the efficiency of iPS cell generation from mouse fibroblasts. Furthermore, retroviral transduction of Sall4 significantly increased the efficiency of iPS cell generation in mouse and some human fibroblast lines. These results demonstrated that Sall4 plays positive roles in the generation of pluripotent stem cells from blastocysts and fibroblasts.Genes to Cells 06/2009; 14(6):683-94. DOI:10.1111/j.1365-2443.2009.01301.x · 2.81 Impact Factor
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