Duane Radial Ray Syndrome (Okihiro Syndrome) Maps to 20q13 and Results from Mutations in SALL4, a New Member of the SAL Family

Department of Neurology, Children's Hospital Boston, Harvard Medical School, MA 02115, USA.
The American Journal of Human Genetics (Impact Factor: 10.99). 12/2002; 71(5):1195-9. DOI: 10.1086/343821
Source: PubMed

ABSTRACT Duane syndrome is a congenital eye movement disorder characterized most typically by absence of abduction, restricted adduction, and retraction of the globe on attempted adduction. Duane syndrome can be coinherited with radial ray anomalies as an autosomal dominant trait, referred to as "Okihiro syndrome" or "Duane radial ray syndrome" (DRRS). We ascertained three pedigrees with DRRS and mapped their disease gene to a 21.6-cM region of chromosome 20 flanked by markers D20S888 and D20S102. A new member of the SAL family of proposed C(2)H(2) zinc finger transcription factors, SALL4, falls within the region. Mutation analysis of SALL4 in the three pedigrees revealed one nonsense and two frameshift heterozygous mutations. SALL4 represents the first identified Duane syndrome gene and the second malformation syndrome resulting from mutations in SAL genes and likely plays a critical role in abducens motoneuron development.

Download full-text


Available from: Raidah Al-Baradie, Mar 15, 2014
1 Follower
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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 · 3.48 Impact Factor
  • Source
    • "Four mammalian genes have been identified, and are widely expressed throughout development (Kohlhase et al. 1996, 1999, 2000; Ott et al. 1996, 2001; Buck et al. 2000, 2001; Al-Baradie et al. 2002; Kohlhase, Heinrich, Liebers, et al. 2002; Kohlhase, Heinrich, Schubert, et al. 2002). Mutation or deletion of these genes in humans is associated with distinct disorders with abnormalities in the limbs, ear, anus, kidney, and heart (Kohlhase et al. 1996, 1999; Al-Baradie et al. 2002; Kohlhase, Heinrich, Schubert, et al. 2002). In Drosophila and other species Sall proteins have been implicated in processes regulating development, including cell fate specification, neuronal differentiation, migration, and cell adhesion (Jurgens 1988; Kuhnlein and Schuh 1996; de Celis et al. 1999; Cantera et al. 2002; Franch-Marro and Casanova 2002; Toker et al. 2003; Barembaum and Bronner-Fraser 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sall1 is a zinc finger containing transcription factor that is highly expressed during mammalian embryogenesis. In humans, the developmental disorder Townes Brocks Syndrome is associated with mutations in the SALL1 gene. Sall1-deficient animals die at birth due to kidney deficits; however, its function in the nervous system has not been characterized. We examined the role of Sall1 in the developing olfactory system. We demonstrate that Sall1 is expressed by cells in the olfactory epithelium and olfactory bulb (OB). Sall1-deficient OBs are reduced in size and exhibit alterations in neurogenesis and mitral cell production. In addition, the olfactory nerve failed to extend past the ventral-medial region of the OB in Sall1-deficient animals. We observed intrinsic patterns of neurogenesis during olfactory development in control animals. In Sall1-mutant animals, these patterns of neurogenesis were disrupted. These findings suggest a role for Sall1 in regulating neuronal differentiation and maturation in developing neural structures.
    Cerebral Cortex 08/2008; 18(7):1604-17. DOI:10.1093/cercor/bhm191 · 8.67 Impact Factor
  • Source
    • "In the cases of human and murine SALL2/Sall2 and SALL4/Sall4, alternative spliced forms have been described that lack this repression domain that would function independently of the NuRD repression complex, although the functional role of these alternative forms is still unexplored. The N-terminal part of the Sall1 shows localization to heterochromatin foci when fused to a nuclear localization signal, suggesting an association between transcriptional repression and protein location (Kiefer et al., 2002; Sato et al., 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The genes of the spalt (sal) family play fundamental roles during animal development. The two members of this family in Drosophila, spalt (sal) and spalt-related (salr) encode Zn-finger transcription factors that link the Decapentaplegic (Dpp)/BMP signalling pathway to the patterning of the wing. They are regulated by the Dpp pathway in the wing disc, and they were shown to mediate some of the morphogenetic activities of the Dpp/BMP4 secreted ligand. The sal genes were initially found by virtue of mutations that produce homeotic transformations in the head and tail of the Drosophila embryo. Since then, a number of other requirements have been associated to these genes in Drosophila, including morphogenesis of the respiratory system, cell fate specification of sensory organs and the differentiation of several photoreceptor cells, among others. Vertebrate sal orthologues (spalt-like/sall) have also important developmental roles during neural development and organogenesis, and at least two human sall genes are linked to the genetic diseases Townes Brocks Syndrome (TBS; SALL1 ) and Okihiro Syndrome (OS; SALL4 ). In this review, we will summarize the main characteristics of the sall genes and proteins, pointing out to the similarities in their developmental roles during Drosophila and vertebrate development.
    The International journal of developmental biology 03/2008; 53(8-10):1385-98. DOI:10.1387/ijdb.072408jd · 2.57 Impact Factor
Show more