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: 10.93). 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.

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Available from: Raidah Al-Baradie, Mar 15, 2014
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    • "This association was earlier thought to be a distinct entity and referred to as 'acro-renal-ocular syndrome' [123], but it is now considered as a continuum of the DRRS spectrum of anomalies, due to the finding in patients with acro-renal-ocular syndrome of heterozygous mutations in SALL4 (Spalt-like transcription factor 4), the causative gene of the DRRS [124]. SALL4, localized on chromosome 20q13, belongs to the SALL family of zinc finger transcription factors and consists of 4 exons containing three highly conserved C2H2 double zinc finger domains [125]. SALL4 mutations are located in exon 2 and, to a lesser extent, in exon 3 and consist of highly penetrant (95%), heterozygous small and gross deletions, small insertions , small indels, short duplications, nonsense mutations (Gln652*, Ser763*, Arg831*, Arg865*, Arg905*) [126] [127]. "
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    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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    • "Linkage analyses of DRS have successfully mapped its associated loci to chromosomes 2q13, 4q27, 8q13, 22q11, and 20q13 [10-13]. Recently mutations of the sal-like 4 (SALL4; MIM# 607343) gene on chromosome 20 have been linked to DRS or DRS associated with radial forearm malformations, also known as Okihiro syndrome [14-17]. "
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    ABSTRACT: To determine the underlying genetic cause of Duane retraction syndrome (DRS) in a non-consanguineous Chinese Han family. Detailed ophthalmic and physical examinations were performed on all members from a pedigree with DRS. All exons and their adjacent splicing junctions of the sal-like 4 (SALL4) gene were amplified with polymerase chain reaction and analyzed with direct sequencing in all the recruited family members and 200 unrelated control subjects. Clinical examination revealed a broad spectrum of phenotypes in the DRS family. Mutation analysis of SALL4 identified a novel heterozygous duplication mutation, c.1919dupT, which was completely cosegregated with the disease in the family and absent in controls. This mutation was predicted to cause a frameshift, introducing a premature stop codon, when translated, resulting in a truncated SALL4 protein, i.e., p.Met640IlefsX25. Bioinformatics analysis showed that the affected region of SALL4 shared a highly conserved sequence across different species. Diversified clinical manifestations were observed in the c.1919dupT carriers of the family. We identified a novel truncating mutation in the SALL4 gene that leads to diversified clinical features of DRS in a Chinese family. This mutation is predicted to result in a truncated SALL4 protein affecting two functional domains and cause disease development due to haploinsufficiency through nonsense-mediated mRNA decay.
    Molecular vision 05/2013; 19:986-994. · 1.99 Impact Factor
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    • "SALL4, a newly identified zinc-finger transcription factor that is a member of the SALL gene family, was originally cloned based on its sequence homology to Drosophila spalt (sal) [7,8]. This protein plays important roles in maintaining embryonic stem cells (ESC) pluripotency and HSC/HPC self-renewal properties, and it has been recently proposed for use in CB expansion [9]. "
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    ABSTRACT: Introduction SALL4 and BMI-1 are important factors in hematopoiesis. Placental tissue (PT) and umbilical cord blood (CB) are rich in hematopoietic stem/progenitor cells (HSCs/HPCs), but their SALL4 and BMI-1 expression levels remain unknown. Methods Real-time PCR was used to determine the expression level of these genes in PT and CB from ten cases, and ten healthy donors were used as controls. Results A significantly higher BMI-1 and SALL4 gene expression level was found in PT (median: 17.548 and 34.362, respectively) than in cord blood mononuclear cells (CBMCs) (median: 2.071 and 11.300, respectively) (P = 0.0001 and P = 0.007) and healthy peripheral blood mononuclear cells (PBMCs) (median: 0.259 and 0.384, respectively) (P = 0.001 and P <0.0001), and their expression level was lower in PBMCs than in CBMCs (P = 0.029 and P = 0.002). A positive correlation between the BMI-1 and SALL4 genes was found in the PT and CB groups, while there was no significant correlation between these genes in the healthy group. There was also no significant correlation between the expression level of each gene in PT and CB. Conclusions These results describe the characteristic features of the BMI-1 and SALL4 gene expression pattern in placental tissue and cord blood. Placental tissue with higher expression level of both genes may be considered as a potential resource for SALL4-related HPC expansion.
    Stem Cell Research & Therapy 04/2013; 4(2):49. DOI:10.1186/scrt199 · 3.37 Impact Factor
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