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Learn about SALL4
> Duane syndrome with radial ray anomalies
SALL4 is the causative gene for Duane syndrome with radial ray anomalies (DRRS)-Okihiro syndrome.
The diagram to the right displays the predicted SALL1-4 protein structures. SALL4 contains one NH2-terminus C2HC-type finger (ZF; black circle) and 7 C2H2-type ZF (oval) domains. The latter are arranges as double ZFs (DZF), with a third finger associated with the second doublet (white oval). The first finger of each pair contains a somewhat variable sequence (yellow, orange and blue ovals), whereas the second finger of each pair contains the conserved SAL-box sequence, FT/STKGNLK (red ovals). The homologies to SALL1-3 are shown. SALL2 also contains three DZF motifs; the first two are highly similar to the other proteins, but the third is divergent (gray ovals).

In contrast, SALL1 and SALL3 each contain three DZF motifs located between the second and third DZF in SALL4. The positions of the SALL4 splice junctions and the three mutations identified by our laboratory in 3 pedigrees whose affected individuals had DRRS1 are superimposed on the schematic protein (V, FN and DA-referring to the 3 different pedigrees). The three mutations are predicted to result in unstable mRNAs or truncated proteins disrupting the fifth and/or lacking the sixth and seventh DZF motifs.

In a recent paper2 Kohlhase et al determined that Okihiro and acrorenalocular syndromes are the result of SALL4 haploinsufficiency (a situation in which the total level of a gene product (a particular protein) produced by the cell is about half of the normal level and that is not sufficient to permit the cell to function normally). These studies examined a loss of heterozygosity in DRS families in whom SALL4 mutations had not previously been identified. Their findings suggest that Duane syndrome with radial ray anomalies are not only caused by truncating(causing shortening of the derived protein) SALL4 mutations but also by deletions of either the whole gene or of single exons.
We are still interested in enrolling individuals with these disorders in our genetic studies and would screen your DNA for SALL4 mutations. Please contact Caroline Caroline Andrews for more information on enrollment. If we were to identify a SALL4 mutation in your DNA, and if you had indicated an interest in results being reported to you, Caroline can coordinate for the CLIA certified DNA Diagnostic Laboratory based at Children's Hospital Boston to undertake confirmatory testing such that results may be released to you.
References
Online Mendelian Inheritance in Man (OMIM). Victor A. McKusick, Editor, Johns Hopkins University, creation date 11/12/2003 (entry number *607343). Home page: http://www3.ncbi.nlm.nih.gov/Omim/

1. Al-Baradie R, Yamada K, St Hilaire C, Chan WM, Andrews C, McIntosh N, Nakano M, Martonyi EJ, Raymond WR, Okumura S, Okihiro MM, Engle EC. Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family. Am J Hum Genet. 2002 Nov;71(5):1195-9. Epub 2002 Oct 22.
2. Borozdin W, Boehm D, Leipoldt M, Wilhelm C, Reardon W, Clayton-Smith J, Becker K, Muhlendyck H, Winter R, Giray O, Silan F, Kohlhase J. SALL4 deletions are a common cause of Okihiro and acro-renal-ocular syndromes and confirm haploinsufficiency as the pathogenic mechanism. J Med Genet. 2004 Sep;41(9):e113

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