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. 2003 Jul;40(7):473–478. doi: 10.1136/jmg.40.7.473

Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and patients previously reported to represent thalidomide embryopathy

J Kohlhase 1, L Schubert 1, M Liebers 1, A Rauch 1, K Becker 1, S Mohammed 1, R Newbury-Ecob 1, W Reardon 1
PMCID: PMC1735528  PMID: 12843316

Abstract

We have recently shown that Okihiro syndrome results from mutation in the putative zinc finger transcription factor gene SALL4 on chromosome 20q13.13-13.2. There is considerable overlap of clinical features of Okihiro syndrome with other conditions, most notably Holt-Oram syndrome, a condition in part resulting from mutation of the TBX5 locus, as well as acro-renal-ocular syndrome. We analysed further families/patients with the clinical diagnosis of Holt-Oram syndrome and acro-renal-ocular syndrome for SALL4 mutations. We identified a novel SALL4 mutation in one family where the father was originally thought to have thalidomide embryopathy and had a daughter with a similar phenotype. We also found two novel mutations in two German families originally diagnosed as Holt-Oram syndrome and a further mutation in one out of two families carrying the diagnosis acro-renal-ocular syndrome. Our results show that some cases of "thalidomide embryopathy" might be the result of SALL4 mutations, resulting in an increased risk for similarly affected offspring. Furthermore we confirm the overlap of acro-renal-ocular syndrome with Okihiro syndrome at the molecular level and expand the phenotype of SALL4 mutations.

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Selected References

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  1. Al-Baradie Raidah, Yamada Koki, St Hilaire Cynthia, Chan Wai-Man, Andrews Caroline, McIntosh Nathalie, Nakano Motoi, Martonyi E. Jean, Raymond William R., Okumura Sada. 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 Oct 22;71(5):1195–1199. doi: 10.1086/343821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Becker K., Beales P. L., Calver D. M., Matthijs G., Mohammed S. N. Okihiro syndrome and acro-renal-ocular syndrome: clinical overlap, expansion of the phenotype, and absence of PAX2 mutations in two new families. J Med Genet. 2002 Jan;39(1):68–71. doi: 10.1136/jmg.39.1.68. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Buck A., Archangelo L., Dixkens C., Kohlhase J. Molecular cloning, chromosomal localization, and expression of the murine SALL1 ortholog Sall1. Cytogenet Cell Genet. 2000;89(3-4):150–153. doi: 10.1159/000015598. [DOI] [PubMed] [Google Scholar]
  4. Cross S. J., Ching Y. H., Li Q. Y., Armstrong-Buisseret L., Spranger S., Lyonnet S., Bonnet D., Penttinen M., Jonveaux P., Leheup B. The mutation spectrum in Holt-Oram syndrome. J Med Genet. 2000 Oct;37(10):785–787. doi: 10.1136/jmg.37.10.785. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Farrell E. R., Münsterberg A. E. csal1 is controlled by a combination of FGF and Wnt signals in developing limb buds. Dev Biol. 2000 Sep 15;225(2):447–458. doi: 10.1006/dbio.2000.9852. [DOI] [PubMed] [Google Scholar]
  6. Farrell E. R., Tosh G., Church E., Münsterberg A. E. Cloning and expression of CSAL2, a new member of the spalt gene family in chick. Mech Dev. 2001 Apr;102(1-2):227–230. doi: 10.1016/s0925-4773(01)00296-9. [DOI] [PubMed] [Google Scholar]
  7. Fraisse J., Bertheas M. F., Frère F., Lauras B., Rolland M. O., Brizard C. P. Un nouveau syndrome : del(20)(q13leads to qter) localisation segmentaire de géne de l'adénosine déaminase (ADA). Ann Genet. 1981;24(4):216–219. [PubMed] [Google Scholar]
  8. Hollemann T., Schuh R., Pieler T., Stick R. Xenopus Xsal-1, a vertebrate homolog of the region specific homeotic gene spalt of Drosophila. Mech Dev. 1996 Mar;55(1):19–32. doi: 10.1016/0925-4773(95)00485-8. [DOI] [PubMed] [Google Scholar]
  9. Kohlhase J., Altmann M., Archangelo L., Dixkens C., Engel W. Genomic cloning, chromosomal mapping, and expression analysis of msal-2. Mamm Genome. 2000 Jan;11(1):64–68. doi: 10.1007/s003350010012. [DOI] [PubMed] [Google Scholar]
  10. Kohlhase J., Hausmann S., Stojmenovic G., Dixkens C., Bink K., Schulz-Schaeffer W., Altmann M., Engel W. SALL3, a new member of the human spalt-like gene family, maps to 18q23. Genomics. 1999 Dec 1;62(2):216–222. doi: 10.1006/geno.1999.6005. [DOI] [PubMed] [Google Scholar]
  11. Kohlhase J. SALL1 mutations in Townes-Brocks syndrome and related disorders. Hum Mutat. 2000 Dec;16(6):460–466. doi: 10.1002/1098-1004(200012)16:6<460::AID-HUMU2>3.0.CO;2-4. [DOI] [PubMed] [Google Scholar]
  12. Kohlhase J., Schuh R., Dowe G., Kühnlein R. P., Jäckle H., Schroeder B., Schulz-Schaeffer W., Kretzschmar H. A., Köhler A., Müller U. Isolation, characterization, and organ-specific expression of two novel human zinc finger genes related to the Drosophila gene spalt. Genomics. 1996 Dec 15;38(3):291–298. doi: 10.1006/geno.1996.0631. [DOI] [PubMed] [Google Scholar]
  13. Kohlhase J., Wischermann A., Reichenbach H., Froster U., Engel W. Mutations in the SALL1 putative transcription factor gene cause Townes-Brocks syndrome. Nat Genet. 1998 Jan;18(1):81–83. doi: 10.1038/ng0198-81. [DOI] [PubMed] [Google Scholar]
  14. Kohlhase Jürgen, Heinrich Marielle, Schubert Lucia, Liebers Manuela, Kispert Andreas, Laccone Franco, Turnpenny Peter, Winter Robin M., Reardon William. Okihiro syndrome is caused by SALL4 mutations. Hum Mol Genet. 2002 Nov 1;11(23):2979–2987. doi: 10.1093/hmg/11.23.2979. [DOI] [PubMed] [Google Scholar]
  15. Koster R., Stick R., Loosli F., Wittbrodt J. Medaka spalt acts as a target gene of hedgehog signaling. Development. 1997 Aug;124(16):3147–3156. doi: 10.1242/dev.124.16.3147. [DOI] [PubMed] [Google Scholar]
  16. Kühnlein R. P., Frommer G., Friedrich M., Gonzalez-Gaitan M., Weber A., Wagner-Bernholz J. F., Gehring W. J., Jäckle H., Schuh R. spalt encodes an evolutionarily conserved zinc finger protein of novel structure which provides homeotic gene function in the head and tail region of the Drosophila embryo. EMBO J. 1994 Jan 1;13(1):168–179. doi: 10.1002/j.1460-2075.1994.tb06246.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. McBride W. G. Thalidomide may be a mutagen. BMJ. 1994 Jun 18;308(6944):1635–1636. doi: 10.1136/bmj.308.6944.1635b. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Newbury-Ecob R. A., Leanage R., Raeburn J. A., Young I. D. Holt-Oram syndrome: a clinical genetic study. J Med Genet. 1996 Apr;33(4):300–307. doi: 10.1136/jmg.33.4.300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Nishinakamura R., Matsumoto Y., Nakao K., Nakamura K., Sato A., Copeland N. G., Gilbert D. J., Jenkins N. A., Scully S., Lacey D. L. Murine homolog of SALL1 is essential for ureteric bud invasion in kidney development. Development. 2001 Aug;128(16):3105–3115. doi: 10.1242/dev.128.16.3105. [DOI] [PubMed] [Google Scholar]
  20. Nogami H., Murachi S. Phalangeal acroosteolysis associated with Down syndrome. Birth Defects Orig Artic Ser. 1975;11(2):344–346. [PubMed] [Google Scholar]
  21. Okihiro M. M., Tasaki T., Nakano K. K., Bennett B. K. Duane syndrome and congenital upper-limb anomalies. A familial occurrence. Arch Neurol. 1977 Mar;34(3):174–179. doi: 10.1001/archneur.1977.00500150060012. [DOI] [PubMed] [Google Scholar]
  22. Onuma Y., Nishinakamura R., Takahashi S., Yokota T., Asashima M. Molecular cloning of a novel Xenopus spalt gene (Xsal-3). Biochem Biophys Res Commun. 1999 Oct 14;264(1):151–156. doi: 10.1006/bbrc.1999.1479. [DOI] [PubMed] [Google Scholar]
  23. Ott T., Kaestner K. H., Monaghan A. P., Schütz G. The mouse homolog of the region specific homeotic gene spalt of Drosophila is expressed in the developing nervous system and in mesoderm-derived structures. Mech Dev. 1996 May;56(1-2):117–128. doi: 10.1016/0925-4773(96)00516-3. [DOI] [PubMed] [Google Scholar]
  24. Pesonen E., Merritt A. T., Heldt G., Sahn D. J., Elias W., Tikkanen I., Fyhrquist F., Andersson S. Correlation of patent ductus arteriosus shunting with plasma atrial natriuretic factor concentration in preterm infants with respiratory distress syndrome. Pediatr Res. 1990 Feb;27(2):137–139. doi: 10.1203/00006450-199002000-00010. [DOI] [PubMed] [Google Scholar]
  25. Shabtai F., Ben-Sasson E., Arieli S., Grinblat J. Chromosome 20 long arm deletion in an elderly malformed man. J Med Genet. 1993 Feb;30(2):171–173. doi: 10.1136/jmg.30.2.171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sweetman Dylan, Smith Terry, Farrell Elizabeth R., Chantry Andrew, Munsterberg Andrea. The conserved glutamine-rich region of chick csal1 and csal3 mediates protein interactions with other spalt family members. Implications for Townes-Brocks syndrome. J Biol Chem. 2002 Dec 13;278(8):6560–6566. doi: 10.1074/jbc.M209066200. [DOI] [PubMed] [Google Scholar]

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