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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
Open accessAbstract
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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“HIC1, HIC2, GZF1, OSR1, OSR2, and SALL4 have all been implicated in development”
From Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN (2018) · cites this paper as [30]
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“and could contribute to developmental abnormalities in fetuses exposed to thalidomide (25–30).”
From Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN (2018) · cites this paper as [30]
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“Remarkably, both DRRS and HOS have large phenotypic overlaps with thalidomide embryopathy (Kohlhase et al., 2003)”
From Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome (2018) · cites this paper as Kohlhase et al., 2003
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“Several of the ZFs identified as degraded in functional experiments, or in vitro binders that could be targeted with further drug development, have been implicated in human disease.”
From Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN (2018) · cites this paper as [30]
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“Strikingly, human genetic research has shown that familial loss of function (LOF) mutations in SALL4 are causatively linked to the clinical syndromes, Duane Radial Ray syndrome (DRRS) also known as Okihiro syndrome, and mutated in some patients with Holt-Oram syndrome (HOS).”
From Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome (2018) · cites this paper as Kohlhase et al., 2003
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Citations
Cites
Mutations in the SALL1 putative transcription factor gene cause Townes-Brocks syndrome
Kohlhase, J., Wischermann, A., Reichenbach, H., Froster, U., & Engel, W. (1998) · Nature Genetics · doi:10.1038/ng0198-81 · Cited by 481
Self-citationMurine homolog of SALL1 is essential for ureteric bud invasion in kidney development
Nishinakamura, R., Matsumoto, Y., Nakao, K., Nakamura, K., Sato, A., Copeland, N. G., Gilbert, D. J., Jenkins, N. A., Scully, S., Lacey, D. L., et al. (2001) · Development · doi:10.1242/dev.128.16.3105 · Cited by 358
Okihiro syndrome is caused by SALL4 mutations
Kohlhase, J. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.23.2979 · Cited by 320
Self-citationAl-Baradie, R., Yamada, K., St. Hilaire, C., Chan, W.-M., Andrews, C., McIntosh, N., Nakano, M., Martonyi, E. J., Raymond, W. R., Okumura, S., et al. (2002) · The American Journal of Human Genetics · doi:10.1086/343821 · Cited by 314
Holt-Oram syndrome: a clinical genetic study.
Newbury-Ecob, R. A., Leanage, R., Raeburn, J. A., & Young, I. D. (1996) · Journal of Medical Genetics · doi:10.1136/jmg.33.4.300 · Cited by 256
Self-citationKühnlein, R. P., Frommer, G., Friedrich, M., González‐Gaitán, M., Weber, A. P. M., Wagner-Bernholz, J. F., Gehring, W. J., Jäckle, H., & Schuh, R. (1994) · The EMBO Journal · doi:10.1002/j.1460-2075.1994.tb06246.x · Cited by 249
Kohlhase, J., Schuh, R., Dowe, G., Kühnlein, R. P., Jäckle, H., Schroeder, B., Schulz-Schaeffer, W., Kretzschmar, H. A., Köhler, A., Müller, U., et al. (1996) · Genomics · doi:10.1006/geno.1996.0631 · Cited by 145
Self-citationMedaka spalt acts as a target gene of hedgehog signaling
Köster, R. W., Stick, R., Loosli, F., & Wittbrodt, J. (1997) · Development · doi:10.1242/dev.124.16.3147 · Cited by 120
SALL3, a new member of the human spalt-like gene family, maps to 18q23.
Kohlhase, J., Hausmann, S., Stojmenovic, G., Dixkens, C., Bink, K., Schulz-Schaeffer, W., Altmann, M., & Engel, W. (1999) · Genomics · doi:10.1006/geno.1999.6005 · Cited by 97
Self-citationDuane Syndrome and Congenital Upper-Limb Anomalies
Okihiro, M. M. (1977) · Archives of Neurology · doi:10.1001/archneur.1977.00500150060012 · Cited by 94
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Cited by
Sorted by citations
Thalidomide-induced Teratogenesis: History and Mechanisms
Vargesson, N. (2015) · Birth Defects Research Part C Embryo Today Reviews · doi:10.1002/bdrc.21096 · Cited by 912
Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN
Sievers, Q. L., Petzold, G., Bunker, R. D., Renneville, A., Słabicki, M., Liddicoat, B. J., Abdulrahman, W., Mikkelsen, T., Ebert, B. L., & Thomä, N. H. (2018) · Science · doi:10.1126/science.aat0572 · Cited by 537
Donovan, K. A., An, J., Nowak, R. P., Yuan, J. C., Fink, E. C., Berry, B. C., Ebert, B. L., & Fischer, E. S. (2018) · eLife · doi:10.7554/elife.38430 · Cited by 509
“, 2003), and this phenotypic resemblance has led to misdiagnosis of patients with SALL4 mutations as cases of thalidomide embryopathy and the hypothesis that the tbx5/sall4 axis might be involved in thalidomide pathogenesis (Knobloch and Rüther, 2008; Kohlhase et al., 2003).”
BackgroundDevelopment of targeted protein degradation therapeutics
Chamberlain, P. P., & Hamann, L. G. (2019) · Nature Chemical Biology · doi:10.1038/s41589-019-0362-y · Cited by 489
SALL4 mediates teratogenicity as a thalidomide-dependent cereblon substrate
Matyskiela, M. E., Couto, S., Zheng, X., Lu, G., Hui, J., Stamp, K., Drew, C., Ren, Y., Wang, M., Carpenter, A., et al. (2018) · Nature Chemical Biology · doi:10.1038/s41589-018-0129-x · Cited by 338
Metadata
- Authors
- Kohlhase, J., Schubert, L., Liebers, M., Rauch, A., Becker, K., Mohammed, S. N., Newbury-Ecob, R., & Reardon, W.
- Affiliations
- University of Göttingen (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Northwick Park Hospital (GB)
- Guy's Hospital (GB)
- St Michael's Hospital (GB)
- Children's Health Ireland at Crumlin (IE)
- Corresponding author
- Kohlhase, J
- ORCID
- Venue
- Journal of Medical Genetics
- Publisher
- BMJ
- Published
- 2003-07
- Volume
- 40
- Issue
- 7
- Pages
- 473-478
- ISSN
- 0022-2593 (ISSN-L)
- 1468-6244
- PMC
- PMC1735528
- OpenAlex
- W2142039491
- Cited by
- 185
- References
- 28
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 12 · 2023: 4 · 2022: 10 · 2021: 5 · 2020: 10 · 2019: 7 · 2018: 10 · 2017: 5 · 2016: 11 · 2015: 8 · 2014: 12 · 2013: 7 · 2012: 6
- FWCI
- 5.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Medical Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- GRO (submittedVersion)
- Funders
- Hospital for Sick Children
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Developmental Biology › Congenital limb and hand anomalies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- SALL4, Holt-Oram syndrome, thalidomide embryopathy, zinc finger transcription factor, TBX5, novel mutations, genotype-phenotype overlap, congenital heart disease, limb malformations
- MeSH terms
- Abnormalities, Multiple, Base Sequence, Chromosomes, Human, Pair 20, DNA, DNA Mutational Analysis, Duane Retraction Syndrome, Family Health, Female, Fetal Diseases, Hand Deformities, Congenital, Heart Septal Defects, Atrial, Humans, Kidney, Male, Mutation, Pedigree, Phenotype, Thalidomide, Thumb, Transcription Factors
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