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HGNC Approved Gene Symbol: SETBP1
SNOMEDCT: 18899000;
Cytogenetic location: 18q12.3 Genomic coordinates (GRCh38) : 18:44,680,073-45,068,510 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q12.3 | Intellectual developmental disorder, autosomal dominant 29 | 616078 | Autosomal dominant | 3 |
| Schinzel-Giedion midface retraction syndrome | 269150 | Autosomal dominant | 3 |
By sequencing clones obtained from a size-fractionated brain cDNA library, Ishikawa et al. (1997) cloned SETBP1, which they designated KIAA0437. RT-PCR detected strong SETBP1 expression in all tissues examined.
Using the N-terminal 277 amino acids of SET (600960) in a yeast 2-hybrid screen of a HeLa cell cDNA library, followed by 5-prime RACE, Minakuchi et al. (2001) cloned SETBP1, which they called SEB. The transcript contains 2 polyadenylation signals, and the deduced protein contains 1,542 amino acids and has a calculated molecular mass of 170 kD. SETBP1 contains a central SKI (164780) homology region and a C-terminal SET-binding domain that is followed by 3 sequential PPLPPPPP repeats. SETBP1 also has 3 bipartite nuclear localization signals, 6 PEST sequences, 4 KxKHKxK repeats, 8 LSxxL repeats, and 10 PxxPS repeats. Northern blot analysis detected a major 5.8-kb transcript in all tissues and cell lines examined. Immunofluorescence analysis detected fluorescence-tagged and endogenous SETBP1 predominantly in nuclei of human cell lines.
By radiation hybrid analysis, Ishikawa et al. (1997) mapped the SETBP1 gene to chromosome 18. Using FISH, Minakuchi et al. (2001) mapped the SETBP1 gene to chromosome 18q21.1.
Gross (2016) mapped the SETBP1 gene to chromosome 18q12.3 based on an alignment of the SETBP1 sequence (GenBank BC062338) with the genomic sequence (GRCh38).
Using deletion and mutagenesis analysis, Minakuchi et al. (2001) determined that amino acids 182 to 223 of SET interacted with amino acids 1238 to 1434 of SETBP1. Immunoprecipitation analysis verified that SETBP1 interacted with endogenous SET in a human osteosarcoma cell line.
Panagopoulos et al. (2007) described a fourth chimera involving the NUP98 gene (601021) in T-cell acute lymphoblastic leukemia (T-ALL). They described T-ALL with t(11;18)(p15;q12) resulting in a novel NUP98 fusion. Fluorescence in situ hybridization showed NUP98 and SETBP1 fusion signals; other analyses showed that exon 12 of NUP98 was fused in-frame with exon 5 of SETBP1. Nested PCR did not amplify the reciprocal SETBP1/NUP98, suggesting that the NUP98/SETBP1 transcript is pathogenetically important. SETBP1 had not previously been implicated in leukemias.
Schinzel-Giedion Syndrome
In 4 unrelated individuals with Schinzel-Giedion syndrome (269150), Hoischen et al. (2010) sequenced the candidate gene SETBP1 and identified de novo heterozygous mutations in all 4 individuals; using Sanger sequencing, they identified de novo heterozygous SETBP1 mutations in 8 of 9 additional individuals with Schinzel-Giedion syndrome (611060.0001-611060.0005). The 5 different mutations occurred within an 11-bp interval, involving 3 of 4 consecutive amino acids that are highly conserved throughout evolution.
In 2 unrelated Thai male infants who fulfilled the diagnostic criteria for Schinzel-Giedion syndrome, Suphapeetiporn et al. (2011) identified heterozygosity for the G870S mutation in the SETBP1 gene (611060.0005).
Autosomal Dominant Intellectual Developmental Disorder 29
In a large study of copy number variation (CNV) in neurodevelopmental disease and genes potentially sensitive to dosage imbalance, Coe et al. (2014) identified 4 nonsense mutations in SETBP1 (e.g., 611060.0007), 2 of which were confirmed to be de novo, as well as 4 frameshift mutations (e.g., 611060.0006), of which 1 was confirmed to be de novo. Coe et al. (2014) created an expanded copy number variant (CNV) morbidity map from 29,085 children with developmental delay in comparison to 19,584 healthy controls, identifying 70 significant CNVs. They then resequenced 26 candidate genes in 4,716 additional cases with developmental delay or autism and 2,193 controls. An integrated analysis of CNV and single-nucleotide variant (SNV) data pinpointed 10 genes enriched for putative loss of function. Among these was SETBP1, haploinsufficiency of which was associated with intellectual disability and loss of expressive language.
Somatic Mutations in Myeloid Malignancies
Using exome sequencing, Piazza et al. (2013) identified somatic alterations of SETBP1 encoding a gly870 to ser (G870S) alteration in 2 of 8 leukocyte samples from individuals with atypical CML (aCML; see 608232). Targeted resequencing of 70 aCMLs, 574 diverse hematologic malignancies, and 344 cancer cell lines identified SETBP1 mutations in 24 cases, including 17 of 70 aCMLs (24.3%; 95% confidence interval = 16-35%). Most mutations (92%) were located between codons 858 and 871 and were identical to changes seen in individuals with Schinzel-Giedion syndrome. Individuals with mutations had higher white blood cell counts (p = 0.008) and worse prognosis (p = 0.01). The G870S alteration abrogated a site for ubiquitination, and cells exogenously expressing this mutant exhibited higher amounts of SETBP1 and SET (600960) protein, lower PP2A (see 176915) activity, and higher proliferation rates relative to those expressing the wildtype protein. Piazza et al. (2013) concluded that mutated SETBP1 represents an oncogene present in aCML and closely related diseases.
Sakaguchi et al. (2013) performed whole-exome sequencing for paired tumor-normal DNA from 13 individuals with juvenile myelomonocytic leukemia (JMML; 607785) (cases), followed by deep sequencing of 8 target genes in 92 tumor samples. JMML was characterized by a paucity of gene mutations (0.85 nonsilent mutations per sample) with somatic or germline RAS pathway involvement in 82 cases (89%). The SETBP1 and JAK3 (600173) mutations were among common targets for secondary mutations. Mutations in JAK3 were often subclonal, and Sakaguchi et al. (2013) hypothesized that they may be involved in the progression rather than the initiation of leukemia; these mutations associated with poor clinical outcomes.
Makishima et al. (2013) reported whole-exome sequencing of individuals with various myeloid malignancies and identified recurrent somatic mutations in SETBP1. Closely positioned somatic SETBP1 mutations encoding changes in asp868, ser869, gly870, ile871, and asp880, which match germline mutations in Schinzel-Giedion midface retraction syndrome (SGS; 269150), were detected in 17% of secondary acute myeloid leukemias and 15% of chronic myelomonocytic leukemia (see 607785) cases. Mutant cases were associated with advanced age and monosomy 7/deletion 7q (252270) constituting poor prognostic factors. Analysis of serially collected samples indicated that SETBP1 mutations were acquired during leukemic evolution. Makishima et al. (2013) concluded that somatic mutations of SETBP1 seem to cause gain of function, are associated with myeloid leukemic transformation, and convey poor prognosis in myelodysplastic syndromes (see 614286) and chronic myelomonocytic leukemia.
In 5 unrelated patients with Schinzel-Giedion syndrome (269150), Hoischen et al. (2010) identified a heterozygous 2612T-C transition in the SETBP1 gene, resulting in a substitution at a highly conserved residue, ile871-to-thr (I871T). The mutation was not found in the 8 parents from whom DNA was available, confirming the de novo nature of the mutation, and was not detected in 188 control chromosomes. One patient died at 3 months of age and another survived to 4.5 years; 2 patients were alive at the time of the report at 2 and 3 years of age, respectively; the age at death was unknown in the fifth patient.
In 4 unrelated patients with Schinzel-Giedion syndrome (269150), Hoischen et al. (2010) identified a de novo heterozygous 2602G-A transition in the SETBP1 gene, resulting in an asp868-to-asn (D868N) substitution at a highly conserved residue. The mutation was not found in any of the parents or in 188 control chromosomes. Two patients with this mutation died in their third year of life, and 2 were alive at 1 year and 1.75 years, respectively.
In a female infant with Schinzel-Giedion syndrome (269150) who died at 6 months of age, Hoischen et al. (2010) identified a 2603A-C transversion in the SETBP1 gene, resulting in an asp868-to-ala (D868A) substitution at a highly conserved residue. The mutation was not detected in 188 control chromosomes.
In a male infant with Schinzel-Giedion syndrome (269150) who died at 7 months of age, Hoischen et al. (2010) identified a de novo 2609G-A transition in the SETBP1 gene, resulting in a gly870-to-asp (G870D) substitution at a highly conserved residue. The mutation was not found in the parents or in 188 control chromosomes.
In a female child with Schinzel-Giedion syndrome (269150) who died at 9.25 years of age, Hoischen et al. (2010) identified a de novo 2608G-A transition in the SETBP1 gene, resulting in a gly870-to-ser (G870S) substitution at a highly conserved residue. The mutation was not found in the parents or in 188 control chromosomes.
In 2 unrelated Thai male infants who fulfilled the diagnostic criteria for Schinzel-Giedion syndrome proposed by Lehman et al. (2008), Suphapeetiporn et al. (2011) identified heterozygosity for the G870S mutation in the SETBP1 gene. The mutation was not found in 100 control chromosomes of Thai ethnicity. The patients displayed some features not previously reported in the disorder, including very short epiglottis, vocal cord paralysis, radioulnar synostosis, and possible hypothyroidism.
In a 14-year-old boy with a normal IQ but with speech delay, motor delay, and dysmorphic facial features (MRD29; 616078), Coe et al. (2014) identified a heterozygous de novo frameshift mutation in the SETBP1 gene, a 1-bp deletion at g.42531769 (GRCh37) resulting in an ile822-to-tyr (I822Y) substitution and a frameshift with a stop codon following 13 amino acids (Ile822TyrfsTer13). The patient's IQ was 76, which is in the borderline range, but was 'disharmonic.' The patient had speech impairment, with first words at 18 months but almost no speak until age 4 years. At age 14 he spoke but was hard to understand, with words in the wrong order and difficulty finding words. Growth parameters were within normal limits. Brain MRI was normal.
In a 19-year-old male with severe intellectual disability, behavioral difficulties, speech and motor delays, and dysmorphic facial features (MRD29; 616078), Coe et al. (2014) detected heterozygosity for a G-to-A transition in the SETBP1 gene (g.42530901G-A, GRCh37), resulting in a trp532-to-ter (W532X) substitution. This mutation was shown to be a de novo event. No seizures or EEG abnormalities were present, and brain MRI was normal. Growth parameters were within normal limits.
In a 17-year-old male with mild intellectual disability, social difficulties, speech and motor delays, and dysmorphic facial features (MRD29; 616078), Coe et al. (2014) identified a heterozygous de novo C-to-G transversion in the SETBP1 gene (g.42532337C-G, GRCh37), resulting in a ser1011-to-ter (S1011X) substitution. The patient had a normal EEG and normal brain MRI. Growth parameters were average.
In a 34-year-old female with severe intellectual disability, speech and motor delays, and dysmorphic facial features (MRD29; 616078), Coe et al. (2014) identified a single-basepair deletion in the SETBP1 gene (g.42281738del, GRCh37) resulting in an arg143-to-val substitution followed by a frameshift and premature termination 64 amino acids downstream (Arg143ValfsTer64). Hypotonia and obesity were present. The patient also had generalized seizures, with onset at 22 years of age.
In a 36-year-old female with mild to moderate intellectual disability, ADHD, social difficulties, speech and motor delays, and dysmorphic facial features (MRD29; 616078), Coe et al. (2014) identified a C-to-T transition in the SETBP1 gene (g.42531178C-T, GRCh37), resulting in an arg625-to-ter (R625X) substitution. The patient had a normal brain MRI and normal growth parameters.
In a 9-year-old female with moderate to severe intellectual disability, absent speech, and dysmorphic features (MRD29; 616078), Coe et al. (2014) identified a C-to-T transition in the SETBP1 gene (g.42531181C-T, GRCh37), resulting in an arg626-to-ter (R626X) substitution. The patient had short stature, but growth parameters were otherwise normal. There was no MRI evaluation.
Coe, B. P., Witherspoon, K., Rosenfeld, J. A., van Bon, B. W. M., Vulto-van Silfhout, A. T., Bosco, P., Friend, K. L., Baker, C., Buono, S., Vissers, L. E. L. M., Schuurs-Hoeijmakers, J. H., Hoischen, A., and 26 others. Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nature Genet. 46: 1063-1071, 2014. [PubMed: 25217958] [Full Text: https://doi.org/10.1038/ng.3092]
Gross, M. B. Personal Communication. Baltimore, Md. 5/26/2016.
Hoischen, A., van Bon, B. W. M., Gilissen, C., Arts, P., van Lier, B., Steehouwer, M., de Vries, P., de Reuver, R., Wieskamp, N., Mortier, G., Devriendt, K., Amorim, M. Z., and 12 others. De novo mutations of SETBP1 cause Schinzel-Giedion syndrome. Nature Genet. 42: 483-485, 2010. [PubMed: 20436468] [Full Text: https://doi.org/10.1038/ng.581]
Ishikawa, K., Nagase, T., Nakajima, D., Seki, N., Ohira, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. VIII. 78 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 4: 307-313, 1997. [PubMed: 9455477] [Full Text: https://doi.org/10.1093/dnares/4.5.307]
Lehman, A. M., McFadden, D., Pugash, D., Sangha, K., Gibson, W. T., Patel, M. S. Schinzel-Giedion syndrome: report of splenopancreatic fusion and proposed diagnostic criteria. Am. J. Med. Genet. 146A: 1299-1306, 2008. [PubMed: 18398855] [Full Text: https://doi.org/10.1002/ajmg.a.32277]
Makishima, H., Yoshida, K., Nguyen, N., Przychodzen, B., Sanada, M., Okuno, Y., Ng, K. P., Gudmundsson, K. O., Vishwakarma, B. A., Jerez, A., Gomez-Segui, I., Takahashi, M., and 18 others. Somatic SETBP1 mutations in myeloid malignancies. Nature Genet. 45: 942-946, 2013. [PubMed: 23832012] [Full Text: https://doi.org/10.1038/ng.2696]
Minakuchi, M., Kakazu, N., Gorrin-Rivas, M. J., Abe, T., Copeland, T. D., Ueda, K., Adachi, Y. Identification and characterization of SEB, a novel protein that binds to the acute undifferentiated leukemia-associated protein SET. Europ. J. Biochem. 268: 1340-1351, 2001. [PubMed: 11231286] [Full Text: https://doi.org/10.1046/j.1432-1327.2001.02000.x]
Panagopoulos, I., Kerndrup, G., Carlsen, N., Strombeck, B., Isaksson, M., Johansson, B. Fusion of NUP98 and the SET binding protein 1 (SETBP1) gene in a paediatric acute T cell lymphoblastic leukaemia with t(11;18)(p15;q12). Brit. J. Haemat. 136: 294-296, 2007. [PubMed: 17233820] [Full Text: https://doi.org/10.1111/j.1365-2141.2006.06410.x]
Piazza, R., Valletta, S., Winkelmann, N., Redaelli, S., Spinelli, R., Pirola, A., Antolini, L., Mologni, L., Donadoni, C., Papaemmanuil, E., Kim, D.-W., and 16 others. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia. Nature Genet. 45: 18-24, 2013. [PubMed: 23222956] [Full Text: https://doi.org/10.1038/ng.2495]
Sakaguchi, H., Okuno, Y., Muramatsu, H., Yoshida, K., Shiraishi, Y., Takahashi, M., Kon, A., Sanada, M., Chiba, K., Tanaka, H., Makishima, H., Wang, X., and 10 others. Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nature Genet. 45: 937-941, 2013. [PubMed: 23832011] [Full Text: https://doi.org/10.1038/ng.2698]
Suphapeetiporn, K., Srichomthong, C., Shotelersuk, V. SETBP1 mutations in two Thai patients with Schinzel-Giedion syndrome. (Letter) Clin. Genet. 79: 391-393, 2011. [PubMed: 21371013] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01552.x]