ArticlePLoS genetics2017
Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies.
Article in PLoS genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 70 citations in OpenAlex.
- Single-cell transcriptional consequences of leukaemogenic SETBP1 mutations.British journal of haematology · 2026Article
- The spectrum of communication abilities in children with 12 rare neurodevelopmental disorders: a qualitative study with caregivers.Journal of child psychology and psychiatry, and allied disciplines · 2026Article
- Behavioral and Prefrontal Circuit Deficits in a Newly DevelopedBiological psychiatry global open science · 2026Article
- Cell-type-specific alternative splicing in the brain and kidney of a Setbp1S858R Schinzel-Giedion syndrome mouse.Disease models & mechanisms · 2026Article
- SETBP1 variants outside the degron disrupt DNA-binding, transcription and neuronal differentiation capacity to cause a heterogeneous neurodevelopmental disorder.Nature communications · 2025Article
- Schinzel-Giedion syndrome: communication, feeding and motor skills in 16 individuals.Neurogenetics · 2025Article
- SET-binding protein 1 (SETBP1) suppresses cell proliferation in estrogen receptor-positive breast cancer.Breast cancer (Tokyo, Japan) · 2025Article
- Reciprocal and non-reciprocal effects of clinically relevant SETBP1 protein dosage changes.Human molecular genetics · 2025Article
- Update on Cancer Screening in Children with Syndromes of Bone Lesions, Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome, and Other Rare Syndromes.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Review
- Expression and regulation of SETBP1 in the song system of male zebra finches (Taeniopygia guttata) during singing.Scientific reports · 2024Article
- Article
- Novel SETBP1 D874V adjacent to the degron causes canonical schinzel-giedion syndrome: a case report and review of the literature.BMC pediatrics · 2024Review
- Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase.American journal of human genetics · 2024Article
- The landscape of SETBP1 gene expression and transcription factor activity across human tissues.PloS one · 2024Article
- Epigenetic regulation of craniofacial development and disease.Birth defects research · 2024Review
- Cell-type-specific gene expression and regulation in the cerebral cortex and kidney of atypical Setbp1Journal of cellular and molecular medicine · 2023Article
- The landscape ofbioRxiv : the preprint server for biology · 2023Article
- The impact of SETBP1 mutations in neurological diseases and cancer.Genes to cells : devoted to molecular & cellular mechanisms · 2023Review
- Balanced SET levels favor the correct enhancer repertoire during cell fate acquisition.Nature communications · 2023Article
- Identification of a novel de novo mutation of SETBP1 and new findings of SETBP1 in tumorgenesis.Orphanet journal of rare diseases · 2023Article
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Authors and funding
46 authors at 20 institutions in 14 countries.
Funding
Abstract
Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.
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