Expanding the role of <i>SETD5</i> haploinsufficiency in neurodevelopment and neuroblastoma

Pires, Sara Ferreira; Tolezano, Giovanna Cantini; Costa, Silvia Souza da; Kawahira, Rachel Sayuri Honjo; Kim, Chong; Rosenberg, Carla; Teixeira, Anne Caroline Barbosa; Bertola, Débora Romeo; Krepischi, Ana Cristina Victorino

doi:10.1002/pbc.28376

Cited by 3 publications

(3 citation statements)

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“…According to data in the PECAN database (https://pecan.stjude.cloud/home), high-grade gliomas and acute lymphoblastic leukemias present SETD5 mutations. SETD5 gene mutations are also associated with prostate cancer, colorectal cancer, and neuroblastoma (36,(59)(60)(61). Furthermore, SETD5 is identified with a rate of high-level amplification at around 10% in bladder cancer (38).…”

Section: Connection Of Setd5 With Tumorigenesismentioning

confidence: 99%

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Structure, activity and function of the lysine methyltransferase SETD5

Hou

Zhang

et al. 2023

Front. Endocrinol.

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SET domain-containing 5 (SETD5) is an uncharacterized member of the protein lysine methyltransferase family and is best known for its transcription machinery by methylating histone H3 on lysine 36 (H3K36). These well-characterized functions of SETD5 are transcription regulation, euchromatin formation, and RNA elongation and splicing. SETD5 is frequently mutated and hyperactive in both human neurodevelopmental disorders and cancer, and could be down-regulated by degradation through the ubiquitin-proteasome pathway, but the biochemical mechanisms underlying such dysregulation are rarely understood. Herein, we provide an update on the particularities of SETD5 enzymatic activity and substrate specificity concerning its biological importance, as well as its molecular and cellular impact on normal physiology and disease, with potential therapeutic options.

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Section: Connection Of Setd5 With Tumorigenesismentioning

confidence: 99%

“…Furthermore, SETD5 is identified with a rate of high-level amplification at around 10% in bladder cancer (38). Either mutation or amplification is demonstrated to promote the proliferation of cancer cells (38,60).…”

Section: Connection Of Setd5 With Tumorigenesismentioning

confidence: 99%

Structure, activity and function of the lysine methyltransferase SETD5

Hou

Zhang

et al. 2023

Front. Endocrinol.

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“…IDD23 is defined as being caused by a heterozygous mutation of SETD5 on chromosome 3p25 in humans, with the corresponding mouse gene being located at chromosome 6 cytoband E3 ( Fernandes et al, 2018 ). Individuals with a 3p25 deletion manifest an array of symptoms including ID, autistic features, epilepsy, eye problems, facial dysmorphism, and congenital heart defects ( Shuib et al, 2009 ; Gunnarsson and Bruun, 2010 ; Peltekova et al, 2012 ; Kellogg et al, 2013 ; Pinto et al, 2014 ; Pires et al, 2020 ) ( Table 2 ; Supplementary Table S1 ). The deletions overlap with a portion, or the entire region, of SETD5 , resulting in the loss of gene function.…”

Section: Introductionmentioning

confidence: 99%

Neurobehavioral characteristics of mice with SETD5 mutations as models of IDD23 and KBG syndromes

2023

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Genomic analysis has revealed that the genes for various chromatin regulators are mutated in many individuals with neurodevelopmental disorders (NDDs), emphasizing the important role of chromatin regulation in nervous system development and function. Chromatin regulation is mediated by writers, readers, and erasers of histone and DNA modifications, with such proteins being defined by specific domains. One of these domains is the SET domain, which is present in enzymes that catalyze histone methylation. Heterozygous loss-of-function mutations of the SETD5 (SET domain containing 5) gene have been identified in individuals with an NDD designated IDD23 (intellectual developmental disorder, autosomal dominant 23). KBG syndrome (named after the initials of the last names of the first three families identified with the condition) is characterized by features that either overlap with or are distinct from those of IDD23 and was initially thought to be caused only by mutations in the ANKRD11 (ankyrin repeat domain containing 11) gene. However, recent studies have identified SETD5 mutations in some KBG syndrome patients without ANKRD11 mutations. Here we summarize the neurobehavioral characterization of Setd5+/− mice performed by four independent research groups, compare IDD23 and KBG phenotypes, and address the utility and future development of mouse models for elucidation of the mechanisms underlying NDD pathogenesis, with a focus on SETD5 and its related proteins.

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