The N-terminal domain of the Schaaf–Yang syndrome protein MAGEL2 likely has a role in RNA metabolism

Sanderson, Matthea R.; Fahlman, Richard P.; Wevrick, Rachel

doi:10.1016/j.jbc.2021.100959

Cited by 10 publications

(28 citation statements)

References 135 publications

(236 reference statements)

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“…Despite being its most deeply studied function, dysregulation of protein trafficking and recycling is not the only consequence of MAGEL2 malfunction. The subcellular localisation of the full MAGEL2 protein [41, 42] and its C-terminal part alone, [39] have been previously studied in heterologous systems, both presenting a mainly cytoplasmic localisation. Our immunocytochemistry assays in different transfected cell lines showed that, in contrast, the heterologously expressed MAGEL2-Gln638* (N-terminal part of the protein) was predominantly located inside the nucleus.…”

Section: Discussionmentioning

confidence: 99%

“…Our immunocytochemistry assays in different transfected cell lines showed that, in contrast, the heterologously expressed MAGEL2-Gln638* (N-terminal part of the protein) was predominantly located inside the nucleus. The new localisation of the protein suggests that, in addition to the loss of the MAGEL2 normal functions, including the translocation of YTHDF2 to the nucleus, [39] SYS-associated mutations could involve new functions of unknown consequences.…”

Section: ]mentioning

confidence: 99%

“…At a structural level, the N-terminal region of MAGEL2 contains a proline-rich domain, whose function remains unclear. [39] At the C-terminus, from amino acid 1027 to 1195, there is the MHD, a highly conserved 170-amino acid sequence present in both type I and type II MAGEs, crucial for protein-protein interaction. [40] Through it, MAGEL2 recognizes and binds the coiled-coil domain of the E3 ubiquitin ligase TRIM27.…”

Section: Introductionmentioning

confidence: 99%

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Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2

Castilla‐Vallmanya

Centeno-Pla

Serrano

et al. 2022

Preprint

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BackgroundSchaaf-Yang syndrome (SYS) is caused by truncating mutations in MAGEL2, mapping to the Prader-Willi region (15q11-q13), with an observed phenotype partially overlapping that of Prader-Willi syndrome. MAGEL2 plays a role in retrograde transport and protein recycling regulation. Our aim is to contribute to the characterization of SYS pathophysiology at clinical, genetic and molecular levels.MethodsWe performed an extensive phenotypic and mutational revision of previously reported SYS patients. We analysed the secretion levels of amyloid-β 1-40 peptide (Aβ1-40), and performed targeted metabolomic and transcriptomic profiles in SYS patients’ fibroblasts (n=7) compared to controls (n=11). We also transfected cell lines with vectors encoding wild-type (WT) or truncated MAGEL2 to assess stability and subcellular localization of the truncated protein.ResultsFunctional studies show significantly decreased levels of secreted Aβ1-40 and intracellular glutamine in SYS fibroblasts compared to wild-type. We also identified 132 differentially expressed genes, including ncRNAs such as HOTAIR, many of them related to developmental processes and mitotic mechanisms. The truncated form of MAGEL2 displayed a stability similar to the wild-type but it was significantly switched to the nucleus, compared to a mainly cytoplasmic distribution of the wild-type MAGEL2. Based on updated knowledge we offer guidelines for clinical management of SYS patients.ConclusionA truncated MAGEL2 protein is stable and localises mainly in the nucleus, where it might exert a pathogenic gain of function effect. Aβ1-40 secretion levels and HOTAIR mRNA levels might be promising biomarkers for SYS. Our findings may improve SYS understanding and clinical management.Key MessagesMAGEL2 truncating mutations cause Schaaf-Yang syndrome (SYS) but the functional effects of the truncated MAGEL2 protein have been poorly defined. By expressing truncated MAGEL2 in cell lines, we now know that a truncated version of the protein is retained in the nucleus, thus exerting a gain-of-function behaviour in addition to the loss of some of its main functions. Patients’ fibroblasts show reduced levels of excreted amyloid beta 1-40 and intracellular glutamine as well as an altered transcriptomic profile, including overexpression of the major regulator HOTAIR. Based on a comprehensive review of genetic and clinical aspects of all reported cases, families and physicians will benefit from the Clinical Management Recommendations that we provide here.

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Section: Discussionmentioning

confidence: 99%

Section: ]mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2

Castilla‐Vallmanya

Centeno-Pla

Serrano

et al. 2022

Preprint

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“…iPSC-derived neurons from SYS patients displayed fewer and shorter dendrites, which could have a detrimental effect on cognition, information processing, and wiring of the brain, depending on what types of cells in what brain regions are affected. It is important to note that a recent study indicated a novel role of the N terminal domain of the SYS protein MAGEL2 in RNA metabolism [ 131 ], which stands in contrast to the involvement of the C terminal domain that interacts with the WASH complex [ 130 ]. In addition, a recent study reports decreased secretory granule and neuropeptide production in cellular and murine models of PWS, which may, in part, underlie the reported dysfunction of the OT system in models of PWS [ 20 , 21 , 59 ].…”

Section: Dysregulation Of Intracellular Pathways In Murine and Ipsc M...mentioning

confidence: 99%

Oxytocin-based therapies for treatment of Prader-Willi and Schaaf-Yang syndromes: evidence, disappointments, and future research strategies

et al. 2022

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The prosocial neuropeptide oxytocin is being developed as a potential treatment for various neuropsychiatric disorders including autism spectrum disorder (ASD). Early studies using intranasal oxytocin in patients with ASD yielded encouraging results and for some time, scientists and affected families placed high hopes on the use of intranasal oxytocin for behavioral therapy in ASD. However, a recent Phase III trial obtained negative results using intranasal oxytocin for the treatment of behavioral symptoms in children with ASD. Given the frequently observed autism-like behavioral phenotypes in Prader-Willi and Schaaf-Yang syndromes, it is unclear whether oxytocin treatment represents a viable option to treat behavioral symptoms in these diseases. Here we review the latest findings on intranasal OT treatment, Prader-Willi and Schaaf-Yang syndromes, and propose novel research strategies for tailored oxytocin-based therapies for affected individuals. Finally, we propose the critical period theory, which could explain why oxytocin-based treatment seems to be most efficient in infants, but not adolescents.

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“…It is a single-exon gene that encodes one of the largest proteins of the type II MAGE protein family consisting of 1249 amino acids. At a structural level, the N-terminal region of MAGEL2 contains a proline-rich domain, whose function remains unclear 39. At the C-terminus, from amino acids 1027 to 1195, there is the MHD, a highly conserved 170-amino acid sequence present in both type I and type II MAGEs, crucial for protein–protein interaction 40.…”

Section: Introductionmentioning

confidence: 99%

Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2

et al. 2022

View full text Add to dashboard Cite

BackgroundSchaaf-Yang syndrome (SYS) is caused by truncating mutations in MAGEL2, mapping to the Prader-Willi region (15q11-q13), with an observed phenotype partially overlapping that of Prader-Willi syndrome. MAGEL2 plays a role in retrograde transport and protein recycling regulation. Our aim is to contribute to the characterisation of SYS pathophysiology at clinical, genetic and molecular levels.MethodsWe performed an extensive phenotypic and mutational revision of previously reported patients with SYS. We analysed the secretion levels of amyloid-β 1–40 peptide (Aβ1-40) and performed targeted metabolomic and transcriptomic profiles in fibroblasts of patients with SYS (n=7) compared with controls (n=11). We also transfected cell lines with vectors encoding wild-type (WT) or mutated MAGEL2 to assess stability and subcellular localisation of the truncated protein.ResultsFunctional studies show significantly decreased levels of secreted Aβ1-40 and intracellular glutamine in SYS fibroblasts compared with WT. We also identified 132 differentially expressed genes, including non-coding RNAs (ncRNAs) such as HOTAIR, and many of them related to developmental processes and mitotic mechanisms. The truncated form of MAGEL2 displayed a stability similar to the WT but it was significantly switched to the nucleus, compared with a mainly cytoplasmic distribution of the WT MAGEL2. Based on the updated knowledge, we offer guidelines for the clinical management of patients with SYS.ConclusionA truncated MAGEL2 protein is stable and localises mainly in the nucleus, where it might exert a pathogenic neomorphic effect. Aβ1-40 secretion levels and HOTAIR mRNA levels might be promising biomarkers for SYS. Our findings may improve SYS understanding and clinical management.

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The N-terminal domain of the Schaaf–Yang syndrome protein MAGEL2 likely has a role in RNA metabolism

Cited by 10 publications

References 135 publications

Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2

Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2

Oxytocin-based therapies for treatment of Prader-Willi and Schaaf-Yang syndromes: evidence, disappointments, and future research strategies

Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2

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