Cellular and disease functions of the Prader–Willi Syndrome gene<i>MAGEL2</i>

Tacer, Klementina Fon; Potts, Patrick Ryan

doi:10.1042/bcj20160616

Cited by 69 publications

(81 citation statements)

References 127 publications

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“…Therefore, truncating variants in MAGEL2 may result in abnormal truncated protein products through a gain-of-function mechanism. Although several articles have raised the possibility of a dominant negative mechanism [5,15], it seems that a gain-offunction mechanism is the most likely pathological mechanism because there is no proof that MAGEL2 forms multimers. MAGEL2 belongs to the MAGE family proteins that were initially identified as tumor-specific antigens [25].…”

Section: Discussionmentioning

confidence: 99%

“…MAGEL2 is known to bind and to enhance the activity of the TRIM27 E3 RING ubiquitin ligase. The MAGEL2-USP7-TRIM27 (MUST) complex plays an important role in a cellular process that recycles membrane proteins from endosomes through the [15,27,28]. Thus, dysregulation of this pathway may be associated with the pathogenesis of SYS.…”

Section: Discussionmentioning

confidence: 99%

“…The pathological mechanism underlying SYS is thought to be the loss of functional MAGEL2 [3,5], yet a gain-offunction mechanism has also been suggested [9,15]. MAGEL2 is located in the PWS critical region and is deleted in deletion-positive PWS patients.…”

Section: Introductionmentioning

confidence: 99%

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Schaaf-Yang syndrome shows a Prader-Willi syndrome-like phenotype during infancy

Negishi

Ieda

Hori

et al. 2019

Orphanet J Rare Dis

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Background: Schaaf-Yang syndrome (SYS) is a newly recognized imprinting related syndrome, which is caused by a truncating variant in maternally imprinted MAGEL2 located in 15q11-q13. Yet, precise pathomechanism remains to be solved. We sequenced MAGEL2 in patients suspected Prader-Willi syndrome (PWS) to delineate clinical presentation of SYS. We examined 105 patients with clinically suspected PWS but without a specific PWS genetic alteration. Sanger sequencing of the entire MAGEL2 gene and methylation-specific restriction enzyme treatment to detect the parent of origin were performed. Clinical presentation was retrospectively assessed in detail. Results: Truncating variants in MAGEL2 were detected in six patients (5.7%), including a pair of siblings. All truncating variants in affected patients were on the paternally derived chromosome, while the healthy father of the affected siblings inherited the variant from his mother. Patients with MAGEL2 variants shared several features with PWS, such as neonatal hypotonia, poor suck, and obesity; however, there were also unique features, including arthrogryposis and a failure to acquire meaningful words. Additionally, an episode of neurological deterioration following febrile illness was confirmed in four of the six patients, which caused severe neurological sequalae. Conclusions: SYS can be present in infants suspected with PWS but some unique features, such as arthrogryposis, can help discriminate between the two syndromes. An episode of neurological deterioration following febrile illness should be recognized as an important complication.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Schaaf-Yang syndrome shows a Prader-Willi syndrome-like phenotype during infancy

Negishi

Ieda

Hori

et al. 2019

Orphanet J Rare Dis

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“…We examined Cyfip1, Cyfip2, and Magel2 transcript levels in the hypothalamus, a brain region important for hyperphagia in PWS 40 and for the effects of Magel2 deletion 53,54 on eating behavior and homeostatic function 55 . Haploinsufficiency of MAGEL2 is associated with PWS-like hyperphagia in humans 54,56,57 .…”

Section: Hypothalamus Dissections For Real-time Quantitative Pcr (Qpcr)mentioning

confidence: 99%

“…We also examined Magel2 which is a nearby imprinted gene that is located within the syntenic, canonical (Type II) PWS locus and has been implicated in changes in eating behavior in mouse models of PWS 55 and PWS-like hyperphagia in humans 54,56,57 . Supplementary Table 3 lists the qPCR results as a function of both Cyfip1 haploinsufficiency and PO.…”

Section: Reduced Transcription Of Cyfip1 But Not Cyfip2 or Magel2 In mentioning

confidence: 99%

Cyfip1 haploinsufficiency increases compulsive-like behavior and modulates palatable food intake: Implications for Prader-Willi Syndrome

Babbs

Ruan

Kelliher

et al. 2018

Preprint

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Binge eating (BE) is a heritable trait associated with eating disorders and involves consumption of a large quantity of food in a short time. We identified cytoplasmic FMRP-interacting protein 2 (Cyfip2) as a major genetic factor underlying BE and concomitant compulsive-like behaviors in mice. CYFIP2 is a gene homolog of CYFIP1 -one of four paternally deleted genes in patients with the more severe Type I Prader-Willi Syndrome (PWS). PWS is a neurodevelopmental genetic disorder where 70% of cases involve paternal deletion of 15q11-q13. PWS is defined phenotypically by the emergence of hyperphagia and obesity during childhood as well as cognitive deficits and obsessive-compulsive behaviors. We tested the hypothesis that Cyfip1 haploinsufficiency would enhance premorbid compulsive-like behavior and palatable food (PF) consumption in a parent-of-origin-selective manner.Additionally, because our initial studies involved mice on a C57BL/6N background that possess the BEassociated missense mutation in Cyfip2, we tested mice on a mixed background where mice were homozygous for the C57BL/6J (B6J) allele at the Cyfip2 locus. Cyfip1 haploinsufficiency increased compulsive-like behavior on both backgrounds and PF consumption was greater with paternal inheritance. Gene expression in the hypothalamus revealed a paternal effect of Cyfip1 deletion on transcription of Cyfip1 but not Cyfip2 or Magel2. To summarize, the selective increased compulsive-like behavior and PF consumption in paternally deleted Cyfip1 +/-mice could translate to enhancing hyperphagia in a subset of individuals with neurodevelopmental disorders involving reduced expression or haploinsufficiency of CYFIP1, including PWS but also Fragile X Syndrome and 15q11.2 Microdeletion Syndrome.

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Magel2 Modulates Bone Remodeling and Mass in Prader-Willi Syndrome by Affecting Oleoyl Serine Levels and Activity

Baraghithy

Smoum

Drori

et al. 2018

Journal of Bone and Mineral Research

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Among a multitude of hormonal and metabolic complications, individuals with Prader-Willi syndrome (PWS) exhibit significant bone abnormalities, including decreased BMD, osteoporosis, and subsequent increased fracture risk. Here we show in mice that loss of Magel2, a maternally imprinted gene in the PWS critical region, results in reduced bone mass, density, and strength, corresponding to that observed in humans with PWS, as well as in individuals suffering from Schaaf-Yang syndrome (SYS), a genetic disorder caused by a disruption of the MAGEL2 gene. The low bone mass phenotype in Magel2 -/mice was attributed to reduced bone formation rate, increased osteoclastogenesis and osteoclast activity, and enhanced trans-differentiation of osteoblasts to adipocytes. The absence of Magel2 in humans and mice resulted in reduction in the fatty acid amide bone homeostasis regulator, N-oleoyl serine (OS), whose levels were positively linked with BMD in humans and mice as well as osteoblast activity. Attenuating the skeletal abnormalities in Magel2 -/mice was achieved with chronic administration of a novel synthetic derivative of OS. Taken together, Magel2 plays a key role in modulating bone remodeling and mass in PWS by affecting OS levels and activity. The use of potent synthetic analogs of OS should be further tested clinically as bone therapeutics for treating bone loss.

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Cellular and disease functions of the Prader–Willi Syndrome geneMAGEL2

Cited by 69 publications

References 127 publications

Schaaf-Yang syndrome shows a Prader-Willi syndrome-like phenotype during infancy

Schaaf-Yang syndrome shows a Prader-Willi syndrome-like phenotype during infancy

Cyfip1 haploinsufficiency increases compulsive-like behavior and modulates palatable food intake: Implications for Prader-Willi Syndrome

Magel2 Modulates Bone Remodeling and Mass in Prader-Willi Syndrome by Affecting Oleoyl Serine Levels and Activity

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