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Truncated variants of MAGEL2 are involved in the etiologies of the Schaaf-Yang and Prader-Willi syndromes.
Heimdörfer, David; Vorleuter, Alexander; Eschlböck, Alexander; Spathopoulou, Angeliki; Suarez-Cubero, Marta; Farhan, Hesso; Reiterer, Veronika; Spanjaard, Melanie; Schaaf, Christian P; Huber, Lukas A; Kremser, Leopold; Sarg, Bettina; Edenhofer, Frank; Geley, Stephan; de Araujo, Mariana E G; Huettenhofer, Alexander.
Affiliation
  • Heimdörfer D; Institute of Genomics and RNomics, Biocenter Innsbruck, Medical University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: david.heimdoerfer@i-med.ac.at.
  • Vorleuter A; Institute of Genomics and RNomics, Biocenter Innsbruck, Medical University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
  • Eschlböck A; Institute for Molecular Biology, Genomics, Stem Cell Biology & Regenerative Medicine Group, University of Innsbruck and CMBI, Technikerstr. 25, 6020 Innsbruck, Austria.
  • Spathopoulou A; Institute for Molecular Biology, Genomics, Stem Cell Biology & Regenerative Medicine Group, University of Innsbruck and CMBI, Technikerstr. 25, 6020 Innsbruck, Austria.
  • Suarez-Cubero M; Institute for Molecular Biology, Genomics, Stem Cell Biology & Regenerative Medicine Group, University of Innsbruck and CMBI, Technikerstr. 25, 6020 Innsbruck, Austria.
  • Farhan H; Institute of Pathophysiology, Biocenter, Medical University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
  • Reiterer V; Institute of Pathophysiology, Biocenter, Medical University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
  • Spanjaard M; Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
  • Schaaf CP; Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
  • Huber LA; Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innrain 80/82, Innsbruck 6020, Austria.
  • Kremser L; Institute of Medical Biochemistry, Protein Core Facility, Biocenter, Medical University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
  • Sarg B; Institute of Medical Biochemistry, Protein Core Facility, Biocenter, Medical University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
  • Edenhofer F; Institute for Molecular Biology, Genomics, Stem Cell Biology & Regenerative Medicine Group, University of Innsbruck and CMBI, Technikerstr. 25, 6020 Innsbruck, Austria.
  • Geley S; Institute of Pathophysiology, Biocenter, Medical University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria.
  • de Araujo MEG; Institute of Cell Biology, Biocenter, Medical University of Innsbruck, Innrain 80/82, Innsbruck 6020, Austria.
  • Huettenhofer A; Institute of Genomics and RNomics, Biocenter Innsbruck, Medical University of Innsbruck, Innrain 80/82, 6020 Innsbruck, Austria. Electronic address: alexander.huettenhofer@i-med.ac.at.
Am J Hum Genet ; 111(7): 1383-1404, 2024 07 11.
Article in En | MEDLINE | ID: mdl-38908375
ABSTRACT
The neurodevelopmental disorders Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS) both arise from genomic alterations within human chromosome 15q11-q13. A deletion of the SNORD116 cluster, encoding small nucleolar RNAs, or frameshift mutations within MAGEL2 result in closely related phenotypes in individuals with PWS or SYS, respectively. By investigation of their subcellular localization, we observed that in contrast to a predominant cytoplasmic localization of wild-type (WT) MAGEL2, a truncated MAGEL2 mutant was evenly distributed between the cytoplasm and the nucleus. To elucidate regulatory pathways that may underlie both diseases, we identified protein interaction partners for WT or mutant MAGEL2, in particular the survival motor neuron protein (SMN), involved in spinal muscular atrophy, and the fragile-X-messenger ribonucleoprotein (FMRP), involved in autism spectrum disorders. The interactome of the non-coding RNA SNORD116 was also investigated by RNA-CoIP. We show that WT and truncated MAGEL2 were both involved in RNA metabolism, while regulation of transcription was mainly observed for WT MAGEL2. Hence, we investigated the influence of MAGEL2 mutations on the expression of genes from the PWS locus, including the SNORD116 cluster. Thereby, we provide evidence for MAGEL2 mutants decreasing the expression of SNORD116, SNORD115, and SNORD109A, as well as protein-coding genes MKRN3 and SNRPN, thus bridging the gap between PWS and SYS.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prader-Willi Syndrome / Intracellular Signaling Peptides and Proteins / Intrinsically Disordered Proteins Limits: Humans Language: En Journal: Am J Hum Genet Year: 2024 Document type: Article Country of publication: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Prader-Willi Syndrome / Intracellular Signaling Peptides and Proteins / Intrinsically Disordered Proteins Limits: Humans Language: En Journal: Am J Hum Genet Year: 2024 Document type: Article Country of publication: United States