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PXD009317

PXD009317 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleDe novo mutations of MSL3 cause a novel X-linked syndrome due to impaired histone H4 lysine 16 acetylation
DescriptionEpigenetic regulation by histone acetylation plays a key role in cellular homeostasis and its misregulation is associated with human disease. Histone 4 Lysine 16 acetylation (H4K16ac) serves a unique role amongst the many histone modifications as it directly affects chromatin structure1. The Male Specific Lethal (MSL) complex associated MOF/KAT8 histone acetyl transferase is responsible for bulk H4K16ac in flies and mammals. Yet, its importance during human development and a potential involvement in human pathologies remains largely unknown. Here, we uncover that pathogenic variants in MSL3, a component of the MSL complex, are causative for a new recognizable X-linked syndrome affecting Histone 4 Lysine 16 acetylation (H4K16ac) in both male and female individuals. Common clinical features of the syndrome include global developmental delay comprising profound speech delay, delayed ability to walk and craniofacial dysmorphism. Using patient-derived primary fibroblasts, we demonstrate that de novo variants or deletions of MSL3 affect the assembly and enzymatic activity of the MSL complex, hence impacting on global H4K16ac levels. Transcriptome analysis from patient cells showed misregulation of cellular pathways involved in serotonergic signaling, morphogenesis, axon guidance and cell structure. Finally, using HDAC inhibitor treatment, we can rescue expression of downregulated target genes, offering potential therapeutic avenues for MSL3-mutated patients. Taken together, we characterize a novel syndrome, named ILyADe (Impaired Lysine 16 acetylation associated disorder), which is caused by mutations of an epigenetic regulator, allowing us for the first time to unravel the crucial role of H4K16ac during human development. ILyaDe thus constitutes a new class of syndromes associated with misregulation of a single epigenetic modification caused by a genetic alteration.
HostingRepositoryPRIDE
AnnounceDate2018-09-18
AnnouncementXMLSubmission_2018-09-21_00:48:47.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterWitold Szymanski
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListmonomethylated residue; trimethyl-L-arginine; acetylated residue; iodoacetamide derivatized residue
InstrumentQ Exactive
Dataset History
RevisionDatetimeStatusChangeLog Entry
02018-03-26 00:38:35ID requested
12018-09-18 02:53:14announced
22018-09-21 00:48:49announcedUpdated publication reference for PubMed record(s): 30224647.
Publication List
Basilicata MF, Bruel AL, Semplicio G, Valsecchi CIK, Akta, ş T, Duffourd Y, Rumpf T, Morton J, Bache I, Szymanski WG, Gilissen C, Vanakker O, Õ, unap K, Mittler G, van der Burgt I, El Chehadeh S, Cho MT, Pfundt R, Tan TY, Kirchhoff M, Menten B, Vergult S, Lindstrom K, Reis A, Johnson DS, Fryer A, McKay V, Fisher RB, Thauvin-Robinet C, Francis D, Roscioli T, Pajusalu S, Radtke K, Ganesh J, Brunner HG, Wilson M, Faivre L, Kalscheuer VM, Thevenon J, Akhtar A, De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation. Nat Genet, 50(10):1442-1451(2018) [pubmed]
Keyword List
ProteomeXchange project tag: Biology/Disease-Driven Human Proteome Project (B/D-HPP), Epigenetic Chromatin (B/D-HPP), Human Proteome Project
curator keyword: Biomedical
submitter keyword: MSL3, X-linked syndrome, histone H4, acetylation, lysine 16
Contact List
Dr. Gerhard Mittler
contact affiliationMax Planck Institute of Immunobiology and Epigenetics Freiburg, Germany
contact emailmittler@ie-freiburg.mpg.de
lab head
Witold Szymanski
contact affiliationMax Planck Institute of Immunobiology and Epigenetics
contact emailszymanski@ie-freiburg.mpg.de
dataset submitter
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