Lysine methyltransferase 2D regulates muscle fiber size and muscle cell differentiation.
Abnormalities, Multiple
/ genetics
Adolescent
Animals
Cell Differentiation
/ genetics
Child
Child, Preschool
DNA-Binding Proteins
/ genetics
Disease Models, Animal
Face
/ abnormalities
Female
Hematologic Diseases
/ genetics
Histone-Lysine N-Methyltransferase
/ genetics
Humans
Infant
Male
Mice
Mice, Transgenic
Muscle Cells
/ metabolism
Muscle Fibers, Skeletal
/ metabolism
Mutation
Myeloid-Lymphoid Leukemia Protein
/ genetics
Neoplasm Proteins
/ genetics
Neuromuscular Junction
/ genetics
Signal Transduction
/ genetics
Vestibular Diseases
/ genetics
Kabuki syndrome
NMJ
muscle differentiation
muscle regeneration
muscle stem cells
muscular dystrophy
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
revised:
27
08
2021
received:
19
05
2021
accepted:
13
09
2021
entrez:
6
10
2021
pubmed:
7
10
2021
medline:
16
11
2021
Statut:
ppublish
Résumé
Kabuki syndrome (KS) is a rare genetic disorder caused primarily by mutations in the histone modifier genes KMT2D and KDM6A. The genes have broad temporal and spatial expression in many organs, resulting in complex phenotypes observed in KS patients. Hypotonia is one of the clinical presentations associated with KS, yet detailed examination of skeletal muscle samples from KS patients has not been reported. We studied the consequences of loss of KMT2D function in both mouse and human muscles. In mice, heterozygous loss of Kmt2d resulted in reduced neuromuscular junction (NMJ) perimeter, decreased muscle cell differentiation in vitro and impaired myofiber regeneration in vivo. Muscle samples from KS patients of different ages showed presence of increased fibrotic tissue interspersed between myofiber fascicles, which was not seen in mouse muscles. Importantly, when Kmt2d-deficient muscle stem cells were transplanted in vivo in a physiologic non-Kabuki environment, their differentiation potential is restored to levels undistinguishable from control cells. Thus, the epigenetic changes due to loss of function of KMT2D appear reversible through a change in milieu, opening a potential therapeutic avenue.
Identifiants
pubmed: 34613626
doi: 10.1096/fj.202100823R
pmc: PMC8500524
mid: NIHMS1740563
doi:
Substances chimiques
DNA-Binding Proteins
0
KMT2D protein, human
0
Neoplasm Proteins
0
Myeloid-Lymphoid Leukemia Protein
149025-06-9
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
Kmt2b protein, mouse
EC 2.1.1.43
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e21955Subventions
Organisme : NICHD NIH HHS
ID : P50 HD105351
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR069582
Pays : United States
Informations de copyright
© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
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