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Neuromolecular Med. 2018 Sep;20(3):409-417. doi: 10.1007/s12017-018-8502-1. Epub 2018 Jul 16.

RNA Sequencing and Pathway Analysis Identify Important Pathways Involved in Hypertrichosis and Intellectual Disability in Patients with Wiedemann-Steiner Syndrome.

Mietton L1,2,3, Lebrun N1,2,3,4, Giurgea I5,6, Goldenberg A7, Saintpierre B1,2,3, Hamroune J1,2,3, Afenjar A8, Billuart P1,2,3,4, Bienvenu T9,10,11,12,13.

Author information

1
Inserm, U1016, Institut Cochin, Paris, France.
2
CNRS, UMR8104, Paris, France.
3
Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
4
Institut de Psychiatrie et de Neurosciences de Paris, Inserm U894, 102 rue de la santé, 75014, Paris, France.
5
U.F. de Génétique moléculaire, Hôpital Armand Trousseau, Assistance Publique - Hôpitaux de Paris, Paris, France.
6
INSERM UMR S933, Faculté de médecine Sorbonne Universités, 75012, Paris, France.
7
Service de génétique, CHU de Rouen et Inserm U1079, Université de Rouen, Centre Normand de Génomique Médicale et Médecine Personnalisée, Rouen, France.
8
Service de génétique et embryologie médicales, Centre de référence Maladie du cervelet, CHU Paris Est - Hôpital d'Enfants Armand-Trousseau, Paris, France.
9
Inserm, U1016, Institut Cochin, Paris, France. thierry.bienvenu@inserm.fr.
10
CNRS, UMR8104, Paris, France. thierry.bienvenu@inserm.fr.
11
Université Paris Descartes, Sorbonne Paris Cité, Paris, France. thierry.bienvenu@inserm.fr.
12
Institut de Psychiatrie et de Neurosciences de Paris, Inserm U894, 102 rue de la santé, 75014, Paris, France. thierry.bienvenu@inserm.fr.
13
Laboratoire de Génétique et Biologie Moléculaires, Hôpital Cochin, HUPC, AP-HP, Paris, France. thierry.bienvenu@inserm.fr.

Abstract

A growing number of histone modifiers are involved in human neurodevelopmental disorders, suggesting that proper regulation of chromatin state is essential for the development of the central nervous system. Among them, heterozygous de novo variants in KMT2A, a gene coding for histone methyltransferase, have been associated with Wiedemann-Steiner syndrome (WSS), a rare developmental disorder mainly characterized by intellectual disability (ID) and hypertrichosis. As KMT2A is known to regulate the expression of multiple target genes through methylation of lysine 4 of histone 3 (H3K4me), we sought to investigate the transcriptomic consequences of KMT2A variants involved in WSS. Using fibroblasts from four WSS patients harboring loss-of-function KMT2A variants, we performed RNA sequencing and identified a number of genes for which transcription was altered in KMT2A-mutated cells compared to the control ones. Strikingly, analysis of the pathways and biological functions significantly deregulated between patients with WSS and healthy individuals revealed a number of processes predicted to be altered that are relevant for hypertrichosis and intellectual disability, the cardinal signs of this disease.

KEYWORDS:

Hypertrichosis; KMT2A; Pathway analysis; RNA sequencing; Wiedemann–Steiner syndrome

PMID:
30014449
DOI:
10.1007/s12017-018-8502-1
[Indexed for MEDLINE]

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