Molecular and cellular issues of kmt2a ...
Document type :
Article dans une revue scientifique: Article original
PMID :
Permalink :
Title :
Molecular and cellular issues of kmt2a variants involved in wiedemann-steiner syndrome
Author(s) :
Giurgea, Irina [Auteur]
CHU Trousseau [APHP]
Goldenberg, Alice [Auteur]
Service de génétique [Rouen]
Dieux, Anne [Auteur]
Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364
Afenjar, Alexandra [Auteur]
CHU Trousseau [APHP]
Ghoumid, Jamal [Auteur]
Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364
Diebold, Bertrand [Auteur]
Hôpital Cochin [AP-HP]
Mietton, Leo [Auteur]
Institut Cochin [IC UM3 (UMR 8104 / U1016)]
Briand-Suleau, Audrey [Auteur]
Institut Cochin [IC UM3 (UMR 8104 / U1016)]
Billuart, Pierre [Auteur]
Institut Cochin [IC UM3 (UMR 8104 / U1016)]
Bienvenu, Thierry [Auteur]
Institut Cochin [IC UM3 (UMR 8104 / U1016)]
CHU Trousseau [APHP]
Goldenberg, Alice [Auteur]
Service de génétique [Rouen]
Dieux, Anne [Auteur]

Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364
Afenjar, Alexandra [Auteur]
CHU Trousseau [APHP]
Ghoumid, Jamal [Auteur]

Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364
Diebold, Bertrand [Auteur]
Hôpital Cochin [AP-HP]
Mietton, Leo [Auteur]
Institut Cochin [IC UM3 (UMR 8104 / U1016)]
Briand-Suleau, Audrey [Auteur]
Institut Cochin [IC UM3 (UMR 8104 / U1016)]
Billuart, Pierre [Auteur]
Institut Cochin [IC UM3 (UMR 8104 / U1016)]
Bienvenu, Thierry [Auteur]
Institut Cochin [IC UM3 (UMR 8104 / U1016)]
Journal title :
European journal of human genetics . EJHG
Abbreviated title :
Eur. J. Hum. Genet.
Volume number :
26
Pages :
107-116
Publication date :
2018-01
ISSN :
1018-4813
HAL domain(s) :
Sciences du Vivant [q-bio]
English abstract : [en]
Variants in KMT2A, encoding the histone methyltransferase KMT2A, are a growing cause of intellectual disability (ID). Up to now, the majority of KMT2A variants are non-sense and frameshift variants causing a typical form ...
Show more >Variants in KMT2A, encoding the histone methyltransferase KMT2A, are a growing cause of intellectual disability (ID). Up to now, the majority of KMT2A variants are non-sense and frameshift variants causing a typical form of Wiedemann-Steiner syndrome. We studied KMT2A gene in a cohort of 200 patients with unexplained syndromic and non-syndromic ID and identified four novel variants, one splice and three missense variants, possibly deleterious. We used primary cells from the patients and molecular approaches to determine the deleterious effects of those variants on KMT2A expression and function. For the putative splice variant c.11322-1G>A, we showed that it led to only one nucleotide deletion and loss of the C-terminal part of the protein. For two studied KMT2A missense variants, c.3460C>T (p.(Arg1154Trp)) and c.8558T>G (p.(Met2853Arg)), located at the cysteine-rich CXXC domain and the transactivation domain of the protein, respectively, we found altered KMT2A target genes expression in patient's fibroblasts compared to controls. Furthermore, we found a disturbed subcellular distribution of KMT2A for the c.3460C>T mutant. Taken together, our results demonstrated the deleterious impact of the splice variant and of the missense variants located at two different functional domains and suggested reduction of KMT2A function as the disease-causing mechanism.Show less >
Show more >Variants in KMT2A, encoding the histone methyltransferase KMT2A, are a growing cause of intellectual disability (ID). Up to now, the majority of KMT2A variants are non-sense and frameshift variants causing a typical form of Wiedemann-Steiner syndrome. We studied KMT2A gene in a cohort of 200 patients with unexplained syndromic and non-syndromic ID and identified four novel variants, one splice and three missense variants, possibly deleterious. We used primary cells from the patients and molecular approaches to determine the deleterious effects of those variants on KMT2A expression and function. For the putative splice variant c.11322-1G>A, we showed that it led to only one nucleotide deletion and loss of the C-terminal part of the protein. For two studied KMT2A missense variants, c.3460C>T (p.(Arg1154Trp)) and c.8558T>G (p.(Met2853Arg)), located at the cysteine-rich CXXC domain and the transactivation domain of the protein, respectively, we found altered KMT2A target genes expression in patient's fibroblasts compared to controls. Furthermore, we found a disturbed subcellular distribution of KMT2A for the c.3460C>T mutant. Taken together, our results demonstrated the deleterious impact of the splice variant and of the missense variants located at two different functional domains and suggested reduction of KMT2A function as the disease-causing mechanism.Show less >
Language :
Anglais
Audience :
Internationale
Popular science :
Non
Administrative institution(s) :
Université de Lille
Collections :
Submission date :
2021-09-02T07:01:11Z
2021-09-22T09:12:00Z
2021-09-22T09:12:00Z