Article Dans Une Revue Human Molecular Genetics Année : 2022

Suleiman-El-Hattab syndrome: a histone modification disorder caused by TASP1 deficiency

Anna L Burgemeister
  • Fonction : Auteur
Vincent Cantagrel
Nathalie Boddaert
  • Fonction : Auteur
Jozef Hertecant
  • Fonction : Auteur
Stephanie Htun
  • Fonction : Auteur
Anne M Slavotinek
Dan Diego-Alvarez
  • Fonction : Auteur
Christian Beetz
  • Fonction : Auteur
Kapil Kampe
  • Fonction : Auteur
Nicole Fleischer
  • Fonction : Auteur
Zain Awamleh
  • Fonction : Auteur
Rosanna Weksberg
Thomas Meitinger
  • Fonction : Auteur
Robert Kopajtich
Jehan Suleiman
Ayman W El-Hattab

Résumé

Background: TASP1 encodes an endopeptidase activating histone methyltransferases of the KMT2 family. Homozygous loss-of-function variants in TASP1 have recently been associated with Suleiman-El-Hattab syndrome. We report six individuals with Suleiman-El-Hattab syndrome and provide functional characterization of this novel histone modification disorder in a multi-omics approach. Methods: Chromosomal microarray/exome sequencing in all individuals. Western blotting from fibroblasts in two individuals. RNA sequencing and proteomics from fibroblasts in one individual. Methylome analysis from blood in two individuals. Knockout of tasp1 orthologue in zebrafish and phenotyping. Results: All individuals had biallelic TASP1 loss-of-function variants and a phenotype including developmental delay, multiple congenital anomalies (including cardiovascular and posterior fossa malformations), a distinct facial appearance and happy demeanor. Western blot revealed absence of TASP1. RNA sequencing/proteomics showed HOX gene downregulation (HOXA4, HOXA7, HOXA1 and HOXB2) and dysregulation of transcription factor TFIIA. A distinct methylation profile intermediate between control and Kabuki syndrome (KMT2D) profiles could be produced. Zebrafish tasp1 knockout revealed smaller head size and abnormal cranial cartilage formation in tasp1 crispants. Conclusion: This work further delineates Suleiman-El-Hattab syndrome, a recognizable neurodevelopmental syndrome. Possible downstream mechanisms of TASP1 deficiency include perturbed HOX gene expression and dysregulated TFIIA complex. Methylation pattern suggests that Suleiman-El-Hattab syndrome can be categorized into the group of histone modification disorders including Wiedemann-Steiner and Kabuki syndrome.

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hal-03853581 , version 1 (31-10-2023)

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Korbinian M Riedhammer, Anna L Burgemeister, Jeanne Amiel, Vincent Cantagrel, Karine Siquier-Pernet, et al.. Suleiman-El-Hattab syndrome: a histone modification disorder caused by TASP1 deficiency. Human Molecular Genetics, 2022, 31 (18), pp.3083 - 3094. ⟨10.1093/hmg/ddac098⟩. ⟨hal-03853581⟩
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