PUBLICATION
Suleiman-El-Hattab syndrome: a histone modification disorder caused by TASP1 deficiency
- Authors
- Riedhammer, K.M., Burgemeister, A.L., Cantagrel, V., Amiel, J., Siquier, K., Boddaert, N., Hertecant, J., Kannouche, P.L., Pouvelle, C., Htun, S., Slavotinek, A.M., Beetz, C., Diego-Alvarez, D., Kampe, K., Fleischer, N., Awamleh, Z., Weksberg, R., Kopajtich, R., Meitinger, T., Suleiman, J., El-Hattab, A.W.
- ID
- ZDB-PUB-220506-23
- Date
- 2022
- Source
- Human molecular genetics 31(18): 3083-3094 (Journal)
- Registered Authors
- Htun, Stephanie, Slavotinek, Anne
- Keywords
- none
- MeSH Terms
-
- Abnormalities, Multiple
- Animals
- Endopeptidases/genetics
- Face/abnormalities
- Hematologic Diseases
- Histone Code*
- Histone Methyltransferases/genetics
- Phenotype
- Transcription Factor TFIIA/genetics
- Vestibular Diseases
- Zebrafish*/genetics
- PubMed
- 35512351 Full text @ Hum. Mol. Genet.
Citation
Riedhammer, K.M., Burgemeister, A.L., Cantagrel, V., Amiel, J., Siquier, K., Boddaert, N., Hertecant, J., Kannouche, P.L., Pouvelle, C., Htun, S., Slavotinek, A.M., Beetz, C., Diego-Alvarez, D., Kampe, K., Fleischer, N., Awamleh, Z., Weksberg, R., Kopajtich, R., Meitinger, T., Suleiman, J., El-Hattab, A.W. (2022) Suleiman-El-Hattab syndrome: a histone modification disorder caused by TASP1 deficiency. Human molecular genetics. 31(18):3083-3094.
Abstract
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. Knock-out 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, HOXB2) and dysregulation of transcription factor TFIIA. A distinct methylation profile intermediate between control and Kabuki syndrome (KMT2D) profiles could be produced. Zebrafish tasp1 knock-out 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping