ORCID Profile
0000-0001-7053-2449
Current Organisations
Karolinska Institutet
,
University of Cambridge
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Publisher: Hindawi Limited
Date: 16-05-2021
DOI: 10.1002/HUMU.24211
Publisher: Elsevier BV
Date: 07-2014
Publisher: The Company of Biologists
Date: 09-2008
DOI: 10.1242/DEV.021097
Abstract: Cited2 is a transcriptional modulator with pivotal roles in different biological processes. Cited2-deficient mouse embryos manifested two major defects in the developing eye. An abnormal corneal-lenticular stalk was characteristic of Cited2-/- developing eyes, a feature reminiscent of Peters' anomaly, which can be rescued by increased Pax6 gene dosage in Cited2-/- embryonic eyes. In addition, the hyaloid vascular system showed hyaloid hypercellularity consisting of aberrant vasculature, which might be correlated with increased VEGF expression in the lens. Deletion of Hif1a (which encodes HIF-1α) in Cited2-/- lens specifically eliminated the excessive accumulation of cellular mass and aberrant vasculature in the developing vitreous without affecting the corneal-lenticular stalk phenotype. These in vivo data demonstrate for the first time dual functions for Cited2:one upstream of, or together with, Pax6 in lens morphogenesis and another in the normal formation of the hyaloid vasculature through its negative modulation of HIF-1 signaling. Taken together, our study provides novel mechanistic revelation for lens morphogenesis and hyaloid vasculature formation and hence might offer new insights into the etiology of Peters'anomaly and ocular hypervascularity.
Publisher: Oxford University Press (OUP)
Date: 05-05-2022
DOI: 10.1093/HMG/DDAC098
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 in iduals 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 in iduals. Western blotting from fibroblasts in two in iduals. RNA sequencing and proteomics from fibroblasts in one in idual. Methylome analysis from blood in two in iduals. Knock-out of tasp1 orthologue in zebrafish and phenotyping. Results: All in iduals 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 roteomics 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 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.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Anne Slavotinek.