Identification of KMT2D and KDM6A variants by targeted sequencing from patients with Kabuki syndrome and other congenital disorders

Yap, Chui-Sun; Jamuar, Saumya Shekhar; Lai, Angeline; Tan, Ee‐Shien; Ng, Ivy; Ting, Teck Wah; Tan, Ene‐Choo

doi:10.1016/j.gene.2020.144360

Cited by 13 publications

(9 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Gdf11 and Sox11), consistent with high arched palate and other distinctive facial features observed in Kabuki syndrome caused by KDM6A mutations (Figure 2E, F) (Adam et al, 2019;Guo et al, 2018;Yap et al, 2020).…”

Section: Kdm6a Ko In Es Cells Results In Expression Changes In Develosupporting

confidence: 80%

“…Here we find that a number of genes with maternal allele-specific downregulation in KDM6A KO cells derived from the BC cross, including Dmrt1, Cbfb, and Stox2, are associated with reproductive processes (Fenstad et al, 2010;Matson et al, 2011;Tunster et al, 2016;Wilson et al, 2016). In addition, imprinted Xlr genes implicated in reproduction are downregulated in KDM6A KO cells, along with other maternally expressed imprinted genes, such as Meg3, a lncRNA gene that interacts with PRC2 components including JARID2 (da Rocha et al, 2014;Kaneko et al, 2014;Mondal et al, 2015;Yen et al, 2018). Among the few paternal allele-specific downregulated DEGs in cells derived from the BC cross, are Fkbp6 and Foxd3, also implicated in reproduction.…”

Section: Discussionmentioning

confidence: 76%

“…KDM6A targets common to both reciprocal crosses include genes such as Gdf11 and Sox11 previously implicated in development of the roof of the mouth and hard palate, malformations of which are often seen in Kabuki syndrome due to mutations in KDM6A (Bogershausen et al, 2016;Silva-Andrade et al, 2019;Yap et al, 2020). GDF11 mutations in human lead to orofacial abnormalities, while SOX11 has a role in human palatogenesis (Cox et al, 2019;Khan et al, 2018;Suzuki et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Allele-specific gene regulation by KDM6A

Pease

et al. 2020

Preprint

View full text Add to dashboard Cite

SUMMARYKDM6A demethylates the repressive histone mark H3K27me3 and thus plays an important role in developmental gene regulation. KDM6A expression is female-biased due to escape from X inactivation, suggesting that this protein may play a role in sex differences. Here, we report that maternal and paternal alleles of a subset of mouse genes are differentially regulated by KDM6A. Knockouts of Kdm6a in male and female embryonic stem cells derived from F1 hybrid mice from reciprocal interspecific crosses resulted in preferential downregulation of maternal alleles of a number of genes implicated in development. Moreover, the majority of these genes exhibited a maternal allele expression bias, which was observed in both reciprocal crosses. Promoters of genes downregulated on maternal but not paternal alleles demonstrated a loss of chromatin accessibility, while the expected increase in H3K27me3 levels occurred only at promoters of genes downregulated on paternal but not maternal alleles. These results illustrate parent-of-origin mechanisms of gene regulation by KDM6A, consistent with histone demethylation-dependent and -independent activities.

show abstract

Section: Kdm6a Ko In Es Cells Results In Expression Changes In Develosupporting

confidence: 80%

Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Allele-specific gene regulation by KDM6A

Pease

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Common heart defects include atrial and ventricular septal defects, bicuspid aortic valves, aortic coarctation, double outlet right ventricle, transposition of great arteries, infundibular pulmonary stenosis, dysplastic mitral valve, Tetralogy of Fallot, etc. (Cocciadiferro et al, 2018; Digilio et al, 2017; Shangguan et al, 2019; Yap et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, mutations in chromatin remodeler Chd7 and histone acetyltransferase Kat6a/b are associated with birth defects leading to Charge and Ohdo syndromes, respectively (Vissers et al, 2004) (Campeau et al, 2012). KMT2D, also known as MLL2 methylates histone 3 at lysine 4 (H3K4) which is associated with transcriptional repression, and KDM6A, demethylates histone 3 at lysine 27 (H3K27), mostly associated with transcriptional actiation (Ali, Hom, Blakeslee, Ikenouye, & Kutateladze, 2014;Hong et al, 2007;Koutsioumpa et al, 2019;Lan et al, 2007), both genes are frequently mutated in patients with Kabuki Syndrome (Cocciadiferro et al, 2018;Gazova, Lengeling, & Summers, 2019;Luperchio, Applegate, Bodamer, & Bjornsson, 2019;Shangguan et al, 2019;Tekendo-Ngongang, Kruszka, Martinez, & Muenke, 2019;Yap et al, 2020) (Ang et al, 2016;Schwenty-Lara, Nurnberger, & Borchers, 2019;Serrano, Demarest, Tone-Pah-Hote, Tristani-Firouzi, & Yost, 2019). KMT2D or lysine-specific methyltransferase 2D, is also known as MLL2 or myeloid/lymphoid or mixed-lineage leukemia 2.…”

Section: Introductionmentioning

confidence: 99%

The role of Kabuki Syndrome genesKMT2DandKDM6Ain development: Analysis in Human sequencing data and compared to mice and zebrafish

Sen

Lencer

Geiger

et al. 2020

Preprint

View full text Add to dashboard Cite

27Congenital Heart Defects (CHDs) are the most common form of birth defects, observed in 4-28 10/1000 live births. CHDs result in a wide range of structural and functional abnormalities of the 29 heart which significantly affect quality of life and mortality. CHDs are often seen in patients with 30 mutations in epigenetic regulators of gene expression, like the genes implicated in Kabuki 31 syndrome -KMT2D and KDM6A, which play important roles in normal heart development and 32 function. Here, we examined the role of two epigenetic histone modifying enzymes, KMT2D and 33 KDM6A, in the expression of genes associated with early heart and neural crest cell (NCC) 34 development. Using CRISPR/Cas9 mediated mutagenesis of kmt2d, kdm6a and kdm6al in 35 zebrafish, we show cardiac and NCC gene expression is reduced, which correspond to affected 36 cardiac morphology and reduced heart rates. To translate our results to a human 37 pathophysiological context and compare transcriptomic targets of KMT2D and KDM6A across 38 species, we performed RNA sequencing (seq) of lymphoblastoid cells from Kabuki Syndrome 39 patients carrying mutations in KMT2D and KDM6A. We compared the human RNA-seq datasets 40 with RNA-seq datasets obtained from mouse and zebrafish. Our comparative interspecies 41 analysis revealed common targets of KMT2D and KDM6A, which are shared between species, 42 and these target genes are reduced in expression in the zebrafish mutants. Taken together, our 43 results show that KMT2D and KDM6A regulate common and unique genes across humans, mice, 44 and zebrafish for early cardiac and overall development that can contribute to the understanding 45 of epigenetic dysregulation in CHDs. 46 47 Running Title: 48 Epigenetic regulation of cardiac development across zebrafish, mice, and humans49

show abstract