Precocious neuronal differentiation and disrupted oxygen responses in Kabuki syndrome

Carosso, Giovanni A.; Boukas, Leandros; Augustin, Jonathan; Nguyen, Ha Nam; Winer, Briana; Cannon, Gabrielle H.; Robertson, Johanna D.; Zhang, Li; Hansen, Kasper D.; Goff, Loyal A.; Björnsson, Hans T.

doi:10.1172/jci.insight.129375

Cited by 49 publications

(34 citation statements)

References 62 publications

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“…KMT2D -caused transcription suppression led to the activity of hypoxia-response pathways. This proves that the loss of KMT2D function suppresses oxygen-responsive gene programs crucial for neural progenitor maintenance, ultimately leading to precocious neuronal differentiation [ 14 ]. A recent zebrafish model aimed to analyze the role of KMT2D and KDM6A in the development of tissue abnormalities, including craniofacial, heart and brain deformities.…”

Section: Molecular Geneticsmentioning

confidence: 99%

Kabuki Syndrome—Clinical Review with Molecular Aspects

Boniel

Sztefko

Śmigiel

et al. 2021

Genes

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Kabuki syndrome (KS) is a rare developmental disorder principally comprised of developmental delay, hypotonia and a clearly defined dysmorphism: elongation of the structures surrounding the eyes, a shortened and depressed nose, thinning of the upper lip and thickening of the lower lip, large and prominent ears, hypertrichosis and scoliosis. Other characteristics include poor physical growth, cardiac, gastrointestinal and renal anomalies as well as variable behavioral issues, including autistic features. De novo or inherited pathogenic/likely pathogenic variants in the KMT2D gene are the most common cause of KS and account for up to 75% of patients. Variants in KDM6A cause up to 5% of cases (X-linked dominant inheritance), while the etiology of about 20% of cases remains unknown. Current KS diagnostic criteria include hypotonia during infancy, developmental delay and/or intellectual disability, typical dysmorphism and confirmed pathogenic/likely pathogenic variant in KMT2D or KDM6A. Care for KS patients includes the control of physical and psychomotor development during childhood, rehabilitation and multi-specialist care. This paper reviews the current clinical knowledge, provides molecular and scientific links and sheds light on the treatment of Kabuki syndrome individuals.

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Section: Molecular Geneticsmentioning

confidence: 99%

Kabuki Syndrome—Clinical Review with Molecular Aspects

Boniel

Sztefko

Śmigiel

et al. 2021

Genes

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“…It is considered that type B includes those in which type A cancer cells proliferate in the mucosal full layer and those in which the cancer invades the entire mucosa and induces fibrosis. Indeed, previous studies have reported that the inactivation of MLL2 induced G2/M cell arrest (14), and G2/M cell cycle arrest in epithelial cells resulted in fibrosis (23). Therefore, in type B, a vicious cycle between fibrosis and cancer can be promoted.…”

Section: Discussionmentioning

confidence: 98%

“…Homozygous and heterozygous mutations of MLL2 gene result in the loss-of-function phenotype. MLL2 mRNA was absent in homozygous mutations and about 50% decreased in heterozygous mutations (14); therefore, under the assumption that mRNA expression and protein expression correlate, we defined scores 0 and 1 as low expression and scores 2-5 as high expression. Based on a previously reported classification (15), the expression of mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) was divided into five scores according to the nuclear positivity rate of carcinoma cells; score 0 (0%), score 1 (0-10%), score 2 (10-30%), score 3 (30-70%), and score 4 (70-100%).…”

Section: Methodsmentioning

confidence: 99%

Low MLL2 Protein Expression Is Associated With Fibrosis in Early Stage Gastric Cancer

Numakura

Uozaki

2021

In Vivo

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“…Ehmt1 was found to be downregulated in brains of mice exposed to VPA in utero, Kdm6a, and Dnmt3b appeared to be upregulated in the same model (Kotajima-Murakami et al, 2019), while Chd7 was downregulated in embryonal carcinoma cells upon VPA exposure (Jergil et al, 2009). In addition, Ehmt1 and its human orthologs were downregulated in neural stem/progenitor cells of a mouse model for KS1 (Carosso et al, 2019) and in lymphoblastoid cell lines derived from 2q23.1 deletion syndrome patients (Mullegama et al, 2016), respectively. Expression of DNMT3B was decreased in iPSCs derived from KS1 patient (Carosso et al, 2019).…”

Section: Shared Epigenetic and Gene Expression Alterationsmentioning

confidence: 93%

Chromatin Imbalance as the Vertex Between Fetal Valproate Syndrome and Chromatinopathies

Parodi

Fede

Peron

et al. 2021

Front. Cell Dev. Biol.

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Prenatal exposure to valproate (VPA), an antiepileptic drug, has been associated with fetal valproate spectrum disorders (FVSD), a clinical condition including congenital malformations, developmental delay, intellectual disability as well as autism spectrum disorder, together with a distinctive facial appearance. VPA is a known inhibitor of histone deacetylase which regulates the chromatin state. Interestingly, perturbations of this epigenetic balance are associated with chromatinopathies, a heterogeneous group of Mendelian disorders arising from mutations in components of the epigenetic machinery. Patients affected from these disorders display a plethora of clinical signs, mainly neurological deficits and intellectual disability, together with distinctive craniofacial dysmorphisms. Remarkably, critically examining the phenotype of FVSD and chromatinopathies, they shared several overlapping features that can be observed despite the different etiologies of these disorders, suggesting the possible existence of a common perturbed mechanism(s) during embryonic development.

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Precocious neuronal differentiation and disrupted oxygen responses in Kabuki syndrome

Cited by 49 publications

References 62 publications

Kabuki Syndrome—Clinical Review with Molecular Aspects

Kabuki Syndrome—Clinical Review with Molecular Aspects

Low MLL2 Protein Expression Is Associated With Fibrosis in Early Stage Gastric Cancer

Chromatin Imbalance as the Vertex Between Fetal Valproate Syndrome and Chromatinopathies

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