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Background
The KMT2A gene encoded lysine methyltransferase plays an essential role in regulating gene expression during early development and hematopoiesis. To date, 92 different mutations of KMT2A have been curated in the human gene mutation database (HGMD), resulting in Wiedemann-Steiner syndrome (WDSTS) and intellectual disability (ID)/developme...
Context in source publication
Context 1
... count of eosinophils (1.847 × 10^9/L, compared to normal level < 0.5*10 9 /L) as well as increased eosinophil ratio (17.1%) [12]. After eight months, his eosinophils numbers and eosinophil ratio still remained at higher levels (1.112 × 10^9/L and 10.8%, respectively). Furthermore, bone marrow puncture analysis showed granulocyte hyperplasia ( Fig. 2) and increased eosinophils ratio (5.5%). In addition, blood lymphocyte subset analysis showed no alteration. Virus detection was negative. C-reactive protein and erythrocyte sedimentation rate were normal. Allergy testing was negative. Other clinical data, such as EKG, echocardiogram, chest X-ray, and ultrason- ography of abdomen, were ...
Citations
... Increased absolute count of eosinophils has been occasionally described. Immunodeficiency is not uncommon in other chromatinopathies, especially Kabuki syndrome [36,44,45] . ...
BACKGROUND
Epigenetic disruptions have been implicated in some cases of infertility and can serve as therapeutic targets. However, the involvement of epigenetics in infertility has not received adequate attention.
AIM
This study aimed to determine the epigenetic basis of infertility in order to enhance public knowledge.
METHODS
Relevant articles on the subject were collected from PubMed, RCA, Google Scholar, SpringerLink, and Scopus. The articles were pooled together and duplicates were removed using Endnote software.
RESULTS
Available information shows that epigenetic mechanisms, mainly DNA methylation, histone modification, and microRNA interference are necessary for normal gametogenesis and embryogenesis. As a result, epigenetic disruptions in genes that control gametogenesis and embryogenesis, such as DDX3X, ADH4, AZF, PLAG1, D1RAS3, CYGB, MEST, JMJD1A, KCNQ1, IGF2, H19, and MTHFR may result in infertility. Aberrant DNA methylation during genomic imprinting and parental epigenetic mark erasures, in particular, may affect the DNA epigenomes of sperm and oocytes, resulting in reproductive abnormalities. Histone epigenetic dysregulation during oocyte development and histone-protamine replacement in the sperm may also cause reproductive abnormalities. Furthermore, overexpression or repression of certain microRNAs embedded in the ovary, testis, embryo, as well as granulosa cells and oocytes may impair reproduction. Male infertility is characterized by spermatogenesis failure, which includes oligozoospermia, asthenozoospermia, and teratozoospermia, while female infertility is characterized by polycystic ovary syndrome. Some epigenetic modifications can be reversed by deactivating the regulatory enzymes, implying that epigenetic reprogramming could help treat infertility in some cases. For some disorders, epigenetic drugs are available, but none have been formulated for infertility.
CONCLUSION
Some cases of infertility have an epigenetic etiology and can be treated by reversing the same epigenetic mechanism that caused it. As a result, medical practitioners are urged to come up with epigenetic treatments for infertility that have an epigenetic cause.
... Immune dysfunction includes recurrent infections of the respiratory tract or urinary tract, poor vaccine responses, eosinophilia, and congenital immunodeficiency with low immunoglobulins levels [13,21,22]. ...
Wiedemann–Steiner syndrome (WDSTS) is an autosomal dominant disorder with a broad and variable phenotypic spectrum characterized by intellectual disability, prenatal and postnatal growth retardation, hypertrichosis, characteristic facial features, behavioral problems, and congenital anomalies involving different systems. Here, we report a five-year-old boy who was diagnosed with WDSTS based on the results of Trio-based whole-exome sequencing and an assessment of his clinical features. He had intellectual disability, short stature, hirsutism, and atypical facial features, including a low hairline, down-slanting palpebral fissures, hypertelorism, long eyelashes, broad and arching eyebrows, synophrys, a bulbous nose, a broad nasal tip, and dental/oral anomalies. However, not all individuals with WDSTS exhibit the classic phenotype, so the spectrum of the disorder can vary widely from relatively atypical facial features to multiple systemic symptoms. Here, we summarize the clinical and molecular spectrum, diagnosis and differential diagnosis, long-term management, and care planning of WDSTS to improve the awareness of both pediatricians and clinical geneticists and to promote the diagnosis and treatment of the disease.
... In addition, KMT2A does not influence the expression of deregulated NKL homeobox gene NANOG in AML cell line NOMO-1 [18] which may support the view that H3K4-methylation is probably not involved in leukemic activation of this group of homeobox genes. Interestingly, a case report on a child with intellectual disability showed both KMT2A-deletion and eosinophilia [48], indicating tumor suppressor gene activity for KMT2A in this malignancy. Therefore, we speculate that NKL homeobox genes HMX2/3 and rearranged KMT2A operate synergistically to promote myeloid leukemogenesis. ...
The NKL-code describes normal expression patterns of NKL homeobox genes in hematopoiesis. Aberrant expression of NKL homeobox gene subclass members have been reported in several hematopoietic malignancies including acute myeloid leukemia (AML). Here, we analyzed the oncogenic role of the HMX-group of NKL homeobox genes in AML. Public expression profiling data–available for HMX1 and HMX2—indicate aberrant activity of HMX2 in circa 2% AML patients overall, rising to 31% in those with KMT2A/MLL rearrangements whereas HMX1 expression remains inconspicuous. AML cell lines EOL-1, MV4-11 and MOLM-13 expressed both, HMX2 and neighboring HMX3 genes, and harbored KMT2A aberrations, suggesting their potential functional association. Surprisingly, knockdown experiments in these cell lines demonstrated that KMT2A inhibited HMX2/3 which, in turn, did not regulate KMT2A expression. Furthermore, karyotyping and genomic profiling analysis excluded rearrangements of the HMX2/3 locus in these cell lines. However, comparative expression profiling and subsequent functional analyses revealed that IRF8, IL7- and WNT-signalling activated HMX2/3 expression while TNFa/NFkB- signalling proved inhibitory. Whole genome sequencing of EOL-1 identified two mutations in the regulatory upstream regions of HMX2/3 resulting in generation of a consensus ETS-site and transformation of a former NFkB-site into an SP1-site. Reporter-gene assays demonstrated that both mutations contributed to HMX2/3 activation, modifying ETS1/ELK1- and TNFalpha-mediated gene regulation. Moreover, DMSO-induced eosinophilic differentiation of EOL-1 cells coincided with HMX2/3 downregulation while knockdown of HMX2 induced cell differentiation, collectively supporting a fundamental role for these genes in myeloid differentiation arrest. Finally, target genes of HMX2/3 were identified in EOL-1 and included suppression of differentiation gene EPX, and activation of fusion gene FIP1L1-PDGFRA and receptor-encoding gene HTR7, both of which enhanced oncogenic ERK-signalling. Taken together, our study documents a leukemic role for deregulated NKL homeobox genes HMX2 and HMX3 in AML, revealing molecular mechanisms of myeloid differentiation arrest.
... Strikingly, the cerebellar disseminated tumor in patient 1 contained seven subclonal mutations that were absent in the pons. Among these were mutations in genes encoding a cell adhesion gene (CTNNA2), and the chromatin regulators KMT2A and SMARCB1, known to be altered in other types of pediatric cancers [41][42][43] . www.nature.com/scientificreports/ ...
Children diagnosed with brain tumors have the lowest overall survival of all pediatric cancers. Recent molecular studies have resulted in the discovery of recurrent driver mutations in many pediatric brain tumors. However, despite these molecular advances, the clinical outcomes of high grade tumors, including H3K27M diffuse midline glioma (H3K27M DMG), remain poor. To address the paucity of tissue for biological studies, we have established a comprehensive protocol for the coordination and processing of donated specimens at postmortem. Since 2010, 60 postmortem pediatric brain tumor donations from 26 institutions were coordinated and collected. Patient derived xenograft models and cell cultures were successfully created (76% and 44% of attempts respectively), irrespective of postmortem processing time. Histological analysis of mid-sagittal whole brain sections revealed evidence of treatment response, immune cell infiltration and the migratory path of infiltrating H3K27M DMG cells into other midline structures and cerebral lobes. Sequencing of primary and disseminated tumors confirmed the presence of oncogenic driver mutations and their obligate partners. Our findings highlight the importance of postmortem tissue donations as an invaluable resource to accelerate research, potentially leading to improved outcomes for children with aggressive brain tumors.
... In addition, Li et al. have described 11 unreported mutations in a study comparing French and Chinese cohorts [15,16]. Besides WDSTS, deleterious variants in KMT2A were also described in association with epilepsy [17], primary immunodeficiency [18], and eosinophilia [19]. ...
... KMT2A variants are reported also in one Coffin-Siris (CSS) patient (pt #K2431 in Bramswig et al. [20]), in two Cornelia de Lange syndrome (CdLS) patients (Yuan et al. [21], patient CdLS #3 and Parenti et al. [22], patient #1), in two patients with a diagnosis of Kabuki syndrome (KS) (patients KS8 and KS29 in Sobreira et al. [23]) and in another RSTS-like patient from our previous cohort (Negri et al. [24], pt #103). Recently, several papers [12][13][14][15][17][18][19] report KMT2A pathogenic variants in patients without the "obligate" specific WDSTS clinical feature showing a broader phenotypic spectrum due to KMT2A alterations. All the above cited clinical conditions and in particular WDSTS and RSTS show several phenotypic overlapping (e.g., growth deficiency, neurological/cognitive impairment, similar dysmorphisms, and limb anomalies), as observed in our cohort, but we can envisage also a shared molecular cause. ...
Lysine-specific methyltransferase 2A (KMT2A) is responsible for methylation of histone H3 (K4H3me) and contributes to chromatin remodeling, acting as “writer” of the epigenetic machinery. Mutations in KMT2A were first reported in Wiedemann–Steiner syndrome (WDSTS). More recently, KMT2A variants have been described in probands with a specific clinical diagnosis comprised in the so-called chromatinopathies. Such conditions, including WDSTS, are a group of overlapping disorders caused by mutations in genes coding for the epigenetic machinery. Among them, Rubinstein–Taybi syndrome (RSTS) is mainly caused by heterozygous pathogenic variants in CREBBP or EP300. In this work, we used next generation sequencing (either by custom-made panel or by whole exome) to identify alternative causative genes in individuals with a RSTS-like phenotype negative to CREBBP and EP300 mutational screening. In six patients we identified different novel unreported variants in KMT2A gene. The identified variants are de novo in at least four out of six tested individuals and all of them display some typical RSTS phenotypic features but also WDSTS specific signs. This study reinforces the concept that germline variants affecting the epigenetic machinery lead to a shared molecular effect (alteration of the chromatin state) determining superimposable clinical conditions.
... Increased absolute count of eosinophils has been occasionally described. Immunodeficiency is not uncommon in other chromatinopathies, especially Kabuki syndrome [36,44,45] . ...
Wiedemann-Steiner syndrome (OMIM #605130) is a rare congenital
malformation syndrome characterized by hypertrichosis cubiti associated with short stature; consistent facial features, including long eyelashes, thick or arched eyebrows with a lateral flare, wide nasal bridge, and downslanting and vertically narrow palpebral fissures; mild to moderate intellectual disability; behavioral difficulties; and hypertrichosis on the back. It is caused by heterozygous pathogenic variants in KMT2A. This gene has an established role in histone methylation, which explains the overlap of Wiedemann-Steiner syndrome with other chromatinopathies, a heterogeneous group of syndromic conditions that share a common trigger: The disruption of one of the genes involved in chromatin modification, leading to dysfunction of the epigenetic machinery.
Background
Wiedemann–Steiner syndrome (WDSTS) is a rare autosomal dominant disorder caused by mutations in the KMT2A gene and is usually characterized by hairy elbows, short stature, developmental delay, intellectual disability and obvious facial dysmorphism.
Case presentation
Here, we report a 5-year-old girl with clinical features similar to WDSTS, including postnatal growth delay, retarded intellectual development, and ocular hypertelorism. Through whole-exome sequencing (WES), a frameshift variant of KMT2A was found in the patient but not in her parents’ genomic DNA. By bioinformatics analysis, the KMT2A variant was demonstrated to be the top candidate pathogenic variant for the clinical phenotype consistent with WDSTS. Moreover, a duplication of exon 1 in ADAMTS8 (belonging to the zinc metalloproteinase family) was found in the genomic DNA of this patient, which may be responsible for the characteristics that are different from those of WDSTS, including early teething, rapid tooth replacement, and dysplastic enamel.
Conclusions
From the above results, we propose that in our patient, the frameshift variant in KMT2A is the main reason for the WDSTS phenotype, and the unreported mutation in ADAMTS8 may be the candidate reason for other characteristics that are different from those of WDSTS. Therefore, this study not only provides a new KMT2A variant associated with WDSTS but is also a reminder that combined mutations may be present in a case with more characteristics than those seen in WDSTS.
Eosinophilia is defined as a condition with increased eosinophil cell counts in blood more than the standard value. In this regard, when extensive evaluation fails to reveal the underlying causes of this disease, hypereosinophilic syndrome (HES) diagnosis should be considered. Moreover, it is possible that the mutation of the tyrosine kinase genes, as the most common type of cryptic mutations, is associated with HES syndrome. We report a case of a 47-year-old man who was initially diagnosed with HES by Microscopic examination of bone marrow aspiration and peripheral blood cell analysis. After diagnosis, the patient was administered with cortisone acetate, leading to an initial remission. One month after the initial remission, the disease relapsed, and the patient eventually died. This case report provides the first report of HES, in which a novel variant of partial tandem duplication (PTD) was detected in the KMT2A gene.
The KMT2 (lysine methyltransferase) family of histone modifying proteins play essential roles in regulating developmental pathways, and mutations in the genes encoding these proteins have been strongly linked to many blood and solid tumor cancers. The KMT2A-D proteins are histone 3 lysine 4 (H3K4) methyltransferases embedded in large COMPASS-like complexes important for RNA Polymerase II-dependent transcription. KMT2 mutations were initially associated with pediatric Mixed Lineage Leukemias (MLL) and found to be the result of rearrangements of the MLL1/KMT2A gene at 11q23. Over the past several years, large-scale tumor DNA sequencing studies have revealed the potential involvement of other KMT2 family genes, including heterozygous somatic mutations in the paralogous MLL3/KMT2C and MLL2(4)/KMT2D genes that are now among the most frequently associated with human cancer. Recent studies have provided a better understanding of the potential roles of disrupted KMT2C and KMT2D family proteins in cell growth aberrancy. These findings, together with an examination of cancer genomics databases provide new insights into the contribution of KMT2C/D proteins in epigenetic gene regulation and links to carcinogenesis.
