Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Elisabetta Di Fede
 -- 2099 2022-04-02 11:50:18 |
2 format done
Vicky Zhou
 -2 word(s) 2097 2022-04-02 12:03:02 | |
3 format done
Vicky Zhou
 Meta information modification 2097 2022-04-02 12:21:03 | |
4 format done
Vicky Zhou
 Meta information modification 2097 2022-04-02 12:39:59 | |
5 format done
Vicky Zhou
 + 1 word(s) 2098 2022-04-06 10:03:27 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Di Fede, E.; , .; Bernardelli, C.; Lettieri, A.; Grazioli, P.; Colombo, E.; Milani, D.; Ottaviano, E.; Borghi, E.; Massa, V.; et al. KMT2A (Lysine Methyltransferase 2A). Encyclopedia. Available online: https://encyclopedia.pub/entry/21310 (accessed on 17 June 2024).
Di Fede E,  , Bernardelli C, Lettieri A, Grazioli P, Colombo E, et al. KMT2A (Lysine Methyltransferase 2A). Encyclopedia. Available at: https://encyclopedia.pub/entry/21310. Accessed June 17, 2024.
Di Fede, Elisabetta, , Clara Bernardelli, Antonella Lettieri, Paolo Grazioli, Elisa Colombo, Donatella Milani, Emerenziana Ottaviano, Elisa Borghi, Valentina Massa, et al. "KMT2A (Lysine Methyltransferase 2A)" Encyclopedia, https://encyclopedia.pub/entry/21310 (accessed June 17, 2024).
Di Fede, E., , ., Bernardelli, C., Lettieri, A., Grazioli, P., Colombo, E., Milani, D., Ottaviano, E., Borghi, E., Massa, V., Vignoli, A., Lesma, E., & Gervasini, C. (2022, April 02). KMT2A (Lysine Methyltransferase 2A). In Encyclopedia. https://encyclopedia.pub/entry/21310
Di Fede, Elisabetta, et al. "KMT2A (Lysine Methyltransferase 2A)." Encyclopedia. Web. 02 April, 2022.
KMT2A (Lysine Methyltransferase 2A)
Edit
This entry is adapted from the peer-reviewed paper 10.3390/genes13030514

KMT2A (Lysine methyltransferase 2A) is a member of the epigenetic machinery, encoding a lysine methyltransferase responsible for the transcriptional activation through lysine 4 of histone 3 (H3K4) methylation. KMT2A has a crucial role in gene expression, thus it is associated to pathological conditions when found mutated. KMT2A germinal mutations are associated to Wiedemann–Steiner syndrome and also in patients with initial clinical diagnosis of several other chromatinopathies (i.e., Coffin–Siris syndromes, Kabuki syndrome, Cornelia De Lange syndrome, Rubinstein–Taybi syndrome), sharing an overlapping phenotype. On the other hand, KMT2A somatic mutations have been reported in several tumors, mainly blood malignancies. Due to its evolutionary conservation, the role of KMT2A in embryonic development, hematopoiesis and neurodevelopment has been explored in different animal models, and epigenetic treatments for disorders linked to KMT2A dysfunction have been extensively investigated. 

KMT2A chromatinopathies tumors Wiedemann–Steiner syndrome

1. Introduction

KMT2A (Lysine methyltransferase 2A), also known as MLL1, is a protein coding gene mapping to human chromosome 11 (11q23.3), made up of 90,343 bases (GRCh38/hg38) and 37 exons belonging to KMTs (Lysine methyltransferases) family.
KMTs catalyze the transfer of methyl groups from S-adenosylmethionine to the lysine residues on histone tails, particularly the histone H3 tail. Unlike other epigenetic enzymes such as acetyltransferases (HATs), KMTs are more specific and usually modify one or two lysines on a single histone [1]. The effect on chromatin state, i.e., whether it activates transcription or represses it, depends on the methylation states and their positions (Figure 1) [2][3][4][5][6][7][8][9][10][11][12][13][14][15]. KMTs are so called writers, enzymes that catalyze the addition of chemical groups to histone tails or to DNA; these modifications are not permanent but can be removed by erasers to reverse the influence on gene expression. Readers possess specialized domains able to recognize and interpret different chemical modifications. Writers, erasers and readers form the epigenetic machinery, and mutations in genes coding for this apparatus lead to ann altered chromatin conformation and an incorrect gene expression, resulting in a series of syndromes known as chromatinopathies, Mendelian genetic diseases, most of them with a dominant character [16][17][18]. Pathogenic mutations in KMTs and KDMs (Lysine demethylases) lead to haploinsufficiency in numerous developmental syndromes (Figure 2) (Table 1) [10][19].
Genes 13 00514 g001
Figure 1. Representation of methylated lysines of histone tails. Lysines (yellow dots) of histone (H1, H2, H3, H4) tails can be mono-, bi-, tri-methylated (little lilac, blue and grey dots). The figure is not drawn to scale.
Genes 13 00514 g002
Figure 2. Representation of syndromes caused by mutations in genes coding for KMTs (Lysine methyltransferases) or KDMs (Lysisne demethylases). Syndromes (yellow inner ring) and the corresponding causative gene (coding for KMTs or KDMs, listed in the middle blue ring) are represented. The outer arcs indicate the site of epigenetic modification (NEDSID: Neurodevelopmental disorder with speech impairment and dysmorphic facies; EPEDD: Epilepsy, early-onset, with or without developmental delay).
Table 1. Details of genes and syndromes represented in Figure 2.
Gene (OMIM *) Associated Developmental Disorder(s) (OMIM #) Targeted Lysine Residue
SETD1A (611052) Neurodevelopmental disorder with speech impairment and dysmorphic facies NEDSID (619056)/Epilepsy, early-onset, with or without developmental delay EPEDD (618832) H3K4 (met)
SETD2 (612778) Luscan-Lumish S. (616831) H3K36 (met)
KDM1A (609132) Cleft palate, psychomotor retardation, distinctive facial features (616728) H3K4 (demet)
H3K9 (demet)
KDM5C (314690) Claes-Jensen S. (300534) H3K4 (demet)
KDM6A (300128) Kabuki S. 2 (300867) H3K27 (demet)
KMT2A (159555) Wiedemann–Steiner S. (605130) H3K4 (met)
KMT2B (606834) Dystonia 28 (617284) H3K4 (met)
KMT2C (606833) Kleefstra S. 2 (617768) H3K4 (met)
KMT2D (602113) Kabuki S. 1 (147920) H3K4 (met)
KMT5B (610881) Intellectual disability (617788) H4K20 (met)
EZH2 (601573) Weaver S. (277590) H3K9 (met)
H3K27 (met)
EHMT1 (607001) Kleefstra S. 1 (610253) H3K9 (met)
ASH1L (607999) Intellectual disability (617796) H3K36 (met)
NSD1 (606681) Sotos S. (117550) H3K36 (met)
H4K20 (met)
NSD2 (602952) Wolf Hirschhorn S. (194190) H3K36 (met)
PHF8 (300560) Siderius S. (300263) H3K9 (demet)
H3K27 (demet)
H4K20 (demet)
*: Gene, #: Associated Developmental Disorder(s).
Many species have a KMT2A ortholog, including fishes, birds, amphibians, and mammals; thus, its evolutionary conservation allowed a comprehensive study of KMT2A molecular functions through in vivo experiments on animal models (Drosophila melanogaster, Danio rerio, Mus musculus). KMT2A expression is mainly nuclear and ubiquitously present in 27 tissues, especially in ovary, lymph node, endometrium, thyroid and brain tissue [20]. KMT2A encodes a lysine methyltransferase (KMT) formed of 3969 amino acids, a transcriptional co-activator which plays a crucial role in hematopoiesis, in regulating gene expression at early developmental stages, and in the control of circadian gene expression. KMT2A is processed by the endopeptidase Taspase 1 in two fragments (MLL-C and MLL-N) which heterodimerize and regulate the transcription of specific genes, including HOX genes [21]. KMT2A protein has 18 domains, including the CXXC-type zinc finger, the extended PHD domain and the bromodomain. The SET domain has the methyltransferase activity (mono-, di-, tri-methylation) on lysine 4 of histone 3 (H3K4 me1/2/3), a post-transcriptional modification (PTM) responsible of epigenetic transcriptional activation and which efficiency can be increased when the protein is associated with another component of the MLL1/MLL complex (Figure 3) [22].
Genes 13 00514 g003
Figure 3. Schematic view of KMT2A protein domains (below) and its main interactors (upper). KMT2A domains: MBM, high-affinity Menin-binding motif, residues 6–10; LBD, LEDGF-binding domain, residues 109–153; ATH1-2-3, AT-Hook1/2/3, residue 169–180, residues 217–227, residue 301–309; SNL1-2, nuclear-localization signal 1/2, residues 400–443, residues 1008–1106; CxxC, including: pre-CxxC region, residues 1149–1154, CxxC domain, residues 1147–1242, post-CxxC residues 1298–1337; PHD1-2-3-4, plant homology domain 1/2/3/4, residues 1431–1482, residues 1479–1533, residues 1566–1627, residues 1931–1978; BRD, bromodomain, residues 1703–1748; FYRN, FY-rich N-terminal domain, residues 2018–2074; TAD, transactivator domain, residues 2829–2883; FYRC, FY-rich C-terminal domain, residues 3666–3747; Win, WDR5 interaction motif, residues 3762–3773; SET, Su(Var)3-9 enhancer-of-zeste trithorax domain, residues 3829–2945. KMT2A has two sites for cutting by Taspase1: TCS1-2, taspase1 cleavage site 1/2, residue 2666–2670 and residues 2718–2722.
As other members of KMTs family, KMT2A regulates gene transcription through chromatin opening or closure and its activity is antagonized by the lysine demethylases (KDMs) family.

2. KMT2A Germline Mutations

2.1. Wiedemann–Steiner Syndrome

KMT2A germinal variants are associated to the Wiedemann–Steiner syndrome (WDSTS, OMIM #605130), a rare autosomal dominant disorder characterized by different features, mainly intellectual disability (ID), developmental delay (DD), pre- and post-natal growth deficiency, hypertrichosis, short stature, hypotonia, distinctive facial features (thick eyebrows, long eyelashes, narrow palpebral fissures, broad nasal tip, down slanting palpebral fissures), skeletal abnormalities (clinodactyly, brachydactyly, accelerated skeletal maturation), feeding problems and behavioral difficulties (Table 2) [23][24][25]. KMT2A variants are distributed throughout the gene, with a pathogenic mutation hotspot in exon 27, and most of them lead to KMT2A loss of function. WDSTS patients usually present de novo private mutations, and the diagnosis is based on clinical evaluation of signs and symptoms then confirmed by molecular analysis. Unfortunately, a specific treatment is not available, thus possible interventions aim at reducing the severity of symptoms.
Table 2. Clinical signs reported in patients with a KMT2A mutation and an initial clinical diagnosis of chromatinopathy. Presence of all features is compared with the one in WDSTS.
  WDSTS CdLS CSS KS RSTS
[26] 1 + 1 pt [27][28] 1 pt [29] 2 pt [30] 1 + 6 pt [26][31]
Vision problems − 0/2 1/1 1/2 1/7
Cardiac problems + 1/2 1/1 1/2 0/7
CNS problems +/− 1/2 0/1 NA 0/7
Genitourinary problems − 0/2 1/1 1/2 2/7
Feeding problems + 0/2 1/1 1/2 3/7
Behavior problems + 1/2 0/1 NA 3/7
Frequent infection − 0/2 1/1 1/2 0/7
Seizures +/− 0/2 0/1 1/2 1/7
ID ++ 2/2 1/1 1/2 7/7
Speech delay ++ 1/2 1/1 NA 5/7
Microcephaly − 2/2 NA NA 3/7
Eyes anomalies (thick eyebrows, synophrys, long eyelashes, ptosis, downslanting/narrow palpebral fissure) + 2/2 1/1 2/2 7/7
Nose anomalies (depressed nasal bridge, broad nasal tip) + 2/2 1/1 2/2 7/7
Mouth anomalies (high arched palate, thin upper vermilion) +/− 2/2 1/1 0/2 4/7
Hands/feet anomalies (clinodactyly, brachydactyly, persistent fetal finger pads, broad halluces) +/− 2/2 1/1 2/2 6/7
Delayed bone age + 0/2 NA NA 0/7
Hirsutism + 1/2 1/1 NA 4/7
Hypotonia ++ NA 1/1 2/2 3/7
WDSTS: Wiedemann–Steiner syndrome, CdLS: Cornelia De Lange syndrome, CSS: Coffin–Siris syndromes, KS: Kabuki syndrome, RSTS: Rubinstein–Taybi syndrome, CNS: Central nervous system, ID: intellectual disability. ++ = 70–100% WDSTS patients; + = 20–70% WDSTS patients; +/− = 5–20% WDSTS patients; − = <5% WDSTS patients; NA = not assessed.

2.2. Other Chromatinopathies

Mutations in KMT2A have been also found in patients with a clinical presentation suggestive of other chromatinopathies (i.e., Coffin–Siris syndromes, Kabuki syndrome, Cornelia De Lange syndrome, Rubinstein–Taybi syndrome) but negative for alterations in the related known-causative genes. Their clinical presentation shares with WDSTS some phenotypic features and it is caused by alterations of genes involved in the regulation and maintenance of chromatin state as KMT2A. Indeed, these syndromes are caused by mutations in genes of the epigenetic machinery and therefore are known as chromatinopathies [16][18].

3. KMT2A Somatic Mutations

KMT2A somatic mutations are implicated in several tumors. The most common types of alterations involving KMT2A are mutations (3.62%), fusions (0.13%) (with more than 80 different partners identified) [32], losses (0.10%), amplifications (0.07%), and KMT2A-EP300 fusions (0.19%) [33]. Among the mutations, the most frequent observed in patient-derived samples are missense (54.36%), synonymous (13.61%) and nonsense substitutions (7.34%) [34]. On the contrary, in patients with germline KMT2A mutations, the ones more represented are frameshift (41%) and stop mutations (29%), followed by missense variants (18%) [26]. The project GENIE, led by the American Association for Cancer Research, highlighted how KMT2A is implicated in many diseases, especially in blood cancers such as acute myeloid leukemia (2.49%), T-cell lymphoblastic leukemia (5.63%) and up to 14% in high grade B-cell lymphoma (Figure 5). KMT2A is altered also in 4.65% of malignant solid tumors, such as lung adenocarcinoma, colon adenocarcinoma and bladder urothelial carcinoma (Figure 5). Interestingly, KMT2A is not the only gene of the epigenetic apparatus whose somatic mutations give rise to tumors, especially in blood malignancies. In fact, somatic alterations in other chromatinopathies genes were found in myelodysplastic syndromes (ASXL1, ATRX, DNMT3A, EED, EZH2, KDM6A, KMT2 family genes, PHF6) [35], acute myeloid leukemia (ASXL1, DNMT3A, PHF6) [36], multiple myeloma (KDM6A, KMT2B, KMT2C, WHSC1) [37] and lymphoid malignancies such as acute lymphoblastic leukemia (CREBBP, DNMT3A, EP300, EED, EZH2, PHF6) and diffuse large B-cell lymphoma (CREBBP/EP300, EZH2, KMT2C/D) [37][38].
Figure 5. KMT2A somatic mutations in tumors ordered by percentage of positive cases (AACR Project GENIE).

4. Effects of KMT2A Mutations in Animal Models 

KMT2A is an evolutionary conserved gene, involved in several functional process of embryonic development, ranging from hematopoiesis to neurogenesis. Indeed, in 1995, Yu and colleagues showed that the complete disruption of KMT2A was embryonic lethal in mice, and heterozygous animals were anemic and affected by growth delay, hematopoietic anomalies and skeletal malformations [39]. Developmental defects were investigated in Drosophila melanogaster too, where mutations in KMT2A homolog (trx) led to a wide range of homeotic transformations [40]. Interestingly, KMT2A was demonstrated as having an important role in the maintenance of memory Th2 cell function [41] and in hematopoiesis, as its absence caused defects both in self-renewal of murine hematopoietic stem cells and in hematopoietic progenitor cell differentiation in zebrafish  [42][43]. In addition, impairments in neural development were observed knocking down Kmt2a in zebrafish, and in murine models Mll1 was identified as a crucial component in memory formation, complex behaviors and synaptic plasticity [44][45][46][47][48].
Thus, KMT2A-depleted animal models recapitulate phenotypes described for patients with both germline and somatic mutations. KMT2A associated syndromes show clinical signs such as ID, behavioral problems, speech and growth delay and peculiar dysmorphisms, while the most frequent tumors enriched in KMT2A mutations are the hematological ones (e.g., B-cell lymphoma, T-cell lymphoblastic leukemia, acute myeloid leukemia), according to neurodevelopmental and hematopoietic defects found in the aforementioned in vivo models.

5. Conclusions

Epigenetic modifications are fundamental for many biological processes; indeed, alterations of genes with this activity can lead to neurodevelopmental disorders or tumorigenesis, when germinal or somatic mutations respectively occur [49][50]. This is the case of KMT2A, a lysin methyltransferase-coding gene, whose variants are associated with a chromatinopathy (WDSTS) at germinal level or can be found in both blood cancers and solid tumors in regard to malignancies.
Interestingly, due to exome- and genome-wide analyses, patients described above with a defined initial chromatinopathy diagnosis but lacking the molecular one were found to be carriers of pathogenetic variants in the KMT2A gene and could have obtained a clinical re-evaluation. Indeed, mutations in different genes involved in the regulation and maintenance of chromatin state can lead to a clinical overlapping phenotype, suggesting a common affected pathway during embryonic development and the evaluation of an expanded set of genes when investigating the molecular causes for a correct diagnosis of these syndromes.
In addition, somatic mutations in KMT2A have been reported in different tumors, as well as alterations in all KMT2 family genes [51] and in other genes associated to chromatinopathies. Curiously, it is observed that germline mutations described in the literature are more frequently nonsense than missense, in contrast to somatic ones. This could be explained by the consequent loss of function mechanism characterizing most of chromatinopathies due to a defective protein production, which strongly impacts on embryonic development.
To conclude, since molecular defects in KMT2A also characterize some types of tumors, and research in the field of epigenetic drugs for malignancies is rapidly evolving [52],  a therapeutic approach targeting KMT2A interaction or its pathway could be considered also for chromatinopathies, modulating epigenetic dysfunction with pharmaceutical products or diet-based interventions.

References

  1. Kouzarides, T. Chromatin Modifications and Their Function. Cell 2007, 128, 693–705.
  2. Black, J.C.; Van Rechem, C.; Whetstine, J.R. Histone Lysine Methylation Dynamics: Establishment, Regulation, and Biological Impact. Mol. Cell 2012, 48, 491–507.
  3. Garcia, B.A.; Hake, S.B.; Diaz, R.L.; Kauer, M.; Morris, S.A.; Recht, J.; Shabanowitz, J.; Mishra, N.; Strahl, B.D.; Allis, C.D.; et al. Organismal Differences in Post-Translational Modifications in Histones H3 and H4. J. Biol. Chem. 2007, 282, 7641–7655.
  4. Trojer, P.; Zhang, J.; Yonezawa, M.; Schmidt, A.; Zheng, H.; Jenuwein, T.; Reinberg, D. Dynamic Histone H1 Isotype 4 Methylation and Demethylation by Histone Lysine Methyltransferase G9a/KMT1C and the Jumonji Domain-Containing JMJD2/KDM4 Proteins. J. Biol. Chem. 2009, 284, 8395–8405.
  5. Daujat, S.; Weiss, T.; Mohn, F.; Lange, U.C.; Ziegler-Birling, C.; Zeissler, U.; Lappe, M.; Schübeler, D.; Torres-Padilla, M.E.; Schneider, R. H3K64 Trimethylation Marks Heterochromatin and Is Dynamically Remodeled during Developmental Reprogramming. Nat. Struct. Mol. Biol. 2009, 16, 777–781.
  6. Weiss, T.; Hergeth, S.; Zeissler, U.; Izzo, A.; Tropberger, P.; Zee, B.M.; Dundr, M.; Garcia, B.A.; Daujat, S.; Schneider, R. Histone H1 Variant-Specific Lysine Methylation by G9a/KMT1C and Glp1/KMT1D. Epigenet. Chromatin 2010, 3, 7.
  7. Rodríguez-Paredes, M.; Esteller, M. Cancer Epigenetics Reaches Mainstream Oncology. Nat. Med. 2011, 17, 330–339.
  8. van Aller, G.S.; Reynoird, N.; Barbash, O.; Huddleston, M.; Liu, S.; Zmoos, A.F.; McDevitt, P.; Sinnamon, R.; Le, B.C.; Mas, G.; et al. Smyd3 Regulates Cancer Cell Phenotypes and Catalyzes Histone H4 Lysine 5 Methylation. Epigenetics 2012, 7, 340–343.
  9. Hyun, K.; Jeon, J.; Park, K.; Kim, J. Writing, Erasing and Reading Histone Lysine Methylations. Exp. Mol. Med. 2017, 49, e324.
  10. Husmann, D.; Gozani, O. Histone Lysine Methyltransferases in Biology and Disease. Nat. Struct. Mol. Biol. 2019, 26, 880–889.
  11. Liu, Y.; Qin, S.; Chen, T.Y.; Lei, M.; Dhar, S.S.; Ho, J.C.; Dong, A.; Loppnau, P.; Li, Y.; Lee, M.G.; et al. Structural Insights into Trans-Histone Regulation of H3K4 Methylation by Unique Histone H4 Binding of MLL3/4. Nat. Commun. 2019, 10, 36.
  12. Guo, L.; Lee, Y.T.; Zhou, Y.; Huang, Y. Targeting Epigenetic Regulatory Machinery to Overcome Cancer Therapy Resistance. Semin. Cancer Biol. 2021, in press.
  13. Zhang, T.; Zhang, W.; Liu, L.; Chen, Y. Simultaneous Detection of Site-Specific Histone Methylations and Acetylation Assisted by Single Template Oriented Molecularly Imprinted Polymers. Analyst 2020, 145, 1376–1383.
  14. Di Nisio, E.; Lupo, G.; Licursi, V.; Negri, R. The Role of Histone Lysine Methylation in the Response of Mammalian Cells to Ionizing Radiation. Front. Genet. 2021, 12, 482.
  15. Khare, S.P.; Habib, F.; Sharma, R.; Gadewal, N.; Gupta, S.; Galande, S. HIstome—A Relational Knowledgebase of Human Histone Proteins and Histone Modifying Enzymes. Nucleic Acids Res. 2012, 40, D337–D342.
  16. Fahrner, J.A.; Bjornsson, H.T. Mendelian Disorders of the Epigenetic Machinery: Tipping the Balance of Chromatin States. Annu. Rev. Genom. Hum. Genet. 2014, 15, 269–293.
  17. Bjornsson, H.T. The Mendelian Disorders of the Epigenetic Machinery. Genome Res. 2015, 25, 1473–1481.
  18. Fahrner, J.A.; Bjornsson, H.T. Mendelian Disorders of the Epigenetic Machinery: Postnatal Malleability and Therapeutic Prospects. Hum. Mol. Genet. 2019, 28, R254–R264.
  19. Faundes, V.; Newman, W.G.; Bernardini, L.; Canham, N.; Clayton-Smith, J.; Dallapiccola, B.; Davies, S.J.; Demos, M.K.; Goldman, A.; Gill, H.; et al. Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders. Am. J. Hum. Genet. 2018, 102, 175–187.
  20. Fagerberg, L.; Hallstrom, B.M.; Oksvold, P.; Kampf, C.; Djureinovic, D.; Odeberg, J.; Habuka, M.; Tahmasebpoor, S.; Danielsson, A.; Edlund, K.; et al. Analysis of the Human Tissue-Specific Expression by Genome-Wide Integration of Transcriptomics and Antibody-Based Proteomics. Mol. Cell. Proteom. MCP 2014, 13, 397–406.
  21. Hess, J.L. MLL: A Histone Methyltransferase Disrupted in Leukemia. Trends Mol. Med. 2004, 10, 500–507.
  22. Southall, S.M.; Wong, P.S.; Odho, Z.; Roe, S.M.; Wilson, J.R. Structural Basis for the Requirement of Additional Factors for MLL1 SET Domain Activity and Recognition of Epigenetic Marks. Mol. Cell 2009, 33, 181–191.
  23. Wiedemann, H.R.; Kunze, J.; Grosse, F.R.; Dibbern, H. A Syndrome of Abnormal Facies, Short Stature, and Psychomotor Retardation. In Atlas of Clinical Syndromes: A Visual Aid to Diagnosis for Clinicians and Practicing Physicians, 2nd ed.; Wolfe Publishing Ltd.: London, UK, 1989; pp. 198–199.
  24. Miyake, N.; Tsurusaki, Y.; Koshimizu, E.; Okamoto, N.; Kosho, T.; Brown, N.J.; Tan, T.Y.; Yap, P.J.J.; Suzumura, H.; Tanaka, T.; et al. Delineation of Clinical Features in Wiedemann-Steiner Syndrome Caused by KMT2A Mutations. Clin. Genet. 2016, 89, 115–119.
  25. Aggarwal, A.; Rodriguez-Buritica, D.F.; Northrup, H. Wiedemann-Steiner Syndrome: Novel Pathogenic Variant and Review of Literature. Eur. J. Med. Genet. 2017, 60, 285–288.
  26. di Fede, E.; Massa, V.; Augello, B.; Squeo, G.; Scarano, E.; Perri, A.M.; Fischetto, R.; Causio, F.A.; Zampino, G.; Piccione, M.; et al. Expanding the Phenotype Associated to KMT2A Variants: Overlapping Clinical Signs between Wiedemann–Steiner and Rubinstein–Taybi Syndromes. Eur. J. Hum. Genet. 2021, 29, 88–98.
  27. Yuan, B.; Pehlivan, D.; Karaca, E.; Patel, N.; Charng, W.-L.; Gambin, T.; Gonzaga-Jauregui, C.; Sutton, V.R.; Yesil, G.; Bozdogan, S.T.; et al. Global Transcriptional Disturbances Underlie Cornelia de Lange Syndrome and Related Phenotypes. J. Clin. Investig. 2015, 125, 636–651.
  28. Parenti, I.; Teresa-Rodrigo, M.E.; Pozojevic, J.; Ruiz Gil, S.; Bader, I.; Braunholz, D.; Bramswig, N.C.; Gervasini, C.; Larizza, L.; Pfeiffer, L.; et al. Mutations in Chromatin Regulators Functionally Link Cornelia de Lange Syndrome and Clinically Overlapping Phenotypes. Hum. Genet. 2017, 136, 307–320.
  29. Bramswig, N.C.; Lüdecke, H.J.; Alanay, Y.; Albrecht, B.; Barthelmie, A.; Boduroglu, K.; Braunholz, D.; Caliebe, A.; Chrzanowska, K.H.; Czeschik, J.C.; et al. Exome Sequencing Unravels Unexpected Differential Diagnoses in Individuals with the Tentative Diagnosis of Coffin–Siris and Nicolaides–Baraitser Syndromes. Hum. Genet. 2015, 134, 553–568.
  30. Sobreira, N.; Brucato, M.; Zhang, L.; Ladd-Acosta, C.; Ongaco, C.; Romm, J.; Doheny, K.F.; Mingroni-Netto, R.C.; Bertola, D.; Kim, C.A.; et al. Patients with a Kabuki Syndrome Phenotype Demonstrate DNA Methylation Abnormalities. Eur. J. Hum. Genet. 2017, 25, 1335–1344.
  31. Negri, G.; Magini, P.; Milani, D.; Crippa, M.; Biamino, E.; Piccione, M.; Sotgiu, S.; Perrìa, C.; Vitiello, G.; Frontali, M.; et al. Exploring by Whole Exome Sequencing Patients with Initial Diagnosis of Rubinstein–Taybi Syndrome: The Interconnections of Epigenetic Machinery Disorders. Hum. Genet. 2019, 138, 257–269.
  32. Meyer, C.; Kowarz, E.; Hofmann, J.; Renneville, A.; Zuna, J.; Trka, J.; Ben Abdelali, R.; Macintyre, E.; De Braekeleer, E.; De Braekeleer, M.; et al. New Insights to the MLL Recombinome of Acute Leukemias. Leukemia 2009, 23, 1490–1499.
  33. Sweeney, S.M.; Cerami, E.; Baras, A.; Pugh, T.J.; Schultz, N.; Stricker, T.; Lindsay, J.; Del Vecchio Fitz, C.; Kumari, P.; Micheel, C.; et al. AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov. 2017, 7, 818–831.
  34. Forbes, S.A.; Beare, D.; Boutselakis, H.; Bamford, S.; Bindal, N.; Tate, J.; Cole, C.G.; Ward, S.; Dawson, E.; Ponting, L.; et al. COSMIC: Somatic Cancer Genetics at High-Resolution. Nucleic Acids Res. 2017, 45, D777–D783.
  35. Ogawa, S. Genetics of MDS. Blood 2019, 133, 1049–1059.
  36. Kishtagari, A.; Levine, R.L. The Role of Somatic Mutations in Acute Myeloid Leukemia Pathogenesis. Cold Spring Harb. Perspect. Med. 2021, 11, a034975.
  37. Mullighan, C.G. Genome Sequencing of Lymphoid Malignancies. Blood 2013, 122, 3899–3907.
  38. Huang, Y.H.; Cai, K.; Xu, P.P.; Wang, L.; Huang, C.X.; Fang, Y.; Cheng, S.; Sun, X.J.; Liu, F.; Huang, J.Y.; et al. CREBBP/EP300 Mutations Promoted Tumor Progression in Diffuse Large B-Cell Lymphoma through Altering Tumor-Associated Macrophage Polarization via FBXW7-NOTCH-CCL2/CSF1 Axis. Signal Transduct. Target. Ther. 2021, 6, 10.
  39. Yu, B.D.; Hess, J.L.; Horning, S.E.; Brown, G.A.J.; Korsmeyer, S.J. Altered HOX Expression and Segmental Identity in Mll-Mutant Mice. Nature 1995, 378, 505–508.
  40. Katsani, K.R.; Arredondo, J.J.; Kal, A.J.; Verrijzer, C.P. A Homeotic Mutation in the Trithorax SET Domain Impedes Histone Binding. Genes Dev. 2001, 15, 2197–2202.
  41. Yamashita, M.; Hirahara, K.; Shinnakasu, R.; Hosokawa, H.; Norikane, S.; Kimura, M.Y.; Hasegawa, A.; Nakayama, T. Crucial Role of MLL for the Maintenance of Memory T Helper Type 2 Cell Responses. Immunity 2006, 24, 611–622.
  42. McMahon, K.A.; Hiew, S.Y.L.; Hadjur, S.; Veiga-Fernandes, H.; Menzel, U.; Price, A.J.; Kioussis, D.; Williams, O.; Brady, H.J.M. Mll Has a Critical Role in Fetal and Adult Hematopoietic Stem Cell Self-Renewal. Cell Stem Cell 2007, 1, 338–345.
  43. Wan, X.; Hu, B.; Liu, J.X.; Feng, X.; Xiao, W. Zebrafish Mll Gene Is Essential for Hematopoiesis. J. Biol. Chem. 2011, 286, 33345–33357.
  44. Huang, Y.C.; Shih, H.Y.; Lin, S.J.; Chiu, C.C.; Ma, T.L.; Yeh, T.H.; Cheng, Y.C. The Epigenetic Factor Kmt2a/Mll1 Regulates Neural Progenitor Proliferation and Neuronal and Glial Differentiation. Dev. Neurobiol. 2015, 75, 452–462.
  45. Gupta, S.; Kim, S.Y.; Artis, S.; Molfese, D.L.; Schumacher, A.; Sweatt, J.D.; Paylor, R.E.; Lubin, F.D. Histone Methylation Regulates Memory Formation. J. Neurosci. 2010, 30, 3589–3599.
  46. Kerimoglu, C.; Sakib, M.S.; Jain, G.; Benito, E.; Burkhardt, S.; Capece, V.; Kaurani, L.; Halder, R.; Agís-Balboa, R.C.; Stilling, R.; et al. KMT2A and KMT2B Mediate Memory Function by Affecting Distinct Genomic Regions. Cell Rep. 2017, 20, 538–548.
  47. Jakovcevski, M.; Ruan, H.; Shen, E.Y.; Dincer, A.; Javidfar, B.; Ma, Q.; Peter, C.J.; Cheung, I.; Mitchell, A.C.; Jiang, Y.; et al. Neuronal Kmt2a/Mll1 Histone Methyltransferase Is Essential for Prefrontal Synaptic Plasticity and Working Memory. J. Neurosci. 2015, 35, 5097–5108.
  48. Shen, E.Y.; Jiang, Y.; Javidfar, B.; Kassim, B.; Loh, Y.H.E.; Ma, Q.; Mitchell, A.C.; Pothula, V.; Stewart, A.F.; Ernst, P.; et al. Neuronal Deletion of Kmt2a/Mll1 Histone Methyltransferase in Ventral Striatum Is Associated with Defective Spike-Timing-Dependent Striatal Synaptic Plasticity, Altered Response to Dopaminergic Drugs, and Increased Anxiety. Neuropsychopharmacology 2016, 41, 3103–3113.
  49. Jakovcevski, M.; Akbarian, S. Epigenetic Mechanisms in Neurological Disease. Nat. Med. 2012, 18, 1194–1204.
  50. Cheng, Y.; He, C.; Wang, M.; Ma, X.; Mo, F.; Yang, S.; Han, J.; Wei, X. Targeting Epigenetic Regulators for Cancer Therapy: Mechanisms and Advances in Clinical Trials. Signal Transduct. Target. Ther. 2019, 4, 62.
  51. Fagan, R.J.; Dingwall, A.K. COMPASS Ascending: Emerging Clues Regarding the Roles of MLL3/KMT2C and MLL2/KMT2D Proteins in Cancer. Cancer Lett. 2019, 458, 56–65.
  52. Cheng, L.H.; Liu, Y.W.; Wu, C.C.; Wang, S.; Tsai, Y.C. Psychobiotics in Mental Health, Neurodegenerative and Neurodevelopmental Disorders. J. Food Drug Anal. 2019, 27, 632–648.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Genetics & Heredity
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Elisabetta Di Fede
,
,
Clara Bernardelli
,
Antonella Lettieri
,
Paolo Grazioli
,
Elisa Colombo
,
Donatella Milani
,
Emerenziana Ottaviano
,
Elisa Borghi
,
VALENTINA MASsA
,
Aglaia Vignoli
,
Elena Lesma
,
Cristina Gervasini
View Times: 847
Revisions: 5 times (View History)
Update Date: 06 Apr 2022
Table of Contents
    1000/1000
    Hot Most Recent
    Video Production Service
    Feedback