inactivating mutations
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2021 ◽  
Vol 36 (4) ◽  
pp. 167-174
Author(s):  
Kwan-Sik Min ◽  
Munkhzaya Byambaragchaa ◽  
Seung-Hee Choi ◽  
Hyo-Eun Joo ◽  
Sang-Gwon Kim ◽  
...  

2021 ◽  
Vol 12 (4) ◽  
pp. 69-81
Author(s):  
V. N. Gorbunova ◽  
N. V. Buchinskaya

The review describes the clinical, biochemical and molecular genetic characteristics of autosomal recessive mucopolysaccharidosis type III, or Sanfilippo syndrome. This is a genetically heterogeneous group of rare, but similar in nature, diseases caused by a deficiency of one of the four lysosomal enzymes involved in the degradation of heparan sulfate. All types of mucopolysaccharidosis III are characterized by severe degeneration of the central nervous system in combination with mild somatic manifestations, which is explained by the accumulation of high concentrations of heparan sulfate in the lysosomes of various cells, including the central nervous system. The primary biochemical defect in the most common type of mucopolysaccharidosis IIIA, occurring with a frequency of 1 : 105 and presented in 60% of all cases of the disease, is heparan-N-sulfatase, or sulfamidase deficiency. Mucopolysaccharidosis IIIB type occurs twice less often and accounts for about 30% of all cases of Sanfilippo syndrome. It is caused by the presence of inactivating mutations in the lysosomal -N-acetylglucosaminidase gene. Mucopolysaccharidosis IIIC and IIID are 4% and 6%, and occur at frequencies of 0.7 and 1.0 : 106. Mucopolysaccharidosis IIIC is caused by inactivating mutations in the gene of membrane-bound lysosomal acetyl-CoA:-glucosaminid-N-acetyltransferase, or N-acetyltransferase. Mucopolysaccharidosis IIID is based on the deficiency of lysosomal N-acetylglucosamine-6-sulfatase. The role of experimental models in the study of the biochemical basis of the pathogenesis of Sanfilippo syndrome and the development of various therapeutic approaches are discussed. The possibility of neonatal screening, early diagnosis, prevention and pathogenetic therapy of these severe lysosomal diseases are considered. As an example, a clinical case of diagnosis and treatment of a child with type IIIB mucopolysaccharidosis is presented.


2021 ◽  
Vol 1 ◽  
pp. 75
Author(s):  
Christopher A. Emerling ◽  
Mark S. Springer ◽  
John Gatesy ◽  
Zachary Jones ◽  
Deana Hamilton ◽  
...  

Background: The study of regressive evolution has yielded a wealth of examples where the underlying genes bear molecular signatures of trait degradation, such as pseudogenization or deletion. Typically, it appears that such disrupted genes are limited to the function of the regressed trait, whereas pleiotropic genes tend to be maintained by natural selection to support their myriad purposes. One such set of pleiotropic genes is involved in the synthesis (AANAT, ASMT) and signaling (MTNR1A, MTNR1B) of melatonin, a hormone secreted by the vertebrate pineal gland. Melatonin provides a signal of environmental darkness, thereby influencing the circadian and circannual rhythmicity of numerous physiological traits. Therefore, the complete loss of a pineal gland and the underlying melatonin pathway genes seems likely to be maladaptive, unless compensated by extrapineal sources of melatonin. Methods: We examined AANAT, ASMT, MTNR1A and MTNR1B in 123 vertebrate species, including pineal-less placental mammals and crocodylians. We searched for inactivating mutations and modelled selective pressures (dN/dS) to test whether the genes remain functionally intact. Results: We report that crocodylians retain intact melatonin genes and express AANAT and ASMT in their eyes, whereas all four genes have been repeatedly inactivated in the pineal-less xenarthrans, pangolins, sirenians, and whales. Furthermore, colugos have lost these genes, and several lineages of subterranean mammals have partial melatonin pathway dysfunction. These results are supported by the presence of shared inactivating mutations across clades and analyses of selection pressure based on the ratio of non-synonymous to synonymous substitutions (dN/dS), suggesting extended periods of relaxed selection on these genes. Conclusions: The losses of melatonin synthesis and signaling date to tens of millions of years ago in several lineages of placental mammals, raising questions about the evolutionary resilience of pleiotropic genes, and the causes and consequences of losing melatonin pathways in these species.


PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0255706
Author(s):  
Ling Tian ◽  
Monique Chavez ◽  
Gue Su Chang ◽  
Nichole M. Helton ◽  
Casey D. S. Katerndahl ◽  
...  

Kdm6a/Utx, a gene on the X chromosome, encodes a histone H3K27me3 demethylase that has an orthologue on the Y chromosome (Uty) (Zheng et al. 2018). We previously identified inactivating mutations of Kdm6a in approximately 50% of mouse acute promyelocytic leukemia samples; however, somatic mutations of KDM6A are more rare in human AML samples, ranging in frequency from 2–15% in different series of patients, where their role in pathogenesis is not yet clear. In this study, we show that female Kdm6aflox/flox mice (with allele inactivation initiated by Vav1-Cre in hematopoietic stem and progenitor cells (HSPCs) have a sex-specific phenotype that emerges with aging, with features resembling a myelodysplastic syndrome (MDS). Female Kdm6a-knockout (KO) mice have an age-dependent expansion of their HSPCs with aberrant self-renewal, but they did not differentiate normally into downstream progeny. These mice became mildly anemic and thrombocytopenic, but did not develop overt leukemia, or die from these cytopenias. ChIP-seq and ATAC-seq studies showed only minor changes in H3K27me3, H3K27ac, H3K4me, H3K4me3 and chromatin accessibility between Kdm6a-WT and Kdm6a-KO mice. Utilizing scRNA-seq, Kdm6a loss was linked to the transcriptional repression of genes that mediate hematopoietic cell fate determination. These data demonstrate that Kdm6a plays an important role in normal hematopoiesis, and that its inactivation may contribute to AML pathogenesis.


2021 ◽  
Author(s):  
JASON G RANDALL ◽  
John Gatesy ◽  
Mark Springer

The loss of teeth and evolution of baleen racks in Mysticeti was a profound transformation that permitted baleen whales to radiate and diversify into a previously underutilized ecological niche of bulk filter-feeding on zooplankton and other small prey. Ancestral state reconstructions suggest that teeth were lost in the common ancestor of crown Mysticeti. Genomic studies provide some support for this hypothesis and suggest that the genetic toolkit for enamel production was inactivated in the common ancestor of living baleen whales. However, molecular studies to date have not provided direct evidence for the complete loss of teeth, including their dentin component, on the stem mysticete branch. Given these results, several questions remain unanswered: (1) Were teeth lost in a single step or did enamel loss precede dentin loss? (2) Was enamel lost early or late on the stem mysticete branch? (3) If enamel and dentin/tooth loss were decoupled in the ancestry of baleen whales, did dentin loss occur on the stem mysticete branch or independently in different crown mysticete lineages? To address these outstanding questions, we compiled and analyzed complete protein-coding sequences for nine tooth-related genes from cetaceans with available genome data. Seven of these genes are associated with enamel formation (ACP4, AMBN, AMELX, AMTN, ENAM, KLK4, MMP20) whereas two other genes are either dentin-specific (DSPP) or tooth-specific (ODAPH) but not enamel-specific. Molecular evolutionary analyses indicate that all seven enamel-specific genes have inactivating mutations that are scattered across branches of the mysticete tree. Three of the enamel genes (ACP4, KLK4, MMP20) have inactivating mutations that are shared by all mysticetes. The two genes that are dentin-specific (DSPP) or tooth-specific (ODAPH) do not have any inactivating mutations that are shared by all mysticetes, but there are shared mutations in Balaenidae as well as in Plicogulae (Neobalaenidae + Balaenopteroidea). These shared mutations suggest that teeth were lost at most two times. Shared inactivating mutations and dN/dS analyses, in combination with cetacean divergence times, were used to estimate inactivation times of genes and by proxy enamel and tooth phenotypes. The results of these analyses are most compatible with a two-step model for the loss of teeth in the ancestry of living baleen whales: enamel was lost very early on the stem Mysticeti branch followed by the independent loss of dentin (and teeth) in the common ancestors of Balaenidae and Plicogulae, respectively. These results imply that some stem mysticetes, and even early crown mysticetes, may have had vestigial teeth comprised of dentin with no enamel. Our results also demonstrate that all odontocete species (in our study) with absent or degenerative enamel have inactivating mutations in one or more of their enamel genes.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 501-501
Author(s):  
Willem K. Smits ◽  
Carlo Vermeulen ◽  
Rico Hagelaar ◽  
Shunsuke Kimura ◽  
Eric Vroegindeweij ◽  
...  

Abstract Introduction. The CCCTC-binding factor (CTCF) regulates the 3D chromatin architecture by facilitating chromosomal loops and forming the boundaries of structural domains. In addition, CTCF is an important transcription factor and regulator of antigen receptor and T cell receptor recombination events. CTCF inactivating events have been found in various human cancers. Loss-of-heterozygosity (LOH) or inactivating missense mutations in specific zinc- fingers have been identified in many human cancers including sporadic breast cancer, prostate cancer, Wilms-tumors and acute lymphoblastic leukemia (ALL). Heterozygous deletions or point mutations have been identified in over half of the patients with breast cancer or uterine endometrial cancers, deregulating global gene expression by altering methylated genomic states and poor survival. Here, we investigated the functional significance and molecular-cytogenetic associations of CTCF aberrations in T-cell acute lymphoblastic leukemia patients. Methods. Biopsies from a cohort of 181 pediatric T-ALL patients who enrolled on DCOG or COALL protocols and/or their derivative patient-derived xenograft models were screened for alterations in global DNA copy number, methylation status, topologically associating domain organization and CTCF and cohesion binding patterns and changes in local TLX3 and BCL11B promoter enhancer loops using array-comparative genomic hybridization, single molecule Molecular Inversion Probe sequencing, targeted locus amplification, gene expression and DNA methylation microarrays, Hi-C sequencing, Chromatin Immunoprecipitation and/or real-time quantitative PCR. Ctcf f/fl mice 1 were crossed on a the Lck-cre transgenic background 2 to study the impact of Ctcf loss during early T-cell development. Results. We here describe that inactivation of CTCF can drive subtle and local genomic effects that elevate oncogene expression levels from driver chromosomal rearrangements. We find that for T cell acute lymphoblastic leukemia (T-ALL), heterozygous CTCF deletions or inactivating mutations are present in nearly 50 percent of t(5;14)(q35;q32.2) rearranged patients that positions the TLX3 oncogene in the vicinity of the BCL11B enhancer. Functional CTCF loss results in diminished expression of the αβ-lineage commitment factor BCL11B from the non-rearranged allele and γδ-lineage development. Unexpectedly, it also drives higher levels of the TLX3 oncogene from the translocated allele. We demonstrate that heterozygous CTCF aberrations specifically occur in TLX3-rearranged patients with distal breakpoints that preserve CTCF bindings sites in the translocation breakpoint areas in between the BCL11B enhancer and the TLX3 oncogene. We show that these intervening CTCF sites insulate TLX3 from the enhancer by forming competitive loops with TLX3. Upon loss of CTCF, or the deletion of the intervening CTCF sites, these competitive loops are weakened and loops with the BCL11B enhancer are stimulated, boosting TLX3 oncogene expression levels and leukemia burden in these T-ALL patients. Conclusions. CTCF aberrations are especially associated with t(5;14)(q35;q32.2) rearranged T-ALL patients who maintain TLX3-proximal CTCF sites reflects a necessity to neutralize these sites in order to topologically enable the distal BCL11B enhancer to interact with the TLX3 oncogene and to boost its expression. Collectively, this provides direct demonstration of a mechanism in which loss of CTCF result in removal of enhancer insulation that facilitates elevated levels of an oncogene in leukemia. References. 1. Heath H, Ribeiro de Almeida C, Sleutels F, et al. CTCF regulates cell cycle progression of alphabeta T cells in the thymus. EMBO J. 2008;27(21):2839-2850. 2. Lee PP, Fitzpatrick DR, Beard C, et al. A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity. 2001;15(5):763-774. Disclosures Splinter: Cergentis BV: Current Employment. Van Eyndhoven: Agilent Technologies Netherland: Current Employment. Van Min: Cergentis BV: Current Employment. Mullighan: Pfizer: Research Funding; Illumina: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Amgen: Current equity holder in publicly-traded company.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1148-1148
Author(s):  
Sunisa Kongkiatkamon ◽  
Xiaorong Gu ◽  
Kwok Peng Ng ◽  
Simona Pagliuca ◽  
Vera Adema ◽  
...  

Abstract Introduction/Methods: Enzymes that modify histone H3 at lysine 27 (H3K27) to thereby regulate gene transcription (epigenetic enzymes) are recurrently inactivated by deletion and/or mutation in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and acute myeloid leukemias (AML). Frustrating understanding of mechanisms is that writers and erasers of the same modification, e.g., methyltransferases that create, and demethylases that remove, H3K27 trimethylation (H3K27me3), a repression ('off') mark, are recurrently inactivated. Moreover, acetyltransferases that write H3K27 acetylation (H3K27ac), an 'on' mark mutually exclusive with H3K27me3, are also recurrently inactivated. One clue to underlying mechanisms is that MDS/MPN/AML present with diverse lineage and maturation phenotypes - perhaps these emerge from, or select for, the diverse epigenetic enzyme mutations. We therefore identified genes upregulated with specific myeloid lineage-commitment, maturation and function fates (~500 genes each) and then examined distributions of H3K27me3 and H3K27ac at these gene-loci in: (i) embryonic stem cells (ESC); (ii) hematopoietic stem and progenitor cells (HSPC); (iii) mature myeloid cells (monocyte [mono], pro-erythroblast, megakaryocyte [MK]); and (iv) AML cells. Results: Terminal-myeloid programs underwent substantial remodeling to gain H3K27ac 'on' mark from ESC/HSPC to mature myeloid (Fig.1A). Providing a mechanism for this, the H3K27 acetyltransferases EP300 and CREBBP were recruited into the RUNX1/SPI1 myeloid-lineage master transcription factor (MTF) hub by cooperation between their transcription activating domains. Mutated/translocated RUNX1, or mutated-NPM1 that cytoplasmically dislocated SPI1, disrupted this cooperation, and reverted hub content to default recruitment of histone deacetylases (HDAC) instead. Demonstrating cause-effect, inhibiting these HDAC renewed AML cell maturation to terminal lineage-fates. Meanwhile, MYC-target (proliferation) genes have high baseline H3K27ac in ESC and HSPC and do not require major remodeling during ontogeny (Fig.1A). An H3K27ac remodeling requirement for lineage-maturation but not proliferation/housekeeping explains selection pressure for inactivating mutations in EP300 or CREBBP, that we found in ~1.2% of MDS/MPN/AML in our (n=690) and other series. Consistent with pan-lineage-maturation needs for H3K27ac, the mutations were found in all lineage sub-types. H3K27me3 'off' mark was mostly erased from myeloid programs in HSPC, but was greater at MK vs erythroid, and also at mono vs granulocyte genes (Fig.1B). This implied more need for H327me3 demethylase (KDM6A/UTX) for HSPC commitment into MK vs erythroid, or mono vs granulocyte, lineages. Accordingly, KDM6A was most upregulated in MK and mono-lineage cells (Fig.1C), and myeloid-conditional Kdm6a knockout decreased platelets and increased red cells in the spleen - reported by others: https://doi.org/10.1182/blood.V128.22.1467.1467. RUNX1-ETO has been shown to specifically impede granulocytic but not mono differentiation - https://www.nature.com/articles/2403396 and KDM6A inactivating mutations were significantly more likely to occur secondary to RUNX1-ETO (4-9% BEAT and AMLSG case series) vs other cytogenetics (0.005%). Selection for KDM6A secondary mutations could thus be to channel myeloid precursors toward lineages most efficiently impeded by primary mutations. Although H3K27me3 was substantially erased at all myeloid-commitment and terminal programs (except MK) in HSPC vs ESC, subsequent lineage-commitment and maturation entailed rewriting H3K27me3 at preceding HSPC and alternate lineage-fate programs, including at MTF genes for alternate fates (Fig.1B, D). Primary MDS/MPN/AML and AML cell lines with inactivating mutations/deletions in H3K27 methyltransferase EZH2 thus displayed aberrant co-expression of lineage MTFs and gene expression programs of normally mutually exclusive lineages (Fig.1E-G). Conclusion. Epigenetic remodeling requirements vary by myeloid lineage and maturation stage. Thus, epigenetic enzyme mutations are selected by, and cause, lineage-context of transformation. This knowledge can guide choice of specific epigenetic enzyme inhibitors to remedy the lineage-maturation defects that drive and define myeloid malignancies. Figure 1 Figure 1. Disclosures Haferlach: MLL Munich Leukemia Laboratory: Other: Part ownership. Haferlach: MLL Munich Leukemia Laboratory: Other: Part ownership. Maciejewski: Novartis: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Regeneron: Consultancy; Alexion: Consultancy. Saunthararajah: EpiDestiny: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi120-vi120
Author(s):  
Nicholas Nuechterlein ◽  
Patrick Cimino

Abstract Inactivating mutations in NOTCH1 occur in many cancer types and are frequently observed in IDH-mutant, 1p/19q-codeleted oligodendroglioma. Although the role of NOTCH1 as a tumor suppressor in diffuse glioma has become appreciated in human tissue and small animal models, the spectrum of inactivating mutations in Notch pathway genes in diffuse astrocytic gliomas has not been well described. To address this, we queried the TCGA lower-grade glioma and glioblastoma datasets to establish the extent of inactivation of Notch pathway genes, specifically by cataloging single nucleotide variants and those with copy number loss or deletion. Key alteration frequencies were found to be similar in two-independent glioma cohorts (Col, MSK). Notch pathway genes with inactivating alterations (overwhelmingly copy number loss) were present in 77% of TCGA diffuse gliomas. Across all diffuse gliomas, DLL3 loss was the most common alteration (TCGA 31%). For IDH-mutant diffuse astrocytic gliomas, JAG2 loss was the most common alteration (TCGA 23.0%, Col 35%, MSK 27%). DLL1 loss and MAML1 loss were mutually exclusive (p< 0.001) in TCGA IDH-mutant astrocytomas with a combined frequency of 39% (Col 47%, MSK 56%). The presence of any alteration in the top 10 altered Notch pathway genes indicated a shorter progression-free survival (p = 0.028) for TCGA IDH-mutant diffuse astrocytomas. For IDH-wildtype diffuse astrocytic gliomas, EP300 loss was the most common inactivating alteration (TCGA 35.4%, Col 49%, MSK 38%). EP300 loss, DLL1 loss, DLL4 loss were mutually exclusive (p = 0.006) in TCGA IDH-wildtype diffuse astrocytic gliomas with a combined frequency of 61% (Col 72%, MSK 66%). The presence of alterations in any of these three genes indicated a decreased overall survival (p = 0.045) in TCGA IDH-wildtype diffuse astrocytic gliomas. Overall, loss of differential Notch pathway genes has prognostic implications in both IDH-wildtype and IDH-mutant diffuse astrocytic gliomas.


2021 ◽  
Author(s):  
Mitch J Syberg-Olsen ◽  
Arkadiy I Garber ◽  
Patrick J Keeling ◽  
John McCutcheon ◽  
Filip Husnik

Prokaryotic genomes are generally gene dense and encode relatively few pseudogenes, or nonfunctional/inactivated remnants of genes. However, in certain contexts, such as recent ecological shifts or extreme population bottlenecks (such as those experienced by symbionts and pathogens), pseudogenes can quickly accumulate and form a substantial fraction of the genome. Identification of pseudogenes is, thus, a critical step for understanding the evolutionary forces acting upon, and the functional potential encoded within, prokaryotic genomes. Here, we present Pseudofinder, an open-source software dedicated to pseudogene identification and analysis. With Pseudofinder's multi-pronged, reference-based approach, we demonstrate its capacity to detect a wide variety of pseudogenes, including those that are highly degraded and typically missed by gene-calling pipelines, as well newly formed pseudogenes, which can have only one or a few inactivating mutations. Additionally, Pseudofinder can detect intact genes undergoing relaxed selection, which may indicate incipient pseudogene formation. Implementation of Pseudofinder in annotation pipelines will not only clarify the functional potential of sequenced microbes, but will also generate novel insights and hypotheses regarding the evolutionary dynamics of bacterial and archaeal genomes.


Author(s):  
Е.В. Бычкова ◽  
М.Ю. Дорофеева ◽  
В.В. Стрельников ◽  
К.И. Аношкин

Туберозный склероз - орфанное аутосомно-доминантное наследственное заболевание, причиной которого являются инактивирующие мутации в генах TSC1 или TSC2, сопровождающиеся гиперактивацией сигнального пути mTOR, отвечающего за регуляцию роста, пролиферации, выживаемости клеток, а также аутофагии. Одним из основных клинических симптомов туберозного склероза является наличие туберов в головном мозге. Данные образования характеризуются нарушениями кортикальной ламинации, появлением аномальных нейронов и выраженным глиозом. Известно, что количество кортикальных туберов коррелирует с развитием нейропсихиатрических расстройств, в том числе фармакорезистентной эпилепсии. В данной статье освещены вопросы молекулярной генетики туберозного склероза, приведена гистопатологическая характеристика кортикальных туберов, рассмотрен молекулярный механизм морфогенеза кортикальных туберов, а также приведены данные о связи этих образований с развитием неврологических проявлений и методах их лечения. Tuberous sclerosis is an orphan autosomal dominant hereditary disease caused by inactivating mutations in the TSC1 or TSC2 genes, accompanied by hyperactivation of the mTOR signaling pathway, which is responsible for the regulation of growth, proliferation, cell survival, and autophagy. One of the main clinical symptoms of tuberous sclerosis is the formation of tubers in the brain. These formations are characterized by disorders of the cortical lamination, the appearance of abnormal neurons and severe gliosis. It is known that the presence of cortical tubers correlates with the development of neuropsychiatric disorders, including drug-resistant epilepsy. This article highlights the issues of molecular genetics of tuberous sclerosis, presents the histopathological characteristics of cortical tubers, considers mechanism of morphogenesis of cortical tubers, and also presents the data on relationship of these formations with the development of neurological manifestations and methods of their treatment.


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