RESUMEN

Objective: Patients with pathogenic variants in the GATA Binding Protein 2 (GATA2), a hematopoietic transcription factor, are at risk for human papillomavirus-related (HPV) anogenital cancer at younger than expected ages. A female cohort with GATA2 haploinsufficiency was systematically assessed by two gynecologists to characterize the extent and severity of anogenital HPV disease, which was also compared with affected males. Methods: A 17-year retrospective review of medical records, including laboratory, histopathology and cytopathology records was performed for patients diagnosed with GATA2 haploinsufficiency followed at the National Institutes of Health. Student's t-test and Mann-Whitney U test or Fisher's exact test were used to compare differences in continuous or categorical variables, respectively. Spearman's rho coefficient was employed for correlations. Results: Of 68 patients with GATA2 haploinsufficiency, HPV disease was the initial manifestation in 27 (40%). HPV occurred at median 18.9 (15.2-26.2) years in females, and 25.6 (23.4-26.9) years in males. Fifty-two (76%), 27 females and 25 males, developed HPV-related squamous intraepithelial lesions (SIL) including two males with oral cancer. Twenty-one patients developed anogenital high-grade SIL (HSIL) or carcinoma (16 females versus 5 males, (59% versus 20%, respectively, p=0.005) at median 27 (18.6-59.3) years for females and 33 (16.5-40.1) years for males. Females were more likely than males to require >2 surgeries to treat recurrent HSIL (p=0.0009). Of 30 patients undergoing hematopoietic stem cell transplant (HSCT) to manage disease arising from GATA2 haploinsufficiency, 12 (nine females, three males) had persistent HSIL/HPV disease. Of these nine females, eight underwent peri-transplant surgical treatment of HSIL. Five of seven who survived post-HSCT received HPV vaccination and had no or minimal evidence of HPV disease 2 years post-HSCT. HPV disease persisted in two receiving immunosuppression. HPV disease/low SIL (LSIL) resolved in all three males. Conclusion: Females with GATA2 haploinsufficiency exhibit a heightened risk of recurrent, multifocal anogenital HSIL requiring frequent surveillance and multiple treatments. GATA2 haploinsufficiency must be considered in a female with extensive, multifocal genital HSIL unresponsive to multiple surgeries. This population may benefit from early intervention like HSCT accompanied by continued, enhanced surveillance and treatment by gynecologic oncologists and gynecologists in those with anogenital HPV disease.

Asunto(s)

Deficiencia GATA2 , Factor de Transcripción GATA2 , Predisposición Genética a la Enfermedad , Infecciones por Papillomavirus , Humanos , Femenino , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/complicaciones , Adulto , Masculino , Estudios Retrospectivos , Deficiencia GATA2/genética , Adolescente , Factor de Transcripción GATA2/genética , Factor de Transcripción GATA2/deficiencia , Adulto Joven , Neoplasias de los Genitales Femeninos/genética , Neoplasias de los Genitales Femeninos/virología , Neoplasias del Ano/genética , Neoplasias del Ano/etiología , Neoplasias del Ano/virología , Haploinsuficiencia , Papillomaviridae/genética , Virus del Papiloma Humano

RESUMEN

The maintenance of proper brain function relies heavily on the balance of excitatory and inhibitory neural circuits, governed in part by synaptic adhesion molecules. Among these, MDGA1 (MAM domain-containing glycosylphosphatidylinositol anchor 1) acts as a suppressor of synapse formation by interfering with Neuroligin-mediated interactions, crucial for maintaining the excitatory-inhibitory (E/I) balance. Mdga1-/- mice exhibit selectively enhanced inhibitory synapse formation in their hippocampal pyramidal neurons, leading to impaired hippocampal long-term potentiation (LTP) and hippocampus-dependent learning and memory function; however, it has not been fully investigated yet if the reduction in MDGA1 protein levels would alter brain function. Here, we examined the behavioral and synaptic consequences of reduced MDGA1 protein levels in Mdga1+/- mice. As observed in Mdga1-/- mice, Mdga1+/- mice exhibited significant deficits in hippocampus-dependent learning and memory tasks, such as the Morris water maze and contextual fear-conditioning tests, along with a significant deficit in the long-term potentiation (LTP) in hippocampal Schaffer collateral CA1 synapses. The acute administration of D-cycloserine, a co-agonist of NMDAR (N-methyl-d-aspartate receptor), significantly ameliorated memory impairments and restored LTP deficits specifically in Mdga1+/- mice, while having no such effect on Mdga1-/- mice. These results highlight the critical role of MDGA1 in regulating inhibitory synapse formation and maintaining the E/I balance for proper cognitive function. These findings may also suggest potential therapeutic strategies targeting the E/I imbalance to alleviate cognitive deficits associated with neuropsychiatric disorders.

Asunto(s)

Cicloserina , Haploinsuficiencia , Hipocampo , Potenciación a Largo Plazo , Trastornos de la Memoria , Animales , Potenciación a Largo Plazo/efectos de los fármacos , Cicloserina/farmacología , Ratones , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/genética , Trastornos de la Memoria/metabolismo , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Ratones Noqueados , Masculino , Ratones Endogámicos C57BL , Sinapsis/metabolismo , Sinapsis/efectos de los fármacos , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Memoria/efectos de los fármacos , Células Piramidales/metabolismo , Células Piramidales/efectos de los fármacos

RESUMEN

LMNA-related dilated cardiomyopathy (DCM) is an autosomal-dominant genetic condition with cardiomyocyte and conduction system dysfunction often resulting in heart failure or sudden death. The condition is caused by mutation in the Lamin A/C (LMNA) gene encoding Type-A nuclear lamin proteins involved in nuclear integrity, epigenetic regulation of gene expression, and differentiation. The molecular mechanisms of the disease are not completely understood, and there are no definitive treatments to reverse progression or prevent mortality. We investigated possible mechanisms of LMNA-related DCM using induced pluripotent stem cells derived from a family with a heterozygous LMNA c.357-2A>G splice-site mutation. We differentiated one LMNA-mutant iPSC line derived from an affected female (Patient) and two non-mutant iPSC lines derived from her unaffected sister (Control) and conducted single-cell RNA sequencing for 12 samples (four from Patients and eight from Controls) across seven time points: Day 0, 2, 4, 9, 16, 19, and 30. Our bioinformatics workflow identified 125,554 cells in raw data and 110,521 (88%) high-quality cells in sequentially processed data. Unsupervised clustering, cell annotation, and trajectory inference found complex heterogeneity: ten main cell types; many possible subtypes; and lineage bifurcation for cardiac progenitors to cardiomyocytes (CMs) and epicardium-derived cells (EPDCs). Data integration and comparative analyses of Patient and Control cells found cell type and lineage-specific differentially expressed genes (DEGs) with enrichment, supporting pathway dysregulation. Top DEGs and enriched pathways included 10 ZNF genes and RNA polymerase II transcription in pluripotent cells (PP); BMP4 and TGF Beta/BMP signaling, sarcomere gene subsets and cardiogenesis, CDH2 and EMT in CMs; LMNA and epigenetic regulation, as well as DDIT4 and mTORC1 signaling in EPDCs. Top DEGs also included XIST and other X-linked genes, six imprinted genes (SNRPN, PWAR6, NDN, PEG10, MEG3, MEG8), and enriched gene sets related to metabolism, proliferation, and homeostasis. We confirmed Lamin A/C haploinsufficiency by allelic expression and Western blot. Our complex Patient-derived iPSC model for Lamin A/C haploinsufficiency in PP, CM, and EPDC provided support for dysregulation of genes and pathways, many previously associated with Lamin A/C defects, such as epigenetic gene expression, signaling, and differentiation. Our findings support disruption of epigenomic developmental programs, as proposed in other LMNA disease models. We recognized other factors influencing epigenetics and differentiation; thus, our approach needs improvement to further investigate this mechanism in an iPSC-derived model.

Asunto(s)

Cardiomiopatía Dilatada , Diferenciación Celular , Haploinsuficiencia , Células Madre Pluripotentes Inducidas , Lamina Tipo A , Miocitos Cardíacos , Transcriptoma , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/patología , Humanos , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/patología , Cardiomiopatía Dilatada/metabolismo , Lamina Tipo A/genética , Lamina Tipo A/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Diferenciación Celular/genética , Haploinsuficiencia/genética , Femenino , Transcriptoma/genética , Pericardio/patología , Pericardio/metabolismo , Linaje de la Célula/genética , Análisis de la Célula Individual , Regulación de la Expresión Génica , Mutación/genética , Adulto

RESUMEN

Loss of function (LoF) mutations affecting the histone methyl transferase SETD1A are implicated in the aetiology of a range of neurodevelopmental disorders including schizophrenia. We examined indices of development and adult behaviour in a mouse model of Setd1a haploinsufficiency, revealing a complex pattern of sex-related differences spanning the pre- and post-natal period. Specifically, male Setd1a+/- mice had smaller placentae at E11.5 and females at E18.5 without any apparent changes in foetal size. In contrast, young male Setd1a+/- mice had lower body weight and showed enhanced growth, leading to equivalent weights by adulthood. Embryonic whole brain RNA-seq analysis revealed expression changes that were significantly enriched for mitochondria-related genes in Setd1a+/ samples. In adulthood, we found enhanced acoustic startle responding in male Setd1a+/- mice which was insentitive to the effects of risperidone, but not haloperidol, both commonly used antipsychotic drugs. We also observed reduced pre-pulse inhibition of acoustic startle, a schizophrenia-relevant phenotype, in both male and female Setd1a+/- mice which could not be rescued by either drug. In the open field and elevated plus maze tests of anxiety, Setd1a haplosufficiency led to more anxiogenic behaviour in both sexes, whereas there were no differences in general motoric ability and memory. Thus, we find evidence for changes in a number of phenotypes which strengthen the support for the use of Setd1a haploinsufficient mice as a model for the biological basis of schizophrenia. Furthermore, our data point towards possible underpinning neural and developmental mechanisms that may be subtly different between the sexes.

Asunto(s)

Conducta Animal , Haploinsuficiencia , N-Metiltransferasa de Histona-Lisina , Animales , Femenino , N-Metiltransferasa de Histona-Lisina/genética , Masculino , Ratones , Esquizofrenia/genética , Ansiedad/genética , Modelos Animales de Enfermedad , Reflejo de Sobresalto/genética , Embarazo , Caracteres Sexuales , Factores Sexuales , Ratones Endogámicos C57BL

RESUMEN

TNF-α-induced protein 3 (TNFAIP3), commonly referred to as A20, is an integral part of the ubiquitin-editing complex that significantly influences immune regulation, apoptosis, and the initiation of diverse immune responses. The A20 protein is characterized by an N-terminal ovarian tumor (OTU) domain and a series of seven zinc finger (ZNF) domains. Mutations in the TNFAIP3 gene are implicated in various immune-related diseases, such as Behçet's disease, polyarticular juvenile idiopathic arthritis, autoimmune thyroiditis, autoimmune hepatitis, and rheumatoid arthritis. These mutations can lead to a spectrum of symptoms, including, but not limited to, recurrent fever, ulcers, rashes, musculoskeletal and gastrointestinal dysfunctions, cardiovascular issues, and respiratory infections. The majority of these mutations are either nonsense (STOP codon) or frameshift mutations, which are typically associated with immune dysfunctions. Nonetheless, missense mutations have also been identified as contributors to these conditions. These genetic alterations may interfere with several biological pathways, notably abnormal NF-κB signaling and dysregulated ubiquitination. Currently, there is no definitive treatment for A20 haploinsufficiency; however, therapeutic strategies can alleviate the symptoms in patients. This review delves into the mutations reported in the TNFAIP3 gene, the clinical progression in affected individuals, potential disease mechanisms, and a brief overview of the available pharmacological interventions for A20 haploinsufficiency. Mandatory genetic testing of the TNFAIP3 gene should be performed in patients diagnosed with autoinflammatory disorders to better understand the genetic underpinnings and guide treatment decisions.

Asunto(s)

Haploinsuficiencia , Mutación , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/metabolismo , Humanos , Haploinsuficiencia/genética , Inflamación/genética , Predisposición Genética a la Enfermedad , Animales

RESUMEN

Diamond-Blackfan anemia syndrome (DBA) is a ribosomopathy associated with loss-of-function variants in more than 20 ribosomal protein (RP) genes. Here, we report the genetic, functional, and biochemical dissection of 2 multigenerational pedigrees with variants in RPL17, a large ribosomal subunit protein-encoding gene. Affected individuals had clinical features and erythroid proliferation defects consistent with DBA. Further, RPL17/uL22 depletion resulted in anemia and micrognathia in zebrafish larvae, and in vivo complementation studies indicated that RPL17 variants were pathogenic. Lymphoblastoid cell lines (LCLs) derived from patients displayed a ribosomal RNA maturation defect reflecting haploinsufficiency of RPL17. The proteins encoded by RPL17 variants were not incorporated into ribosomes, but 10%-20% of 60S ribosomal subunits contained a short form of 5.8S rRNA (5.8SC), a species that is marginal in normal cells. These atypical 60S subunits were actively engaged in translation. Ribosome profiling showed changes of the translational profile, but those are similar to LCLs bearing RPS19 variants. These results link an additional RP gene to DBA. They show that ribosomes can be modified substantially by RPL17 haploinsufficiency but support the paradigm that translation alterations in DBA are primarily related to insufficient ribosome production rather than to changes in ribosome structure or composition.

Asunto(s)

Anemia de Diamond-Blackfan , Proteínas Ribosómicas , Pez Cebra , Anemia de Diamond-Blackfan/genética , Proteínas Ribosómicas/genética , Humanos , Pez Cebra/genética , Animales , Masculino , Femenino , Linaje , Haploinsuficiencia

RESUMEN

BACKGROUND: Biallelic SUFU variants have originally been linked to Joubert syndrome, comprising cerebellar abnormalities, dysmorphism, and polydactyly. In contrast, heterozygous truncating variants have recently been associated with developmental delay and ocular motor apraxia, but only a limited number of patients have been reported. Here, we aim to delineate further the mild end of the phenotypic spectrum related to SUFU haploinsufficiency. METHODS: Nine individuals (from three unrelated families) harboring truncating SUFU variants were investigated, including two previously reported individuals (from one family). We provide results from a comprehensive assessment comprising neuroimaging, neuropsychology, video-oculography, and genetic testing. RESULTS: We identified three inherited or de novo truncating variants in SUFU (NM_016169.4): c.895C>T p.(Arg299∗), c.71dup p.(Ala25Glyfs∗23), and c.71del p.(Pro24Argfs∗72). The phenotypic expression showed high variability both between and within families. Clinical features include motor developmental delay (seven of nine), axial hypotonia (five of nine), ocular motor apraxia (three of nine), and cerebellar signs (three of nine). Four of the six reported children had macrocephaly. Neuropsychological and developmental assessments revealed mildly delayed language development in the youngest children, whereas general cognition was normal in all variant carriers. Subtle but characteristic SUFU-related neuroimaging abnormalities (including superior cerebellar dysplasia, abnormalities of the superior cerebellar peduncles, rostrally displaced fastigium, and vermis hypoplasia) were observed in seven of nine individuals. CONCLUSIONS: Our data shed further light on the mild but recognizable features of SUFU haploinsufficiency and underline its marked phenotypic variability, even within families. Notably, neurodevelopmental and behavioral abnormalities are mild compared with Joubert syndrome and seem to be well compensated over time.

Asunto(s)

Discapacidades del Desarrollo , Haploinsuficiencia , Fenotipo , Humanos , Masculino , Femenino , Niño , Preescolar , Discapacidades del Desarrollo/diagnóstico por imagen , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/etiología , Discapacidades del Desarrollo/fisiopatología , Adolescente , Cerebelo/diagnóstico por imagen , Cerebelo/anomalías , Apraxias/diagnóstico por imagen , Apraxias/genética , Apraxias/fisiopatología , Apraxias/congénito , Enfermedades Renales Quísticas/genética , Enfermedades Renales Quísticas/diagnóstico por imagen , Anomalías Múltiples/genética , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/fisiopatología , Neuroimagen , Anomalías del Ojo/genética , Anomalías del Ojo/diagnóstico por imagen , Retina/diagnóstico por imagen , Retina/anomalías , Síndrome de Cogan

RESUMEN

Genetic TNFAIP3 (A20) inactivation is a classical somatic lymphoma lesion and the genomic trait in haploinsufficiency of A20 (HA20). In a cohort of 34 patients with HA20, we show that heterozygous TNFAIP3 loss skews immune repertoires toward lymphocytes with classical self-reactive antigen receptors typically found in B and T cell lymphomas. This skewing was mediated by a feed-forward tumor necrosis factor (TNF)/A20/nuclear factor κB (NF-κB) loop that shaped pre-lymphoma transcriptome signatures in clonally expanded B (CD81, BACH2, and NEAT1) or T (GATA3, TOX, and PDCD1) cells. The skewing was reversed by anti-TNF treatment but could also progress to overt lymphoma. Analysis of conditional TNFAIP3 knock-out mice reproduced the wiring of the TNF/A20/NF-κB signaling axis with permissive antigen receptors and suggested a distinct regulation in B and T cells. Together, patients with the genetic disorder HA20 provide an exceptional window into A20/TNF/NF-κB-mediated control of immune homeostasis and early steps of lymphomagenesis that remain clinically unrecognized.

Asunto(s)

Haploinsuficiencia , Homeostasis , FN-kappa B , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/metabolismo , Animales , Humanos , Ratones , FN-kappa B/metabolismo , Ratones Noqueados , Femenino , Masculino , Transducción de Señal , Persona de Mediana Edad , Linfocitos/inmunología , Linfocitos/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Adulto , Factor de Necrosis Tumoral alfa/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfoma/genética , Linfoma/inmunología , Linfoma/patología

RESUMEN

BACKGROUND: Sotos syndrome is a rare and complex genetic disorder caused by haploinsufficiency of the NSD1 gene. This syndrome is characterized by rapid early childhood growth, distinct facial features, a learning disability, and multiple other developmental and behavioral challenges. METHODS AND RESULTS: In this work, we describe four Moroccan patients with variable clinical presentations of Sotos syndrome, in whom we identified four novel NSD1 monoallelic pathogenic variants by conducting targeted Next Generation Sequencing. Genetic testing allowed us to provide a precise medical diagnosis to our patients and tailor interventions to each patient's needs. CONCLUSIONS: Being the first work describing a series of Moroccan patients with this syndrome, this case series contributes to the growing body of literature on Sotos syndrome and provides valuable insights into the clinical and molecular characteristics of this rare disorder.

Asunto(s)

N-Metiltransferasa de Histona-Lisina , Mutación , Síndrome de Sotos , Humanos , N-Metiltransferasa de Histona-Lisina/genética , Síndrome de Sotos/genética , Masculino , Femenino , Mutación/genética , Preescolar , Niño , Lactante , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Péptidos y Proteínas de Señalización Intracelular/genética , Marruecos , Fenotipo , Histona Metiltransferasas/genética , Haploinsuficiencia/genética , Adolescente

RESUMEN

ABSTRACT: This is the first report of pediatric catatonia syndrome in MED13L haploinsufficiency syndrome. This report describes unique challenges in diagnosis and management of catatonia in rare genetic conditions. The case also illustrates the use of electroconvulsive therapy in patients with epilepsy, epileptic encephalopathy, or other epileptic diathesis and the clinical conundrum in determining the course of maintenance electroconvulsive therapy.

Asunto(s)

Catatonia , Terapia Electroconvulsiva , Epilepsia , Haploinsuficiencia , Adolescente , Humanos , Masculino , Catatonia/terapia , Catatonia/genética , Catatonia/complicaciones , Epilepsia/genética , Epilepsia/complicaciones , Epilepsia/terapia , Complejo Mediador/genética

RESUMEN

An exome sequencing strategy employed to identify pathogenic variants in patients with pediatric-onset systemic lupus or Evans syndrome resulted in the discovery of six novel monoallelic mutations in PTPN2. PTPN2 is a phosphatase that acts as an essential negative regulator of the JAK/STAT pathways. All mutations led to a loss of PTPN2 regulatory function as evidenced by in vitro assays and by hyperproliferation of patients' T cells. Furthermore, patients exhibited high serum levels of inflammatory cytokines, mimicking the profile observed in individuals with gain-of-function mutations in STAT factors. Flow cytometry analysis of patients' blood cells revealed typical alterations associated with autoimmunity and all patients presented with autoantibodies. These findings further supported the notion that a loss of function in negative regulators of cytokine pathways can lead to a broad spectrum of autoimmune manifestations and that PTPN2 along with SOCS1 haploinsufficiency constitute a new group of monogenic autoimmune diseases that can benefit from targeted therapy.

Asunto(s)

Anemia Hemolítica Autoinmune , Autoinmunidad , Haploinsuficiencia , Lupus Eritematoso Sistémico , Proteína Tirosina Fosfatasa no Receptora Tipo 2 , Humanos , Haploinsuficiencia/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 2/genética , Anemia Hemolítica Autoinmune/genética , Anemia Hemolítica Autoinmune/inmunología , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Femenino , Masculino , Niño , Autoinmunidad/genética , Adolescente , Mutación , Trombocitosis/genética , Trombocitosis/inmunología , Proteína 1 Supresora de la Señalización de Citocinas/genética , Autoanticuerpos/inmunología , Citocinas/metabolismo , Preescolar , Linfocitos T/inmunología , Trombocitopenia

RESUMEN

Heterozygous loss-of-function mutations in the GRN gene are a major cause of hereditary frontotemporal dementia. The mechanisms linking frontotemporal dementia pathogenesis to progranulin deficiency are not well understood, and there is currently no treatment. Our strategy to prevent the onset and progression of frontotemporal dementia in patients with GRN mutations is to utilize small molecule positive regulators of GRN expression to boost progranulin levels from the remaining functional GRN allele, thus restoring progranulin levels back to normal within the brain. This work describes a series of blood-brain-barrier-penetrant small molecules which significantly increase progranulin protein levels in human cellular models, correct progranulin protein deficiency in Grn+/- mouse brains, and reverse lysosomal proteome aberrations, a phenotypic hallmark of frontotemporal dementia, more efficiently than the previously described small molecule suberoylanilide hydroxamic acid. These molecules will allow further elucidation of the cellular functions of progranulin and its role in frontotemporal dementia and will also serve as lead structures for further drug development.

Asunto(s)

Demencia Frontotemporal , Haploinsuficiencia , Lisosomas , Progranulinas , Proteoma , Progranulinas/metabolismo , Progranulinas/genética , Animales , Humanos , Demencia Frontotemporal/genética , Demencia Frontotemporal/metabolismo , Demencia Frontotemporal/tratamiento farmacológico , Proteoma/metabolismo , Ratones , Lisosomas/metabolismo , Lisosomas/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Vorinostat/farmacología

RESUMEN

In their paper, using zebrafish models, Gioacchino et al. have demonstrated the GATA2 haploinsufficiency, the genetic hallmark of GATA2 deficiency syndrome, promotes erythroid and myeloid cytopenia, and have discovered a self-regulatory mechanism to compensate GATA2 levels and protein function. Commentary on: Gioacchino et al. GATA2 heterozygosity causes an epigenetic feedback mechanism resulting in myeloid and erythroid dysplasia. Br J Haematol 2024;205:580-593.

Asunto(s)

Deficiencia GATA2 , Factor de Transcripción GATA2 , Pez Cebra , Deficiencia GATA2/genética , Animales , Pez Cebra/genética , Humanos , Factor de Transcripción GATA2/genética , Factor de Transcripción GATA2/deficiencia , Haploinsuficiencia , Modelos Animales de Enfermedad , Epigénesis Genética

RESUMEN

Rho-associated protein kinase-2 (ROCK2) is a critical player in many cellular processes and was incriminated in cardiovascular and neurological disorders. Recent evidence has shown that non-selective pharmacological blockage of ROCKs ameliorates behavioral alterations in a mouse model of 16p11.2 haploinsufficiency. We had revealed that 16p11.2-deficient mice also display cerebrovascular abnormalities, including endothelial dysfunction. To investigate whether genetic blockage of ROCK2 also exerts beneficial effects on cognition and angiogenesis, we generated mice with both 16p11.2 and Rock2 haploinsufficiency (16p11.2df/+;Rock2+/-). We find that Rock2 heterozygosity on a 16p11.2df/+ background significantly improved recognition memory. Furthermore, brain endothelial cells from 16p11.2df/+;Rock2+/- mice display improved angiogenic capacity compared to cells from 16p11.2df/+ littermates. Overall, this study implicates Rock2 gene as a modulator of 16p11.2-associated alterations, highlighting its potential as a target for treatment of autism spectrum disorders.

Asunto(s)

Trastorno Autístico , Deleción Cromosómica , Trastornos de los Cromosomas , Cromosomas Humanos Par 16 , Modelos Animales de Enfermedad , Quinasas Asociadas a rho , Animales , Quinasas Asociadas a rho/genética , Quinasas Asociadas a rho/metabolismo , Cromosomas Humanos Par 16/genética , Ratones , Trastorno Autístico/genética , Trastornos de los Cromosomas/genética , Heterocigoto , Reconocimiento en Psicología/fisiología , Células Endoteliales/metabolismo , Haploinsuficiencia , Masculino , Ratones Endogámicos C57BL , Anomalías Craneofaciales/genética , Discapacidad Intelectual/genética

RESUMEN

Introduction: The NPRL3 gene is a critical component of the GATOR1 complex, which negatively regulates the mTORC1 pathway, essential for neurogenesis and brain development. Located on chromosome 16p13.3, NPRL3 is situated near the α-globin gene cluster. Haploinsufficiency of NPRL3, either by deletion or a pathogenic variant, is associated with a variable phenotype of focal epilepsy, with or without malformations of cortical development, with known decreased penetrance. Case Description: This work details the diagnostic odyssey of a neurotypical 10-year-old boy who presented at age 2 with unusual nocturnal episodes and a history of microcytic anemia, as well as a review of the existing literature on NPRL3-related epilepsy, with an emphasis on individuals with deletions who also present with α-thalassemia trait. The proband's episodes were mistaken for gastroesophageal reflux disease for several years. He had molecular testing for his α-thalassemia trait and was noted to carry a deletion encompassing the regulatory region of the α-thalassemia gene cluster. Following the onset of overt focal motor seizures, genetic testing revealed a heterozygous loss of NPRL3, within a 106 kb microdeletion on chromosome 16p13.3, inherited from his mother. This deletion encompassed the entire NPRL3 gene, which overlaps the regulatory region of the α-globin gene cluster, giving him the dual diagnosis of NPRL3-related epilepsy and α-thalassemia trait. Brain imaging postprocessing showed left hippocampal sclerosis and mid-posterior para-hippocampal focal cortical dysplasia, leading to the consideration of epilepsy surgery. Conclusions: This case underscores the necessity of early and comprehensive genetic assessments in children with epilepsy accompanied by systemic features, even in the absence of a family history of epilepsy or a developmental delay. Recognizing phenotypic overlaps is crucial to avoid diagnostic delays. Our findings also highlight the impact of disruptions in regulatory regions in genetic disorders: any individual with full gene deletion of NPRL3 would have, at a minimum, α-thalassemia trait, due to the presence of the major regulatory element of α-globin genes overlapping the gene's introns.

Asunto(s)

Talasemia alfa , Humanos , Masculino , Talasemia alfa/genética , Talasemia alfa/diagnóstico , Niño , Epilepsia/genética , Epilepsia/diagnóstico , Epilepsia/patología , Epilepsias Parciales/genética , Epilepsias Parciales/diagnóstico , Fenotipo , Cromosomas Humanos Par 16/genética , Haploinsuficiencia/genética , Proteínas Activadoras de GTPasa

RESUMEN

The shift to a genotype-first approach in genetic diagnostics has revolutionized our understanding of neurodevelopmental disorders, expanding both their molecular and phenotypic spectra. Kleefstra syndrome (KLEFS1) is caused by EHMT1 haploinsufficiency and exhibits broad clinical manifestations. EHMT1 encodes euchromatic histone methyltransferase-1-a pivotal component of the epigenetic machinery. We have recruited 209 individuals with a rare EHMT1 variant and performed comprehensive molecular in silico and in vitro testing alongside DNA methylation (DNAm) signature analysis for the identified variants. We (re)classified the variants as likely pathogenic/pathogenic (molecularly confirming Kleefstra syndrome) in 191 individuals. We provide an updated and broader clinical and molecular spectrum of Kleefstra syndrome, including individuals with normal intelligence and familial occurrence. Analysis of the EHMT1 variants reveals a broad range of molecular effects and their associated phenotypes, including distinct genotype-phenotype associations. Notably, we showed that disruption of the "reader" function of the ankyrin repeat domain by a protein altering variant (PAV) results in a KLEFS1-specific DNAm signature and milder phenotype, while disruption of only "writer" methyltransferase activity of the SET domain does not result in KLEFS1 DNAm signature or typical KLEFS1 phenotype. Similarly, N-terminal truncating variants result in a mild phenotype without the DNAm signature. We demonstrate how comprehensive variant analysis can provide insights into pathogenesis of the disorder and DNAm signature. In summary, this study presents a comprehensive overview of KLEFS1 and EHMT1, revealing its broader spectrum and deepening our understanding of its molecular mechanisms, thereby informing accurate variant interpretation, counseling, and clinical management.

Asunto(s)

Deleción Cromosómica , Cromosomas Humanos Par 9 , Anomalías Craneofaciales , Metilación de ADN , Estudios de Asociación Genética , N-Metiltransferasa de Histona-Lisina , Discapacidad Intelectual , Fenotipo , Humanos , N-Metiltransferasa de Histona-Lisina/genética , Anomalías Craneofaciales/genética , Discapacidad Intelectual/genética , Cromosomas Humanos Par 9/genética , Metilación de ADN/genética , Femenino , Masculino , Niño , Preescolar , Antígenos de Histocompatibilidad/genética , Adolescente , Cardiopatías Congénitas/genética , Haploinsuficiencia/genética , Mutación

RESUMEN

The transcription factor FOXN1 plays an established role in thymic epithelial development to mediate selection of maturing thymocytes. Patients with heterozygous loss-of-function FOXN1 variants are associated with T cell lymphopenia at birth and low TCR excision circles that can ultimately recover. Although CD4+ T cell reconstitution in these patients is not completely understood, a lower proportion of naive T cells in adults has suggested a role for homeostatic proliferation. In this study, we present an immunophenotyping study of fraternal twins with low TCR excision circles at birth. Targeted primary immunodeficiency testing revealed a heterozygous variant of uncertain significance in FOXN1 (c.1205del, p.Pro402Leufs*148). We present the immune phenotypes of these two patients, as well as their father who carries the same FOXN1 variant, to demonstrate an evolving immune environment over time. While FOXN1 haploinsufficiency may contribute to thymic defects and T cell lymphopenia, we characterized the transcriptional activity and DNA binding of the heterozygous FOXN1 variant in 293T cells and found the FOXN1 variant to have different effects across several target genes. These data suggest multiple mechanisms for similar FOXN1 variants pathogenicity that may be mutation specific. Increased understanding of how these variants drive transcriptional regulation to impact immune cell populations will guide the potential need for therapeutics, risk for infection or autoimmunity over time, and help inform clinical decisions for other variants that might arise.

Asunto(s)

Factores de Transcripción Forkhead , Heterocigoto , Inmunofenotipificación , Humanos , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Masculino , Femenino , Linfopenia/genética , Linfopenia/inmunología , Mutación , Adulto , Haploinsuficiencia , Linfocitos T/inmunología , Células HEK293 , Recién Nacido , Timo/inmunología , Timo/metabolismo

RESUMEN

The mechanisms utilized by neurons to regulate the efficacy of phasic and tonic inhibition and their impacts on synaptic plasticity and behavior are incompletely understood. Cleft lip and palate transmembrane protein 1 (Clptm1) is a membrane-spanning protein that interacts with multiple γ-aminobutyric acid type A receptor (GABAAR) subunits, trapping them in the endoplasmic reticulum and Golgi network. Overexpression and knock-down studies suggest that Clptm1 modulates GABAAR-mediated phasic inhibition and tonic inhibition as well as activity-induced inhibitory synaptic homeostasis in cultured hippocampal neurons. To investigate the role of Clptm1 in the modulation of GABAARs in vivo, we generated Clptm1 knock-out (KO) mice. Here, we show that genetic KO of Clptm1 elevated phasic and tonic inhibitory transmission in both male and female heterozygous mice. Although basal excitatory synaptic transmission was not affected, Clptm1 haploinsufficiency significantly blocked high-frequency stimulation-induced long-term potentiation (LTP) in hippocampal CA3→CA1 synapses. In the hippocampus-dependent contextual fear-conditioning behavior task, both male and female Clptm1 heterozygous KO mice exhibited impairment in contextual fear memory. In addition, LTP and contextual fear memory were rescued by application of L-655,708, a negative allosteric modulator of the extrasynaptic GABAAR α5 subunit. These results suggest that haploinsufficiency of Clptm1 contributes to cognitive deficits through altered synaptic transmission and plasticity by elevation of inhibitory neurotransmission, with tonic inhibition playing a major role.

Asunto(s)

Haploinsuficiencia , Proteínas de la Membrana , Ratones Noqueados , Plasticidad Neuronal , Receptores de GABA-A , Transmisión Sináptica , Animales , Ratones , Masculino , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Femenino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Transmisión Sináptica/fisiología , Plasticidad Neuronal/fisiología , Plasticidad Neuronal/genética , Ratones Endogámicos C57BL , Potenciales Postsinápticos Excitadores/fisiología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Potenciación a Largo Plazo/genética , Hipocampo/metabolismo , Trastornos de la Memoria/genética , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/fisiopatología , Miedo/fisiología , Potenciales Postsinápticos Inhibidores/fisiología , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Memoria/fisiología , Inhibición Neural/fisiología

RESUMEN

Germline heterozygous mutations in DDX41 predispose individuals to hematologic malignancies in adulthood. Most of these DDX41 mutations result in a truncated protein, leading to loss of protein function. To investigate the impact of these mutations on hematopoiesis, we generated mice with hematopoietic-specific knockout of one Ddx41 allele. Under normal steady-state conditions, there was minimal effect on lifelong hematopoiesis, resulting in a mild yet persistent reduction in red blood cell counts. However, stress induced by transplantation of the Ddx41+/- BM resulted in hematopoietic stem/progenitor cell (HSPC) defects and onset of hematopoietic failure upon aging. Transcriptomic analysis of HSPC subsets from the transplanted BM revealed activation of cellular stress responses, including upregulation of p53 target genes in erythroid progenitors. To understand how the loss of p53 affects the phenotype of Ddx41+/- HSPCs, we generated mice with combined Ddx41 and Trp53 heterozygous deletions. The reduction in p53 expression rescued the fitness defects in HSPC caused by Ddx41 heterozygosity. However, the combined Ddx41 and Trp53 mutant mice were prone to developing hematologic malignancies that resemble human myelodysplastic syndrome and acute myeloid leukemia. In conclusion, DDX41 heterozygosity causes dysregulation of the response to hematopoietic stress, which increases the risk of transformation with a p53 mutation.

Asunto(s)

ARN Helicasas DEAD-box , Haploinsuficiencia , Neoplasias Hematológicas , Hematopoyesis , Mutación , Proteína p53 Supresora de Tumor , Animales , Humanos , Ratones , ARN Helicasas DEAD-box/genética , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patología , Neoplasias Hematológicas/etiología , Hematopoyesis/genética , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Ratones Endogámicos C57BL , Ratones Noqueados , Estrés Fisiológico/genética , Proteína p53 Supresora de Tumor/genética

RESUMEN

To comprehensively investigate the neurodevelopmental profile and clinical characteristics associated with SETBP1 haploinsufficiency disorder (SETBP1-HD) and SETBP1-related disorders (SETBP1-RD). We reported genetic results on 34 individuals, with behavior and clinical data from 22 with SETBP1-HD and 5 with SETBP1-RD, by assessing results from medical history interviews and standardized adaptive, clinical, and social measures provided from Simons Searchlight. All individuals with SETBP1-HD and SETBP1-RD exhibited neurological impairments including intellectual disability/developmental delay (IDD), attention-deficit/hyperactivity disorder, autism spectrum disorder, and/or seizures, as well as speech and language delays. While restricted interests and repetitive behaviors present challenges, a relative strength was observed in social motivation within both cohorts. Individuals with SETBP1-RD reported a risk for heart issues and compared to SETBP1-HD greater risks for orthopedic and somatic issues with greater difficulty in bowel control. Higher rates for neonatal feeding difficulties and febrile seizures were reported for individuals with SETBP1-HD. Additional prominent characteristics included sleep, vision, and gastrointestinal issues, hypotonia, and high pain tolerance. This characterization of phenotypic overlap (IDD, speech challenges, autistic, and attention deficit traits) and differentiation (somatic and heart issue risks for SETBP1-RD) between the distinct neurodevelopmental disorders SETBP1-HD and SETBP1-RD is critical for medical management and diagnosis.

Asunto(s)

Trastorno por Déficit de Atención con Hiperactividad , Proteínas Portadoras , Haploinsuficiencia , Discapacidad Intelectual , Fenotipo , Humanos , Haploinsuficiencia/genética , Masculino , Femenino , Niño , Preescolar , Discapacidad Intelectual/genética , Proteínas Portadoras/genética , Trastorno por Déficit de Atención con Hiperactividad/genética , Adolescente , Proteínas Nucleares/genética , Discapacidades del Desarrollo/genética , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/fisiopatología , Adulto , Lactante , Adulto Joven