RESUMEN
KAT5 encodes an essential lysine acetyltransferase, previously called TIP60, which is involved in regulating gene expression, DNA repair, chromatin remodeling, apoptosis, and cell proliferation; but it remains unclear whether variants in this gene cause a genetic disease. Here, we study three individuals with heterozygous de novo missense variants in KAT5 that affect normally invariant residues, with one at the chromodomain (p.Arg53His) and two at or near the acetyl-CoA binding site (p.Cys369Ser and p.Ser413Ala). All three individuals have cerebral malformations, seizures, global developmental delay or intellectual disability, and severe sleep disturbance. Progressive cerebellar atrophy was also noted. Histone acetylation assays with purified variant KAT5 demonstrated that the variants decrease or abolish the ability of the resulting NuA4/TIP60 multi-subunit complexes to acetylate the histone H4 tail in chromatin. Transcriptomic analysis in affected individual fibroblasts showed deregulation of multiple genes that control development. Moreover, there was also upregulated expression of PER1 (a key gene involved in circadian control) in agreement with sleep anomalies in all of the individuals. In conclusion, dominant missense KAT5 variants cause histone acetylation deficiency with transcriptional dysregulation of multiples genes, thereby leading to a neurodevelopmental syndrome with sleep disturbance, cerebellar atrophy, and facial dysmorphisms, and suggesting a recognizable syndrome.
Asunto(s)
Atrofia/genética , Enfermedades Cerebelosas/genética , Discapacidad Intelectual/genética , Lisina Acetiltransferasa 5/genética , Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/genética , Anomalías Múltiples/fisiopatología , Adolescente , Adulto , Atrofia/diagnóstico por imagen , Atrofia/fisiopatología , Enfermedades Cerebelosas/diagnóstico por imagen , Enfermedades Cerebelosas/fisiopatología , Preescolar , Cromatina/genética , Ensamble y Desensamble de Cromatina/genética , Reparación del ADN/genética , Epilepsia/diagnóstico por imagen , Epilepsia/genética , Epilepsia/fisiopatología , Femenino , Heterocigoto , Histonas/genética , Humanos , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/fisiopatología , Masculino , Mutación Missense/genética , Procesamiento Proteico-Postraduccional/genéticaRESUMEN
EMC1 encodes subunit 1 of the endoplasmic reticulum (ER) membrane protein complex (EMC), a transmembrane domain insertase involved in membrane protein biosynthesis. Variants in EMC1 are described as a cause of global developmental delay, hypotonia, cortical visual impairment, and commonly, cerebral atrophy on MRI scan. We report an individual with severe global developmental delay and progressive cerebellar atrophy in whom exome sequencing identified a heterozygous essential splice-site variant in intron-3 of EMC1 (NM_015047.3:c.287-1G>A). Whole genome sequencing (WGS) identified a deep intronic variant in intron-20 of EMC1 (NM_015047.3:c.2588-771C>G) that was poorly predicted by in silico programs to disrupt pre-mRNA splicing. Reverse Transcription-PCR (RT-PCR) revealed stochastic activation of a pseudo-exon associated with the c.2588-771C>G variant and mis-splicing arising from the c.287-1G>A variant. This case highlights the utility of WGS and RNA studies to identify and assess likely pathogenicity of deep intronic variants and expands the genotypic and phenotypic spectrum of EMC1-related disorders.
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Proteínas de la Membrana , Empalme del ARN , Humanos , Empalme del ARN/genética , Mutación , Intrones/genética , Proteínas de la Membrana/genética , Atrofia/genéticaRESUMEN
Biallelic pathogenic variants in the COASY gene have been associated with two distinct disease phenotypes, that is, COASY-protein associated neurodegeneration (CoPAN) and pontocerebellar hypoplasia type 12 (PCH 12). We present two siblings that independently presented with significant hypotonia and respiratory insufficiency at birth. Comprehensive genetic testing revealed homozygous variants within COASY, however, the progressive clinical and neuroradiologic findings described here are unique and have not been described previously. Magnetic resonance imaging showed progressive diffuse parenchymal loss throughout the bilateral cerebral hemispheres and atrophy of the basal ganglia and brainstem. As such, this article brings forth two additional cases of COASY-related disorder with abnormal newborn screening acylcarnitine profiles resembling carnitine palmitoyl transferase 1a (CPT1a) deficiency in two siblings who presented at birth with contractures, marked hypotonia and absent respiratory drive.
Asunto(s)
Enfermedades del Sistema Nervioso Central , Enfermedades Neurodegenerativas , Humanos , Hipotonía Muscular/genética , Hermanos , Encéfalo/diagnóstico por imagen , Atrofia/genética , Fenotipo , Imagen por Resonancia Magnética , TransferasasRESUMEN
OBJECTIVE: To explore the clinical characteristics and genetic etiology of a patient with adolescent-onset hypomyelinated leukodystrophy with atrophy of basal ganglia and cerebellum (H-ABC). METHODS: A patient who was diagnosed with H-ABC in March 2018 at the First Affiliated Hospital of Nanjing Medical University was selected as the study subject. Clinical data was collected. Peripheral venous blood samples of the patient and his parents were collected. The patient was subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. RESULTS: The patient, a 31-year-old male, had manifested with developmental retardation, cognitive decline and abnormal gait. WES revealed that he has harbored a heterozygous c.286G>A variant of the TUBB4A gene. Sanger sequencing confirmed that neither of his parents has carried the same variant. Analysis with SIFT online software indicated the amino acid encoded by this variant is highly conserved among various species. This variant has been recorded by the Human Gene Mutation Database (HGMD) with a low population frequency. The 3D structure constructed by PyMOL software showed that the variant has a harmful effect on the structure and function of the protein. According to the guidelines formulated by the American College of Medical Genetics and Genomics (ACMG), the variant was rated as likely pathogenic. CONCLUSION: The c.286G>A (p.Gly96Arg) variant of the TUBB4A gene probably underlay the hypomyelinating leukodystrophy with atrophy of basal ganglia and cerebellum in this patient. Above finding has enriched the spectrum of TUBB4A gene variants and enabled early definitive diagnosis of this disorder.
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Ganglios Basales , Imagen por Resonancia Magnética , Tubulina (Proteína) , Adolescente , Adulto , Humanos , Masculino , Atrofia/genética , Atrofia/patología , Ganglios Basales/patología , Cerebelo , Mutación , Tubulina (Proteína)/genéticaRESUMEN
Nemo-like kinase (NLK), an evolutionarily conserved serine/threonine kinase, is highly expressed in the brain, but its function in the adult brain remains not well understood. In this study, we identify NLK as an interactor of huntingtin protein (HTT). We report that NLK levels are significantly decreased in HD human brain and HD models. Importantly, overexpression of NLK in the striatum attenuates brain atrophy, preserves striatal DARPP32 levels and reduces mutant HTT (mHTT) aggregation in HD mice. In contrast, genetic reduction of NLK exacerbates brain atrophy and loss of DARPP32 in HD mice. Moreover, we demonstrate that NLK lowers mHTT levels in a kinase activity-dependent manner, while having no significant effect on normal HTT protein levels in mouse striatal cells, human cells and HD mouse models. The NLK-mediated lowering of mHTT is associated with enhanced phosphorylation of mHTT. Phosphorylation defective mutation of serine at amino acid 120 (S120) abolishes the mHTT-lowering effect of NLK, suggesting that S120 phosphorylation is an important step in the NLK-mediated lowering of mHTT. A further mechanistic study suggests that NLK promotes mHTT ubiquitination and degradation via the proteasome pathway. Taken together, our results indicate a protective role of NLK in HD and reveal a new molecular target to reduce mHTT levels.
Asunto(s)
Atrofia/genética , Fosfoproteína 32 Regulada por Dopamina y AMPc/genética , Proteína Huntingtina/genética , Enfermedad de Huntington/genética , Proteínas Serina-Treonina Quinasas/genética , Animales , Atrofia/patología , Encéfalo/metabolismo , Encéfalo/patología , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Humanos , Enfermedad de Huntington/patología , Ratones , Neostriado/metabolismo , Neostriado/patología , Neuronas/metabolismo , Neuronas/patología , Fosforilación/genética , Complejo de la Endopetidasa Proteasomal/genéticaRESUMEN
We report an early-onset autosomal-recessive neurological disease with cerebellar atrophy and lysosomal dysfunction. We identified bi-allelic loss-of-function (LoF) variants in Oxidative Resistance 1 (OXR1) in five individuals from three families; these individuals presented with a history of severe global developmental delay, current intellectual disability, language delay, cerebellar atrophy, and seizures. While OXR1 is known to play a role in oxidative stress resistance, its molecular functions are not well established. OXR1 contains three conserved domains: LysM, GRAM, and TLDc. The gene encodes at least six transcripts, including some that only consist of the C-terminal TLDc domain. We utilized Drosophila to assess the phenotypes associated with loss of mustard (mtd), the fly homolog of OXR1. Strong LoF mutants exhibit late pupal lethality or pupal eclosion defects. Interestingly, although mtd encodes 26 transcripts, severe LoF and null mutations can be rescued by a single short human OXR1 cDNA that only contains the TLDc domain. Similar rescue is observed with the TLDc domain of NCOA7, another human homolog of mtd. Loss of mtd in neurons leads to massive cell loss, early death, and an accumulation of aberrant lysosomal structures, similar to what we observe in fibroblasts of affected individuals. Our data indicate that mtd and OXR1 are required for proper lysosomal function; this is consistent with observations that NCOA7 is required for lysosomal acidification.
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Atrofia/patología , Enfermedades Cerebelosas/patología , Lisosomas/patología , Proteínas Mitocondriales/metabolismo , Enfermedades del Sistema Nervioso/patología , Estrés Oxidativo , Adolescente , Adulto , Animales , Atrofia/genética , Atrofia/metabolismo , Enfermedades Cerebelosas/genética , Enfermedades Cerebelosas/metabolismo , Niño , Drosophila melanogaster/crecimiento & desarrollo , Drosophila melanogaster/metabolismo , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Lisosomas/metabolismo , Masculino , Proteínas Mitocondriales/genética , Enfermedades del Sistema Nervioso/genética , Enfermedades del Sistema Nervioso/metabolismo , Linaje , Fenotipo , Adulto JovenRESUMEN
We report an inborn error of metabolism caused by an expansion of a GCA-repeat tract in the 5' untranslated region of the gene encoding glutaminase (GLS) that was identified through detailed clinical and biochemical phenotyping, combined with whole-genome sequencing. The expansion was observed in three unrelated patients who presented with an early-onset delay in overall development, progressive ataxia, and elevated levels of glutamine. In addition to ataxia, one patient also showed cerebellar atrophy. The expansion was associated with a relative deficiency of GLS messenger RNA transcribed from the expanded allele, which probably resulted from repeat-mediated chromatin changes upstream of the GLS repeat. Our discovery underscores the importance of careful examination of regions of the genome that are typically excluded from or poorly captured by exome sequencing.
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Errores Innatos del Metabolismo de los Aminoácidos/genética , Ataxia/genética , Discapacidades del Desarrollo/genética , Glutaminasa/deficiencia , Glutaminasa/genética , Glutamina/metabolismo , Repeticiones de Microsatélite , Mutación , Atrofia/genética , Cerebelo/patología , Preescolar , Femenino , Genotipo , Glutamina/análisis , Humanos , Masculino , Fenotipo , Reacción en Cadena de la Polimerasa , Secuenciación Completa del GenomaRESUMEN
PURPOSE: Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects. METHODS: Patients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated. RESULTS: Disease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA-S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments. CONCLUSION: A wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families.
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Exoma , Malformaciones del Sistema Nervioso , Niño , Humanos , Exoma/genética , Mutación , Malformaciones del Sistema Nervioso/genética , Atrofia/genética , Receptor 1 de Folato/genética , CinesinasRESUMEN
The biallelic variations of the LNPK gene are associated with the "neurodevelopmental disorder with epilepsy and hypoplasia of the corpus callosum" phenotype [MIM:618090] in the Online Mendelian Inheritance In Men database, and so far, two families have been identified in the literature. A third family with novel clinical features, who bears a novel variant in LNPK (NM_030650.3: c.770delA, p.D257fs*31) is described in the present study. The coexistence of psychomotor regression and neurodegeneration in brain magnetic resonance imaging was found for the first time in the present study, thanks to the long-term follow-up data on the case, which contributed to the phenotypic and mutation spectrum by means of the novel variation.
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Encéfalo , Cuerpo Calloso , Atrofia/genética , Atrofia/patología , Encéfalo/patología , Cuerpo Calloso/patología , Humanos , Mutación , FenotipoRESUMEN
Telomere shortening is associated with aging and age-associated diseases. Additionally, telomere dysfunction resulting from telomerase gene mutation can lead to premature aging, such as apparent skin atrophy and hair loss. However, the molecular signaling linking telomere dysfunction to skin atrophy remains elusive. Here we show that dysfunctional telomere disrupts BMP/pSmad/P63 signaling, impairing epidermal stem cell specification and differentiation of skin and hair follicles. We find that telomere shortening mediated by Terc loss up-regulates Follistatin (Fst), inhibiting pSmad signaling and down-regulating P63 and epidermal keratins in an ESC differentiation model as well as in adult development of telomere-shortened mice. Mechanistically, short telomeres disrupt PRC2/H3K27me3-mediated repression of Fst. Our findings reveal that skin atrophy due to telomere dysfunction is caused by a previously unappreciated link with Fst and BMP signaling that could be explored in the development of therapies.
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Células Madre/metabolismo , Acortamiento del Telómero/fisiología , Animales , Atrofia/genética , Proteínas Morfogenéticas Óseas/metabolismo , Diferenciación Celular/genética , Linaje de la Célula/genética , Proliferación Celular/genética , Células Epidérmicas/metabolismo , Epidermis/metabolismo , Regulación de la Expresión Génica/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Transducción de Señal/genética , Proteínas Smad/metabolismo , Telómero/genética , Acortamiento del Telómero/genética , Transactivadores/metabolismoRESUMEN
BACKGROUND: The arginine-glutamic acid dipeptide repeats gene (RERE) encodes a nuclear receptor coregulator that modulates gene expression through its interaction with transcriptional machinery. In humans, RERE deficiency causes neurodevelopmental disorder with or without structural defects of the brain, eye, heart, and kidney (NEDBEH). Ophthalmological defects are seen in approximately one third of individuals with NEDBEH and in RERE-deficient mice which can serve as a useful animal model. RESULTS: In mice, RERE is expressed in a subset of retinal ganglion cells (RGC), the lens epithelium, and the ciliary body during the embryonic period. RERE expression expands into the outer nuclear layer and the inner nuclear layer during the postnatal period. RERE-deficient mice have retinal and optic nerve atrophy. We show that RERE deficiency causes progressive loss of retinal cells and apoptosis of retinal cells in the ganglion cell layer as early as E17.5. The number of RGCs is also reduced in RERE-deficient embryos and mice. CONCLUSIONS: We conclude that RERE is required to control the apoptosis of retinal cells in the developing retina, and that RERE deficiency results in the retina atrophy through degeneration of the retinal cells and optic nerve atrophy through the loss of RGCs.
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Proteínas del Tejido Nervioso/metabolismo , Nervio Óptico/metabolismo , Proteínas Represoras/metabolismo , Retina/metabolismo , Degeneración Retiniana/metabolismo , Animales , Apoptosis/fisiología , Atrofia/genética , Atrofia/metabolismo , Atrofia/patología , Modelos Animales de Enfermedad , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Nervio Óptico/patología , Proteínas Represoras/genética , Retina/patología , Degeneración Retiniana/genética , Degeneración Retiniana/patologíaRESUMEN
OBJECTIVE: To explore the genetic basis for a child with myopathy and cerebellar atrophy with ataxia. METHODS: Clinical examinations and laboratory testing were carried out for the patient. The proband and the parents' genomic DNA was extracted from peripheral blood samples and subjected to trio whole-exome sequencing. Candidate variant was validated by Sanger sequencing. RESULTS: The 1-year-and-8-month-old boy manifested motor developmental delay, ataxia, hypomyotonia, increased serum creatine kinase. Cranial MRI showed cerebellar atrophy with progressive aggravation. Genetic testing revealed that the patient has harbored compound heterozygous variants of the MSTO1 gene, namely c.13delG (p.Ala5ProfsTer68) and c.971C>T (p.Thr324Ile), which were respectively inherited from his mother and father. The former was unreported previously and was predicted to be likely pathogenic, whilst the latter has been reported previously and was predicted to be of uncertain significance. CONCLUSION: The compound heterozygous c.13delG (p.Ala5ProfsTer68) and c.971C>T (p.Thr324Ile) variants probably underlay the disease in the proband. Above finding has enriched the spectrum of MSTO1 gene variants underlying mitochondrial myopathy and cerebellar atrophy with ataxia.
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Miopatías Mitocondriales , Enfermedades Neurodegenerativas , Ataxia/genética , Atrofia/genética , Proteínas de Ciclo Celular/genética , Niño , Proteínas del Citoesqueleto/genética , Humanos , Lactante , Masculino , Mutación , Secuenciación del ExomaRESUMEN
Background and Objectives: Brain atrophy is related to cognitive decline. However, the heritability of brain atrophy has not been fully investigated in the Eastern Asian population. Materials and Methods: Brain imaging of 74 Japanese twins registered in the Osaka University Twin Registry was conducted with voxel-based morphometry SPM12 and was processed by individual voxel-based morphometry adjusting covariates (iVAC) toolbox. The atrophy of the measured lobes was obtained by comparing the focal volume to the average of healthy subjects. Classical twin analysis was used to measure the heritability of its z-scores. Results: The heritability of brain atrophy ranged from 0.23 to 0.97, depending upon the lobes. When adjusted to age, high heritability was reported in the frontal, frontal-temporal, and parietal lobes, but the heritability in other lobes was lower than 0.70. Conclusions: This study revealed a relatively lower heritability in brain atrophy compared to other ethnicities. This result suggests a significant environmental impact on the susceptibility of brain atrophy the Japanese. Therefore, environmental factors may have more influence on the Japanese than in other populations.
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Disfunción Cognitiva , Enfermedades Neurodegenerativas , Anciano , Atrofia/genética , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Disfunción Cognitiva/genética , Humanos , Japón/epidemiología , Imagen por Resonancia Magnética/métodosRESUMEN
Local expression of genes encoding IL-1ß, IL-18, MCP-1/CCL2, PEDF, VEGF-A, and ZO-1 in the retina-retinal pigment epithelium-chorioidea tissue complex was studied in healthy rabbits and animals with simulated retinal pigment epithelium atrophy. Retinal pigment epithelium atrophy was modeled by single subretinal injection of 0.01 ml 0.9% NaCl (group 1; n=17) or 0.01 ml solution containing angiogenesis inhibitor bevacizumab in a dose of 0.025 mg (group 2; n=18). The gene expression was evaluated by reverse transcription PCR. In 27.7% cases, atrophic changes in the fundus were accompanied by a significant increase of IL-1ß gene expression and in more than 50% cases by an increase in VEGF-A and MCP-1/CCL2 mRNA levels. These factors contribute to an increase in the permeability of the blood-retina barrier and abolition of the immune privilege of the posterior eye segment, which should be taken into account when testing invasive approaches, in particular, for approbation of various options of replacement therapy with retinal pigment epithelium stem cells and development and use of neuroprotectors and drugs of targeted action.
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Epitelio Pigmentado de la Retina , Serpinas , Animales , Atrofia/genética , Atrofia/metabolismo , Atrofia/patología , Citocinas/genética , Citocinas/metabolismo , Inmunidad , Conejos , Serpinas/genética , Serpinas/metabolismoRESUMEN
Recent clinical investigations indicate that anthracycline-based chemotherapies induce early decline in heart mass in cancer patients. Heart mass decline may be caused by a decrease in cardiac cell number because of increased cell death or by a reduction in cell size because of atrophy. We previously reported that an anthracycline, doxorubicin (DOX), induces apoptotic death of cardiomyocytes by activating cyclin-dependent kinase 2 (CDK2). However, the signaling pathway downstream of CDK2 remains to be characterized, and it is also unclear whether the same pathway mediates cardiac atrophy. Here we demonstrate that DOX exposure induces CDK2-dependent phosphorylation of the transcription factor forkhead box O1 (FOXO1) at Ser-249, leading to transcription of its proapoptotic target gene, Bcl-2-interacting mediator of cell death (Bim). In cultured cardiomyocytes, treatment with the FOXO1 inhibitor AS1842856 or transfection with FOXO1-specific siRNAs protected against DOX-induced apoptosis and mitochondrial damage. Oral administration of AS1842856 in mice abrogated apoptosis and prevented DOX-induced cardiac dysfunction. Intriguingly, pharmacological FOXO1 inhibition also attenuated DOX-induced cardiac atrophy, likely because of repression of muscle RING finger 1 (MuRF1), a proatrophic FOXO1 target gene. In conclusion, DOX exposure induces CDK2-dependent FOXO1 activation, resulting in cardiomyocyte apoptosis and atrophy. Our results identify FOXO1 as a promising drug target for managing DOX-induced cardiotoxicity. We propose that FOXO1 inhibitors may have potential as cardioprotective therapeutic agents during cancer chemotherapy.
Asunto(s)
Atrofia/genética , Cardiotoxicidad/genética , Quinasa 2 Dependiente de la Ciclina/genética , Proteína Forkhead Box O1/genética , Proteínas Musculares/genética , Proteínas de Motivos Tripartitos/genética , Ubiquitina-Proteína Ligasas/genética , Animales , Apoptosis/efectos de los fármacos , Atrofia/inducido químicamente , Atrofia/patología , Cardiotoxicidad/etiología , Cardiotoxicidad/patología , Modelos Animales de Enfermedad , Doxorrubicina/efectos adversos , Proteína Forkhead Box O1/antagonistas & inhibidores , Regulación de la Expresión Génica/efectos de los fármacos , Corazón/efectos de los fármacos , Corazón/fisiopatología , Humanos , Ratones , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Quinolonas/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
The dynamic shape of the endoplasmic reticulum (ER) is a reflection of its wide variety of critical cell biological functions. Consequently, perturbation of ER-shaping proteins can cause a range of human phenotypes. Here, we describe three affected children (from two consanguineous families) who carry homozygous loss-of-function mutations in LNPK (previously known as KIAA1715); this gene encodes lunapark, which is proposed to serve as a curvature-stabilizing protein within tubular three-way junctions of the ER. All individuals presented with severe psychomotor delay, intellectual disability, hypotonia, epilepsy, and corpus callosum hypoplasia, and two of three showed mild cerebellar hypoplasia and atrophy. Consistent with a proposed role in neurodevelopmental disease, LNPK was expressed during brain development in humans and mice and was present in neurite-like processes in differentiating human neural progenitor cells. Affected cells showed the absence of full-length lunapark, aberrant ER structures, and increased luminal mass density. Together, our results implicate the ER junction stabilizer lunapark in establishing the corpus callosum.
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Retículo Endoplásmico/genética , Proteínas de Homeodominio/genética , Mutación/genética , Adolescente , Animales , Atrofia/genética , Diferenciación Celular/genética , Niño , Cuerpo Calloso/patología , Femenino , Humanos , Lactante , Discapacidad Intelectual/genética , Masculino , Proteínas de la Membrana , Ratones , Hipotonía Muscular/genética , Fenotipo , Trastornos Psicomotores/genética , Células Madre/patologíaRESUMEN
BACKGROUND: Cathepsin H (CatH) is a lysosomal cysteine protease with a unique aminopeptidase activity. Its expression level is increased in activated immune cells including dendritic cells, macrophages, and microglia. We have previously reported that CatH deficiency impairs toll-like receptor 3 (TLR3)-mediated activation of interferon regulatory factor 3 (IRF3), and the subsequent secretion of interferon (IFN)-ß from dendritic cells. Furthermore, there is increasing evidence that IFN-ß secreted from microglia/macrophages has neuroprotective effects. These observations prompted further investigation into the effects of CatH deficiency on neuropathological changes. METHODS: In this study, neuropathological changes were examined using histochemical staining (both hematoxylin-eosin (H&E) and Nissl) of the hippocampus of wild-type (WT) and CatH-deficient (CatH-/-) mice after hypoxia-ischemia (HI). The density and the localization of CatH and TLR3 were examined by immunofluorescent staining. CatH processing in microglia was assayed by pulse-chase experiments, while immunoblotting was used to examine TLR3 expression and IRF3 activation in microglia/macrophages in the presence of poly(I:C). Microglial cell death was examined by fluorescence-activated cell sorting (FACS), and primary astrocyte proliferation in the presence of IFN-ß was examined using scratch wound assay. RESULTS: WT mice displayed severe atrophy in association with neuronal death and moderate astrogliosis in the hippocampus following neonatal HI. Somewhat surprisingly, CatH-/- mice showed marked neuronal death without severe atrophy in the hippocampus following HI. Furthermore, there was notable microglia/macrophages cell death and strong astrogliosis in the hippocampus. The TLR3 and phosphorylated IRF3 expression level in the hippocampus or splenocytes (mainly splenic macrophages); from CatH-/- mice was lower than in WT mice. In vitro experiments demonstrated that recombinant IFN-ß suppressed HI-induced microglial cell death and astrocyte proliferation. CONCLUSION: These observations suggest that CatH plays a critical role in the proteolytic maturation and stabilization of TLR3, which is necessary for IFN-ß production. Therefore, impaired TLR3/IFN-ß signaling resulting from CatH deficiency may induce microglial cell death after activation and astrogliosis/glial scar formation in the hippocampus following HI injury, leading to suppression of hippocampal atrophy.
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Catepsina H/genética , Hipocampo/patología , Hipoxia-Isquemia Encefálica/genética , Interferón beta/metabolismo , Receptor Toll-Like 3/metabolismo , Animales , Atrofia/genética , Atrofia/metabolismo , Atrofia/patología , Catepsina H/metabolismo , Muerte Celular/fisiología , Hipocampo/metabolismo , Hipoxia-Isquemia Encefálica/metabolismo , Hipoxia-Isquemia Encefálica/patología , Interferón beta/genética , Ratones , Ratones Noqueados , Microglía/metabolismo , Microglía/patología , Transducción de Señal/fisiología , Receptor Toll-Like 3/genéticaRESUMEN
Pontocerebellar hypoplasia (PCH) is currently classified into 13 subgroups and many gene variants associated with PCH have been identified by next generation sequencing. PCH type 1 is a rare heterogeneous neurodegenerative disorder. The clinical presentation includes early-onset severe developmental delay, progressive motor neuronopathy, and cerebellar and pontine atrophy. Recently two variants in the EXOSC9 gene (MIM: 606180), NM_001034194.1: c.41T>C (p.Leu14Pro) and c.481C>T (p.Arg161*) were identified in four unrelated patients with PCH type 1D (PCH1D) (MIM: 618065). EXOSC9 encodes a component of the exosome complex, which is essential for correct processing and degradation of RNA. We report here two PCH1D families with biallelic EXOSC9 variants: c.239T>G (p.Leu80Arg) and c.484dupA (p.Arg162Lysfs*3) in one family and c.151G>C (p.Gly51Arg) in the other family. Although the patients studied here showed similar clinical features as previously described for PCH1D, relatively greater intellectual development (although still highly restricted) and normal pontine structure were recognized. Our findings expand the clinical consequences of biallelic EXOSC9 variants.
Asunto(s)
Atrofia/patología , Enfermedades Cerebelosas/patología , Complejo Multienzimático de Ribonucleasas del Exosoma/genética , Enfermedad de la Neurona Motora/patología , Atrofia Muscular Espinal/patología , Mutación , Atrofias Olivopontocerebelosas/patología , Proteínas de Unión al ARN/genética , Atrofia/complicaciones , Atrofia/genética , Enfermedades Cerebelosas/complicaciones , Enfermedades Cerebelosas/genética , Femenino , Estudios de Asociación Genética , Humanos , Lactante , Masculino , Enfermedad de la Neurona Motora/complicaciones , Enfermedad de la Neurona Motora/genética , Atrofia Muscular Espinal/complicaciones , Atrofia Muscular Espinal/genética , Atrofias Olivopontocerebelosas/complicaciones , Atrofias Olivopontocerebelosas/genética , LinajeRESUMEN
OBJECTIVE: C9orf72 expansion is the most common genetic cause of frontotemporal dementia (FTD). We examined aging trajectories of cortical thickness (CTh) and surface area in C9orf72 expansion adult carriers compared to healthy controls to characterize preclinical cerebral changes leading to symptoms. METHODS: Data were obtained from the Genetic Frontotemporal Dementia Initiative. T1-weighted magnetic resonance imaging scans were processed with CIVET 2.1 to extract vertex-wide CTh and cortical surface area (CSA). Symptomatic and presymptomatic subjects were compared to age-matched controls using mixed-effects models, controlling for demographic variables. Aging trajectories were compared between carriers and noncarriers by testing the "age by genetic status" interaction. False discovery rate corrections were applied to all vertex-wide analyses. RESULTS: The sample included 640 scans from 386 subjects, including 54 symptomatic C9orf72 carriers (72.2% behavioral variant FTD), 83 asymptomatic carriers, and 249 controls (age range = 18-86 years). Symptomatic carriers showed fairly symmetric reduction in CTh/CSA in most of the frontal lobes, in addition to large temporoparietal areas. Presymptomatic subjects had reduced CTh/CSA in more restricted areas of the medial frontoparietal lobes, in addition to scattered lateral frontal, parietal, and temporal areas. These differences were explained by faster cortical thinning linearly throughout adulthood in a similar anatomical distribution, with differences emerging in the early 30s. CSA reduction was also faster in mutation carriers predominantly in the ventrofrontal regions. INTERPRETATION: C9orf72 mutation carriers have faster cortical thinning and surface loss throughout adulthood in regions that show atrophy in symptomatic subjects. This suggests that the pathogenic effects of the mutation lead to structural cerebral changes decades prior to symptoms. ANN NEUROL 2020 ANN NEUROL 2020;88:113-122.
Asunto(s)
Proteína C9orf72/genética , Corteza Cerebral/diagnóstico por imagen , Expansión de las Repeticiones de ADN , Demencia Frontotemporal/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Atrofia/diagnóstico por imagen , Atrofia/genética , Femenino , Demencia Frontotemporal/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
To date, less than 10 pedigrees have been reported with ZNF335 mutations since it was discovered in 2012 and little is known about ZNF335-related clinical spectrum. We describe a 12 years old male patient who is only child of nonconsanguineous Turkish parents. Trio whole genome sequencing identified previously unreported compound heterozygous variants in ZNF335, namely, c.3889T > A p.(Ser1297Thr) and c.758G > A p.(Arg253Gln) where transmitted by his father and mother, respectively. Patient' magnetic resonance imaging findings were overlapping to those observed in the previous cases with ZNF335 mutations. Here we report the oldest patient with biallelic ZNF335 mutations. We recommend screening for ZNF335 defects in patients with basal ganglia anomaly, secondary white matter abnormalities and microcephaly.