RESUMEN
Several studies have demonstrated the role of the oncogenic mutant p53 in promoting tumor progression; however, there is limited information on the effects of secreted oncogenic mutant p53 on the tumor microenvironment and tumor immune escape. In this study, we found that secretion of mutant p53, determined by exosome content, is dependent on its N-terminal dileucine motif via its binding to ß-adaptin, and inhibited by the CHK2-mediated-Ser 20 phosphorylation. Moreover, we observed that the mutant p53 caused downregulation and dysfunction of CD4+ T lymphocytes in vivo and downregulated the levels and activities of rate-limiting glycolytic enzymes in vitro. Furthermore, inhibition of mutant p53 secretion by knocking down AP1B1 or mutation of dileucine motif could reverse the quantity and function of CD4+ T lymphocytes and restrain the tumor growth. Our study demonstrates that the tumor-derived exosome-mediated secretion of oncogenic mutant p53 inhibits glycolysis to alter the immune microenvironment via functional suppression of CD4+ T cells, which may be the underlying mechanism for tumor immune escape. Therefore, targeting TDE-mediated p53 secretion may serve as a potential therapeutic target for cancer treatment.
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Neoplasias , Proteína p53 Supresora de Tumor , Humanos , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Microambiente Tumoral/genética , Linfocitos T/metabolismo , Mutación , Neoplasias/genética , Línea Celular Tumoral , Complejo 1 de Proteína Adaptadora/genética , Complejo 1 de Proteína Adaptadora/metabolismo , Subunidades beta de Complejo de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/metabolismoRESUMEN
OBJECTIVES: Developmental and epileptic encephalopathies (DEEs) are heterogeneous severe neurodevelopmental disorders characterized by recurrent clinical seizures that begin in the neonatal period and early childhood and regression or delay in cognitive, sensory and motor skills in the context of accompanying epileptiform abnormalities. Adaptor-related protein complex 3 beta-2 subunit (AP3B2) gene variants are thought to cause disruption of neuron-specific neurotransmitter release. METHODS: In this case report, whole exome sequencing (WES) was performed on two of the four pediatric patients who came from two unrelated families and were affected by DEE. As a result of WES, previously unreported variants, that is, p.Ala149Serfs* 34 and p.Pro993Argfs* 5, were detected in the AP3B2 gene. These variants were studied using Sanger sequencing in the siblings affected by DEE of the said pediatric patients and in their healthy parents. RESULTS: Autosomal recessive variants of the AP3B2 are associated with the development of DEE. To date, only 14 cases of AP3B2 mutations have been reported in the literature. Consequentially, DEE phenotype involving severe global developmental delay emerged, which is characterized by early-onset infantile epileptic encephalopathy, severe hypotonia, postnatal microcephaly, poor eye contact, speech retardation, abnormal involuntary movements, stereotypical hand movements, progressive intellectual disability, and behavioral and neuropsychiatric findings. CONCLUSION: Given the limited number of patients reported in the literature, detailed studies of the specific clinical and molecular features of AP3B2 gene variants, will shed light on the genotype-phenotype correlation.
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Complejo 3 de Proteína Adaptadora , Epilepsia , Espasmos Infantiles , Preescolar , Humanos , Complejo 3 de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/genética , Epilepsia/genética , Epilepsia/complicaciones , Homocigoto , Mutación/genética , Fenotipo , Convulsiones/complicaciones , Espasmos Infantiles/genéticaRESUMEN
INTRODUCTION/AIMS: Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune neuromuscular junction disorder. Long noncoding RNA (lncRNA) can regulate the expression of mRNA and is involved in the development of autoimmune diseases, but few genetic studies are available. In this study we aimed to explore the lncRNA and mRNA changes of LEMS. METHODS: Plasma lncRNA and mRNA expression profiles of three LEMS patients with small cell lung cancer (SCLC) and three matched healthy controls were analyzed by microarray. Differentially expressed lncRNAs and adjacent mRNAs were jointly analyzed, and candidates were verified by quantitative real-time polymerase chain reaction (qRT-PCR). The identified genes were subsequently evaluated in 9, 8, and 4 patients with paraneoplastic LEMS, nontumor LEMS, and SCLC, respectively. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to determine possible functions. RESULTS: A total of 320 lncRNA and 168 mRNAs were differentially expressed in the three LEMS with SCLC and compared with healthy controls. Among these, lncRNA LOC338963 and its neighboring mRNA AP3B2 were upregulated jointly, which was confirmed by qRT-PCR. qRT-PCR revealed significant upregulation of the two genes in patients with paraneoplastic LEMS compared with nontumor LEMS or SCLC. GO analysis of AP3B2 identified the enrichment terms anterograde synaptic vesicle transport and establishment of synaptic vesicle localization. KEEG analysis showed that AP3B2 was enriched in lysosomal pathways. DISCUSSION: LOC338963 and AP3B2 were upregulated in patients with paraneoplastic LEMS, suggesting their involvement in pathogenesis. These genes could be targets for exploring the pathomechanism of paraneoplastic LEMS.
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Complejo 3 de Proteína Adaptadora , Subunidades beta de Complejo de Proteína Adaptadora , Síndrome Miasténico de Lambert-Eaton , ARN Largo no Codificante , Complejo 3 de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/genética , Humanos , Neoplasias Pulmonares , ARN Largo no Codificante/sangre , ARN Largo no Codificante/genética , ARN Mensajero , Carcinoma Pulmonar de Células PequeñasAsunto(s)
Síndrome de Hermanski-Pudlak , Enfermedades Pulmonares Intersticiales , Complejo 3 de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/genética , Síndrome de Hermanski-Pudlak/genética , Humanos , Recién Nacido , Enfermedades Pulmonares Intersticiales/genética , MutaciónRESUMEN
Inborn errors in copper metabolism result in a diverse set of abnormalities such as Wilson disease and MEDNIK syndrome. Homozygous pathogenic variants in AP1B1 lead to KIDAR (Keratitis-Ichthyosis-Deafness Syndrome). The main phenotypic features of KIDAR are ichthyosis, keratitis, erythroderma, and progressive hearing loss accompanied by developmental delay and failure to thrive. Herein, we describe a six-and-a-half-year-old boy with KIDAR caused by a novel pathogenic variant in AP1B1 (NM_001127.4:c.1263C > A, p.Tyr421*). The proband presented with ichthyosis, erythroderma, palmoplantar keratoderma, hearing loss, and corneal scarring. He also had hypotonia, global developmental delay, and photophobia. Lastly, we review all of the previously reported cases and the clinical features associated with KIDAR.
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Sordera , Ictiosis , Queratitis , Complejo 1 de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/genética , Niño , Sordera/genética , Humanos , Ictiosis/genética , Ictiosis/patología , Queratitis/genética , Queratitis/patología , Masculino , MutaciónRESUMEN
Through seven decades the inverse association between HDL cholesterol concentrations and risk of atherosclerotic cardiovascular disease (ASCVD) has been observed in case-control and prospective cohort studies. This robust inverse association fuelled the enthusiasm towards development of HDL cholesterol increasing drugs, exemplified by the cholesteryl ester transfer protein (CETP) inhibitor trials and the extended-release niacin HPS2-THRIVE trial. These HDL cholesterol increasing trials were launched without conclusive evidence from human genetics, and despite discrepant species dependent evidence from animal studies. Evidence from human genetics and from randomized clinical trials over the last 13 years now point in the direction that concentrations of HDL cholesterol, do not appear to be a viable future path to target therapeutically for prevention of ASCVD. A likely explanation for the strong observational association between low HDL cholesterol and high ASCVD risk is the concomitant inverse association between HDL cholesterol and atherogenic triglyceride-rich lipoproteins. The purpose of the present review is to bring HDL cholesterol increasing trials into a human genetics context exemplified by candidate gene studies of key players in HDL biogenesis as well as by HDL cholesterol related genome-wide association studies.
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Complejo 3 de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/genética , Aterosclerosis/sangre , Proteínas de Transferencia de Ésteres de Colesterol/genética , HDL-Colesterol/genética , Aterosclerosis/epidemiología , Aterosclerosis/genética , HDL-Colesterol/sangre , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Niacina/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Gout can affect the quality of life of patients due to monosodium urate monohydrate (MSU) crystals. Numerous studies have proposed that long noncoding RNAs (lncRNAs) regulate gout. We aimed to reveal the function of lncRNA small nucleolar RNA host gene 8 (SNHG8) in acute gouty arthritis (GA). A GA mouse model was established by injection of MSU into footpads. The levels of SNHG8, miR-542-3p and adaptor-related protein complex 3 subunit delta 1 (AP3D1) in footpads were detected via polymerase chain reaction analysis. Hematoxylin-eosin staining revealed the paw swelling in mice. Enzyme-linked immunosorbent assay and western blot analysis were applied to determine the concentrations of proinflammatory cytokines. SNHG8 expression was identified to be upregulated after MSU treatment. Ablation of SNHG8 decreased the MSU-induced enhancement of paw swelling and foot thickness. In addition, SNHG8 depletion decreased the protein levels of proinflammatory factors in GA mice. Mechanically, SNHG8 was verified to be a sponge of miR-542-3p, and miR-542-3p targeted AP3D1 3' untranslated region. SNHG8 competitively bound with miR-542-3p to upregulate AP3D1 expression. Finally, results of rescue assays illustrated that AP3D1 upregulation offset the SNHG8-mediated inhibition on paw swelling and protein levels of proinflammatory factors in GA mice. In conclusion, SNHG8 accelerates acute GA development by upregulating AP3D1 in an miR-542-3p-dependent way in mice, providing an effective therapeutic approach to treat acute GA.
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Complejo 3 de Proteína Adaptadora/biosíntesis , Subunidades beta de Complejo de Proteína Adaptadora/biosíntesis , Artritis Gotosa/metabolismo , ARN Largo no Codificante/metabolismo , Regulación hacia Arriba , Enfermedad Aguda , Complejo 3 de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/genética , Animales , Artritis Gotosa/genética , Humanos , Masculino , Ratones , ARN Largo no Codificante/genética , Células THP-1RESUMEN
Although there have been many studies of gene variant association with different stages of HIV/AIDS progression in United States and European cohorts, few gene-association studies have assessed genic determinants in sub-Saharan African populations, which have the highest density of HIV infections worldwide. We carried out genome-wide association studies on 766 study participants at risk for HIV-1 subtype C (HIV-1C) infection in Botswana. Three gene associations (AP3B1, PTPRA, and NEO1) were shown to have significant association with HIV-1C acquisition. Each gene association was replicated within Botswana or in the United States-African American or United States-European American AIDS cohorts or in both. Each associated gene has a prior reported influence on HIV/AIDS pathogenesis. Thirteen previously discovered AIDS restriction genes were further replicated in the Botswana cohorts, extending our confidence in these prior AIDS restriction gene reports. This work presents an early step toward the identification of genetic variants associated with and affecting HIV acquisition or AIDS progression in the understudied HIV-1C afflicted Botswana population.
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Variación Genética , Estudio de Asociación del Genoma Completo , Infecciones por VIH/genética , Síndrome de Inmunodeficiencia Adquirida , Complejo 3 de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/genética , Botswana/epidemiología , Genotipo , Infecciones por VIH/epidemiología , Humanos , Proteínas del Tejido Nervioso/genética , Proteínas Tirosina Fosfatasas Clase 4 Similares a Receptores/genética , Receptores de Superficie Celular/genéticaRESUMEN
Induced pluripotent stem cells (iPSCs) were generated from blood outgrowth endothelial cells (BOECs) obtained from a healthy donor and from a patient diagnosed with Hermansky Pudlak Syndrome type 2 (HPS2), caused by compound heterozygous AP3B1 mutations (c.177delA and c.1839-1842delTAGA). BOECs were reprogrammed with a hOKSM self-silencing polycistronic lentiviral vector, where the generated iPSCs showed normal karyotype, expression of pluripotency associated markers and in vitro spontaneous differentiation towards the three germ layers. The generated iPSCs can be used to study HPS2 pathophysiology and the basic functions of AP3B1 protein in different cell types.
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Síndrome de Hermanski-Pudlak , Células Madre Pluripotentes Inducidas , Complejo 3 de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/genética , Diferenciación Celular , Células Endoteliales , Heterocigoto , Humanos , MutaciónRESUMEN
Angelman syndrome is a neurodevelopmental disorder characterized by intellectual disability (ID), a distinctive gait pattern, abnormal behaviors, severe impairment in language development, and characteristic facial features. Most cases are caused by the absence of a maternal contribution to the imprinted region on chromosome 15q11-q13. Here, we present the first reported case of a 3-year-old boy with an atypical phenotype of Angelman syndrome due to uniparental isodisomy with two recessive homozygous pathogenic variants: in HERC2 and AP3B2. Known phenotypes related to HERC2 and AP3B2 include ID and early infantile epileptic encephalopathy, respectively. The patient had severe global developmental delay and profound ID and showed a happy demeanor, stereotypic laughter, and hand-flapping movements, but also irritability. Craniofacial dysmorphic features, including brachycephaly, strabismus, wide ala nasi, short philtrum, wide open mouth, and slight hypopigmentation were seen. Progressive microcephaly was noted. Magnetic resonance imaging of the brain showed delayed myelination and cerebral atrophy. Trio whole exome sequencing and CGH-SNP array analysis revealed paternal uniparental isodisomy of chromosome 15 and two coexisting recessive diseases resulting from homozygous HERC2 and AP3B2 pathogenic variants. The pathogenic variant in HERC2 was inherited from his heterozygous-carrier father, and the variant in AP3B2 was de novo. We suppose that these unusual features were the combination of the effect of three concomitant disorders.
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Complejo 3 de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/genética , Síndrome de Angelman/genética , Discapacidad Intelectual/genética , Ubiquitina-Proteína Ligasas/genética , Síndrome de Angelman/diagnóstico , Síndrome de Angelman/patología , Preescolar , Cromosomas Humanos Par 15/genética , Predisposición Genética a la Enfermedad , Homocigoto , Humanos , Discapacidad Intelectual/patología , Masculino , Fenotipo , Disomía Uniparental/genética , Secuenciación del ExomaRESUMEN
Critically ill coronavirus disease 2019 (COVID-19) is characterized by severe cytokine storms, a hyperinflammatory condition intimately related to the development of fatal outcomes. Why some individuals seem particularly vulnerable to severe cytokine storms is still unknown. Primary immunodeficiency (PID)-related genes are inherited factors that dysregulate host inflammatory responses to infection, especially hemophagocytic lymphohistiocytosis (HLH)-related genes, established as contributors to the development of excessive cytokine storms. We analyzed the association between PID gene variants with severe cytokine storms in COVID-19. We conducted whole-exome sequencing in 233 hospitalized COVID-19 patients and identified four PID gene (UNC13D, AP3B1, RNF168, DHX58) variants were significantly enriched in COVID-19 patients experiencing severe cytokine storms. The total percentage of COVID-19 patients with variants in UNC13D or AP3B1, two typical HLH genes, was dramatically higher in high-level cytokine group than in low-level group (33.3 vs. 5.7%, P < 0.001). Germline variants in UNC13D and AP3B1 were associated with the development of severe cytokine storms, fatal outcomes in COVID-19. These findings advance the understanding of individual susceptibility to severe cytokine storms and help optimize the current management of COVID-19.
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Complejo 3 de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/genética , COVID-19/genética , COVID-19/patología , Proteínas de la Membrana/genética , Complejo 3 de Proteína Adaptadora/metabolismo , Subunidades beta de Complejo de Proteína Adaptadora/metabolismo , Anciano , COVID-19/inmunología , COVID-19/metabolismo , Síndrome de Liberación de Citoquinas/genética , Humanos , Linfohistiocitosis Hemofagocítica/genética , Proteínas de la Membrana/metabolismo , Persona de Mediana EdadRESUMEN
BACKGROUND: Mitochondrial dysfunction has emerged as an important player in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a common cause of idiopathic interstitial lung disease in adults. Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder that causes a similar type of pulmonary fibrosis in younger adults, although the role of mitochondrial dysfunction in this condition is not understood. METHODS: We performed a detailed characterization of mitochondrial structure and function in lung tissues and alveolar epithelial cells deficient in the adaptor protein complex 3 beta 1 (Ap3b1) subunit, the gene responsible for causing subtype 2 of HPS (HPS-2). RESULTS: We observed widespread changes in mitochondrial homeostasis in HPS-2 cells, including the acquisition of abnormally shaped mitochondria, with reduced number of cristae, and markedly reduced activity of the electron transport chain and the tricarboxylic acid cycle. We also found that mitochondrial redox imbalance and activity of the mitochondrial unfolded protein response were dysregulated in HPS-2 cells and this associated with various other changes that appeared to be compensatory to mitochondrial dysfunction. This included an increase in glycolytic activity, an upregulation in the expression of mitochondrial biogenesis factors and enhanced activation of the energy-conserving enzyme AMP-activated protein kinase. CONCLUSION: In summary, our findings indicate that mitochondrial function is dramatically altered in HPS-2 lung tissues, suggesting dysfunction of this organelle might be a driver of HPS lung disease.
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Complejo 3 de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/genética , Homeostasis/fisiología , Pulmón/fisiopatología , Mitocondrias/fisiología , Alveolos Pulmonares/fisiopatología , Mucosa Respiratoria/fisiopatología , Animales , Síndrome de Hermanski-Pudlak/genética , Síndrome de Hermanski-Pudlak/patología , Síndrome de Hermanski-Pudlak/fisiopatología , Pulmón/patología , Ratones , Ratones Endogámicos C57BL , Alveolos Pulmonares/patología , Mucosa Respiratoria/patologíaAsunto(s)
Complejo 3 de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/genética , Síndrome de Hermanski-Pudlak/genética , Síndrome de Hermanski-Pudlak/patología , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/patología , Piebaldismo/genética , Piebaldismo/patología , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/patología , Adolescente , Niño , Femenino , Eliminación de Gen , Síndrome de Hermanski-Pudlak/inmunología , Humanos , Linfohistiocitosis Hemofagocítica/inmunología , Masculino , Piebaldismo/inmunología , Enfermedades de Inmunodeficiencia Primaria/inmunologíaAsunto(s)
Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Complejo 1 de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/genética , Variación Genética , Fenotipo , Sordera/diagnóstico , Sordera/genética , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Lactante , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/genéticaRESUMEN
The epithelial cell-specific clathrin adaptor protein (AP)-1B has a well-established role in polarized sorting of cargos to the basolateral membrane. Here we show that ß1 integrin was dependent on AP-1B and its coadaptor, autosomal recessive hypercholesterolemia protein (ARH), for sorting to the basolateral membrane. We further demonstrate an unprecedented role for AP-1B at the basal plasma membrane during collective cell migration of epithelial sheets. During wound healing, expression of AP-1B (and ARH in AP-1B-positive cells) slowed epithelial-cell migration. We show that AP-1B colocalized with ß1 integrin in focal adhesions during cell migration using confocal microscopy and total internal reflection fluorescence microscopy on fixed specimens. Further, AP-1B labeling in cell protrusions was distinct from labeling for the endocytic adaptor complex AP-2. Using stochastic optical reconstruction microscopy we identified numerous AP-1B-coated structures at or close to the basal plasma membrane in cell protrusions. In addition, immunoelectron microscopy showed AP-1B in coated pits and vesicles at the plasma membrane during cell migration. Lastly, quantitative real-time reverse transcription PCR analysis of human epithelial-derived cell lines revealed a loss of AP-1B expression in highly migratory metastatic cancer cells suggesting that AP-1B's novel role at the basal plasma membrane during cell migration might be an anticancer mechanism.
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Complejo 1 de Proteína Adaptadora/metabolismo , Subunidades beta de Complejo de Proteína Adaptadora/metabolismo , Movimiento Celular/fisiología , Complejo 1 de Proteína Adaptadora/genética , Complejo 2 de Proteína Adaptadora/metabolismo , Subunidades beta de Complejo de Proteína Adaptadora/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Animales , Línea Celular Tumoral , Membrana Celular/metabolismo , Polaridad Celular/fisiología , Clatrina/metabolismo , Perros , Endosomas/metabolismo , Células Epiteliales/metabolismo , Humanos , Integrina beta1/metabolismo , Células de Riñón Canino Madin Darby , Proteínas de la Membrana/metabolismo , Transporte de Proteínas/fisiologíaRESUMEN
INTRODUCTION: The AP4B1 gene encodes a subunit of adaptor protein complex-4 (AP4), a component of intracellular transportation of proteins which plays important roles in neurons. Bi-allelic mutations in AP4B1 cause autosomal recessive spastic paraplegia-47(SPG47). CASE PRESENTATION: Here we present a Chinese patient with spastic tetraplegia, moderate psychomotor development delay and febrile seizures plus. Brain MRIs showed dilated supratentorial ventricle, thin posterior and splenium part of corpus callosum. The patient had little progress through medical treatments and rehabilitating regimens. Whole exome sequencing identified novel compound heterozygous truncating variants c.1207C > T (p.Gln403*) and c.52_53delAC (p.Cys18Glnfs*7) in AP4B1 gene. Causal mutations in AP4B1 have been reported in 29 individuals from 22 families so far, most of which are homozygous mutations. CONCLUSIONS: Our study enriched the genetic and phenotypic spectrum of SPG47. Early discovery, diagnosis and proper treatment on the conditions generally increase chances of improvement on the quality of life for patients.
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Complejo 4 de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/genética , Proteínas de Unión al ADN/genética , Trastornos Psicomotores/genética , Cuadriplejía/genética , Proteínas de Unión al ARN/genética , Convulsiones Febriles/genética , Pueblo Asiatico , Niño , China , Codón sin Sentido , Heterocigoto , Humanos , Masculino , Fenotipo , Subunidades de Proteína/genética , Trastornos Psicomotores/complicaciones , Cuadriplejía/complicaciones , Convulsiones Febriles/complicaciones , Secuenciación del ExomaRESUMEN
Biallelic mutations in the AP4B1 gene, encoding adaptor-related protein complex 4 beta-1 subunit, have been recognized as an important cause of a group of conditions leading to adaptor-related protein complex 4 (AP4)-associated hereditary spastic paraplegia (SPG47). We describe a homozygous, known variant c.1160_1161delCA (p.Thr387fs) that was found in the largest ever group of patients coming from four families. The patients exhibited early hypotonia progressing to spastic paraplegia, microcephaly, epilepsy, and central nervous system (CNS) defects and global developmental delay that are consistent with the nature of SPG47. Our findings expand phenotypic spectrum of SPG47 to include polymorphic seizures, mild/moderate intellectual disability, and intracerebral cysts as well as point to founder mutation in AP4 deficiency disorders in apparently non-consanguineous Polish families without shared ancestry.
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Complejo 4 de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/genética , Discapacidad Intelectual/genética , Trastornos del Neurodesarrollo/genética , Paraplejía Espástica Hereditaria/genética , Adolescente , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Variación Genética/genética , Homocigoto , Humanos , Lactante , Discapacidad Intelectual/fisiopatología , Masculino , Mutación/genética , Trastornos del Neurodesarrollo/fisiopatología , Linaje , Paraplejía Espástica Hereditaria/fisiopatología , Secuenciación del ExomaRESUMEN
The pearl (pe) mouse mutant has been identified as a model for Hermansky-Pudlak syndrome and bears a mutation in the beta3A subunit of the AP-3 complex, which has a core function in the biogenesis and function of various lysosomal-related organelles. Through large-scale mating, we found that female pearl mice also displayed reduced fertility with a smaller litter size. Abnormal uteri in both 1-month-old and 3-month-old mice were observed as having short and thin uterine horns, indicating abnormal development. Histological studies revealed that the endometrial epithelium and endometrial stoma of the uterus were both thinner than those in the normal controls. We examined some key factors in uterine development, including the Hoxa10, Hoxa11, and Wnt5a genes, and found that they all presented lower mRNA and protein levels. The pearl mouse could serve as a model for uterine hypoplasia, a common problem in female infertility.
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Complejo 3 de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/genética , Mutación , Anomalías Urogenitales/genética , Enfermedades Uterinas/genética , Útero/anomalías , Animales , Modelos Animales de Enfermedad , Femenino , Síndrome de Hermanski-Pudlak/genética , RatonesRESUMEN
Hermansky-Pudlak syndrome type 2 (HPS2) is an extremely rare autosomal recessive inherited disease characterized by partial oculocutaneous albinism (OCA), bleeding diathesis due to a storage pool deficiency and immunodeficiency. The disorder is caused by disruption of the adapter protein 3 complex, which is involved in impaired intracellular vesicle transport. Here, we report the first case of a 1-year-old girl with HPS2 in Asia. She had no specific symptoms other than OCA and neutropenia. We analyzed her platelet function using transmission electron microscopy and a platelet aggregation test, cytotoxic degranulation assay of her natural killer (NK) cells and bleeding time, the results of which led to the diagnosis of HPS2. Although her NK-cell cytotoxic degranulation was impaired, she had not developed signs of hemophagocytic lymphohistiocytosis (HLH) or fibrosing lung disease. Molecular genetic analyses showed novel heterozygous mutations (c.188T>A [p.M63K] and c.2546>A [p.L849X]) in AP3B1. When examining patients with OCA, blood tests should be performed to confirm neutrophil count, bleeding time and platelet agglutination. When HPS2 is suspected, detailed immunological tests should be considered, and attention should be paid to HLH and pulmonary lesions immediately and over the long term.