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Síndromes Compartimentales , Enfermedades Orbitales , Humanos , Masculino , Síndromes Compartimentales/diagnóstico , Síndromes Compartimentales/etiología , Enfermedades Orbitales/diagnóstico , Vacuolas , Enfermedades Autoinmunes/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/genéticaRESUMEN
PURPOSE: Immunodysregulation, Polyendocrinopathy, Enteropathy, and X-linked syndrome (IPEX), caused by pathogenic FOXP3 variants, is a rare autoimmune disorder with diverse clinical features, including early-onset diabetes, eczema, and enteropathy. Atypical cases show milder symptoms and unique signs, requiring different treatments. Therefore, there are ambiguities in the accurate diagnosis and management of IPEX. We sought to present clinical, genetic, and immunological assessments of 12 IPEX patients with long-term follow-up to facilitate the diagnosis and management of the disease. METHODS: Clinical findings and treatment options of the patients were collected over time. Lymphocyte subpopulations, protein expressions, regulatory T (Treg) and circulating T follicular helper (cTFH) cells, and T-cell proliferation were analyzed. RESULTS: Predominant presentations included autoimmunity (91.6%), failure to thrive (66.7%), and eczema (58.3%). There were four classical and eight atypical IPEX individuals. Allergic manifestations were more common in atypical patients. Notably, chronic diarrhea demonstrated heightened severity compared to other manifestations. Four patients (33.3%) demonstrated eosinophilia, and nine (75%) showed high serum IgE levels. Most patients exhibited normal percentages of Treg cells with reduced CD25, FOXP3, and CTLA-4 expressions, corrected after hematopoietic stem cell transplantation (HSCT). Compared to healthy controls, the TH2-like skewing accompanied by reduced TH17-like responses was observed in cTFH and Treg cells of patients. Overall, nine patients (75%) received immunosuppressants (ISs), and six (50%) underwent HSCT, which was the only treatment revealing sustained control. Sirolimus was used in six patients and showed better control than other ISs. CONCLUSIONS: The first cohort from Turkey with long-term follow-up results, comparing typical and atypical cases, provides insights into the outcomes of different therapeutic modalities and T- cell subtype changes in IPEX syndrome.
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Factores de Transcripción Forkhead , Enfermedades Genéticas Ligadas al Cromosoma X , Linfocitos T Reguladores , Humanos , Turquía , Masculino , Preescolar , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Enfermedades Genéticas Ligadas al Cromosoma X/terapia , Linfocitos T Reguladores/inmunología , Lactante , Femenino , Niño , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/congénito , Enfermedades del Sistema Inmune/diagnóstico , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/terapia , Enfermedades del Sistema Inmune/congénito , Autoinmunidad , Adolescente , DiarreaRESUMEN
Objective: To explore the clinical phenotypes and pathogenic gene variation characteristics of three Chinese Han ethnic families affected by Nance-Horan syndrome, a rare X-linked genetic disorder. Methods: A pedigree investigation study was conducted at the First Affiliated Hospital of Zhengzhou University, collecting clinical data from three Chinese Han families with Nance-Horan syndrome between February 2009 and September 2018. Detailed family histories, comprehensive ophthalmological and systemic examinations were documented. Pedigree charts were created, and genetic inheritance patterns were analyzed to preliminarily diagnose the probands and other affected individuals. Genomic DNA was extracted from peripheral blood samples of family members, and next-generation sequencing was used to screen for target gene variations, which were confirmed by Sanger sequencing. Pathogenicity of the genetic variants and their impact on three-dimensional protein structure were analyzed using MutationTaster and computer-aided protein modeling. Results: In Family 1, there are 5 patients, including 4 females (aged 42, 37, 9 and 7) and 1 males (aged 12). In Family 2, there are 5 patients, including 3 females (aged 54, 32 and 16) and 2 males (aged 26 and 9). In Family 3, there are 8 patients, including 5 females (aged 69, 42, 37, 35 and 14) and 3 males (aged 10, 7 and 4). All probands in the three families exhibited nuclear cataracts with typical congenital hereditary cataract features, but no noticeable abnormalities in facial appearance or teeth. Next-generation sequencing identified new variation sites in the NHS gene, specifically c.2519_2520del, exon3del, and c.3847C>T. These variations included nonsense mutation p.(Ser840*), exon deletion p.(?), and nonsense mutation p.(Gln1283*). Combined clinical and genetic sequencing results confirmed X-linked Nance-Horan syndrome in all three families. Bioinformatics analysis indicated these variation sites were pathogenic and resulted in abnormal three-dimensional protein structures, likely being the main cause of Nance-Horan syndrome. Conclusion: The majority of patients from the three Nance-Horan syndrome families studied were affected by congenital hereditary cataracts characterized by nuclear opacities.The NHS gene variations c.2519_2520del, exon3del, and c.3847C>T are newly identified pathogenic sites in Nance-Horan syndrome, reported for the first time across three different families.
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Catarata , Mutación , Linaje , Humanos , Masculino , Femenino , Catarata/genética , Catarata/congénito , Adulto , Persona de Mediana Edad , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Fenotipo , Pueblo Asiatico/genética , Anomalías Dentarias/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Enfermedades Hereditarias del Ojo/genética , Niño , China , Proteínas de la MembranaRESUMEN
BACKGROUND: X-linked agammaglobulinemia (XLA), also referred to as Bruton's tyrosine kinase deficiency, is a rare genetic disorder that affects the immune system. We conducted genetic analysis on patients suffering from immunodeficiency by utilizing Next-Generation Sequencing techniques, as well as their closest relatives, to facilitate accurate diagnosis, offer genetic counseling services, and enhance our comprehension of XLA.
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Agammaglobulinemia , Enfermedades Genéticas Ligadas al Cromosoma X , Neumonía por Mycoplasma , Humanos , Agammaglobulinemia/complicaciones , Agammaglobulinemia/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , Masculino , Neumonía por Mycoplasma/complicaciones , Neumonía por Mycoplasma/microbiología , Agammaglobulinemia Tirosina Quinasa/genética , Mycoplasma pneumoniae/genética , Mycoplasma pneumoniae/aislamiento & purificación , Adulto , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
BACKGROUND: Hearing loss (HL) is the most common sensory birth deficit worldwide, with causative variants in more than 150 genes. However, the etiological contribution and clinical manifestations of X-linked inheritance in HL remain unclear within the Chinese HL population. In this study, we focused on X-linked hereditary HL and aimed to assess its contribution to hereditary HL and identify the genotype-phenotype relationship. METHODS: We performed a molecular epidemiological investigation of X-linked hereditary HL based on next-generation sequencing and third-generation sequencing in 3646 unrelated patients with HL. We also discussed the clinical features associated with X-linked non-syndromic HL-related genes based on a review of the literature. RESULTS: We obtained a diagnostic rate of 52.72% (1922/3646) among our patients; the aggregate contribution of HL caused by genes on the X chromosome in this cohort was ~ 1.14% (22/1922), and POU3F4 variants caused ~ 59% (13/22) of these cases. We found that X-linked HL was congenital or began during childhood in all cases, with representative audiological profiles or typical cochlear malformations in certain genes. Genotypic and phenotypic analyses showed that causative variants in PRPS1 and AIFM1 were mainly of the missense type, suggesting that phenotypic variability was correlated with the different effects that the replaced residues exert on structure and function. Variations in SMPX causing truncation of the protein product were associated with DFNX4, which resulted in typical audiological profiles before and after the age of 10 years, whereas nontruncated proteins typically led to distal myopathy. No phenotypic differences were identified in patients carrying POU3F4 or COL4A6 variants. CONCLUSIONS: Our work constitutes a preliminary evaluation of the molecular contribution of X-linked genes in heritable HL (~ 1.14%). The 15 novel variants reported here expand the mutational spectrum of these genes. Analysis of the genotype-phenotype relationship is valuable for X-linked HL precise diagnostics and genetic counseling. Elucidation of the pathogenic mechanisms and audiological profiles of HL can also guide choices regarding treatment modalities.
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Fenotipo , Humanos , Masculino , Femenino , Niño , Preescolar , Pérdida Auditiva/genética , Adolescente , Adulto , Pueblo Asiatico/genética , China , Factores del Dominio POU/genética , Genotipo , Adulto Joven , Lactante , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Mutación/genética , Persona de Mediana Edad , Genómica , Pueblos del Este de AsiaRESUMEN
Purpose: To determine whether the Lrit3-/- mouse model of complete congenital stationary night blindness with an ON-pathway defect harbors myopic features and whether the genetic defect influences the recovery from lens-induced myopia. Methods: Retinal levels of dopamine (DA) and 3,4 dihydroxyphenylacetic acid (DOPAC) from adult isolated Lrit3-/- retinas were quantified using ultra performance liquid chromatography after light adaptation. Natural refractive development of Lrit3-/- mice was measured from three weeks to nine weeks of age using an infrared photorefractometer. Susceptibility to myopia induction was assessed using a lens-induced myopia protocol with -25 D lenses placed in front of the right eye of the animals for three weeks; the mean interocular shift was measured with an infrared photorefractometer after two and three weeks of goggling and after one and two weeks after removal of goggles. Results: Compared to wild-type littermates (Lrit3+/+), both DA and DOPAC were drastically reduced in Lrit3-/- retinas. Natural refractive development was normal but Lrit3-/- mice showed a higher myopic shift and a lower ability to recover from induced myopia. Conclusions: Our data consolidate the link between ON pathway defect altered dopaminergic signaling and myopia. We document for the first time the role of ON pathway on the recovery from myopia induction.
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Ácido 3,4-Dihidroxifenilacético , Modelos Animales de Enfermedad , Dopamina , Ratones Noqueados , Miopía , Refracción Ocular , Animales , Ratones , Miopía/fisiopatología , Miopía/metabolismo , Miopía/genética , Dopamina/metabolismo , Ácido 3,4-Dihidroxifenilacético/metabolismo , Refracción Ocular/fisiología , Ratones Endogámicos C57BL , Retina/metabolismo , Retina/fisiopatología , Ceguera Nocturna/fisiopatología , Ceguera Nocturna/genética , Ceguera Nocturna/metabolismo , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/fisiopatología , Enfermedades Genéticas Ligadas al Cromosoma X/metabolismo , Recuperación de la Función/fisiología , Masculino , Enfermedades Hereditarias del OjoAsunto(s)
Trasplante de Células Madre Hematopoyéticas , Inmunodeficiencia Combinada Grave , Humanos , Inmunodeficiencia Combinada Grave/terapia , Inmunodeficiencia Combinada Grave/diagnóstico , Inmunodeficiencia Combinada Grave/genética , Masculino , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/terapia , Lactante , Diabetes Mellitus Tipo 1/congénito , Diarrea , Enfermedades del Sistema Inmune/congénitoRESUMEN
X-linked hypophosphataemia is a genetic disease caused by defects in the phosphate regulating endopeptidase homolog X-linked (PHEX) gene and is characterised by X-linked dominant inheritance. The main consequence of PHEX deficiency is increased production of the phosphaturic hormone fibroblast growth factor 23 (FGF23) in osteoblasts and osteocytes. Chronic exposure to circulating FGF23 is responsible for renal phosphate wasting and decreased synthesis of calcitriol, which decreases intestinal phosphate absorption. These mechanisms result in lifelong hypophosphataemia, impaired growth plate and bone matrix mineralisation, and diverse manifestations in affected children and adults, including some debilitating morbidities and possibly increased mortality. Important progress has been made in disease knowledge and management over the past decade; in particular, targeting FGF23 is a therapeutic approach that has substantially improved outcomes. However, patients affected by this complex disease need lifelong care and innovative treatment strategies, such as gene repair of PHEX, are necessary to further limit the disease burden.
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Raquitismo Hipofosfatémico Familiar , Factor-23 de Crecimiento de Fibroblastos , Factores de Crecimiento de Fibroblastos , Endopeptidasa Neutra Reguladora de Fosfato PHEX , Humanos , Factores de Crecimiento de Fibroblastos/metabolismo , Endopeptidasa Neutra Reguladora de Fosfato PHEX/genética , Raquitismo Hipofosfatémico Familiar/terapia , Raquitismo Hipofosfatémico Familiar/genética , Enfermedades Genéticas Ligadas al Cromosoma X/terapia , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Adulto , NiñoRESUMEN
Introduction: X-linked agammaglobulinemia (XLA) is a humoral immunodeficiency disorder characterized by recurrent infections, severe hypogammaglobulinemia, and a deficiency of circulating B cells. While the hallmark clinical manifestations of XLA typically include the respiratory, dermatological, and gastrointestinal systems, renal involvement is infrequent. In this article, we report two cases of XLA with concurrent renal disease, supplemented with a review of documented cases. Case description: The two cases described involve twin brothers, both presenting with respiratory tract infections and renal manifestations. Subsequent genetic testing confirmed the diagnosis of XLA. The younger brother exhibited improvement following intravenous immunoglobulin (IVIG) therapy and anti-infection treatment. Due to financial constraints, the older brother received only anti-infection and symptomatic treatments. Seven months after discharge, the older brother developed nephritis. However, he showed improvement following IVIG treatment. Conclusion: Immune profiling and genetic testing should be considered in male children with recurrent infections to facilitate the effective diagnosis of XLA. Regular monitoring is also imperative to detect and treat immune-mediated renal diseases in patients with XLA.
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Agammaglobulinemia , Enfermedades Genéticas Ligadas al Cromosoma X , Inmunoglobulinas Intravenosas , Humanos , Agammaglobulinemia/diagnóstico , Agammaglobulinemia/genética , Agammaglobulinemia/complicaciones , Masculino , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Enfermedades Genéticas Ligadas al Cromosoma X/complicaciones , Inmunoglobulinas Intravenosas/uso terapéutico , Niño , PreescolarRESUMEN
Dent disease-1 (DD-1) is a rare X-linked tubular disorder characterized by low-molecular-weight proteinuria (LMWP), hypercalciuria, nephrolithiasis and nephrocalcinosis. This disease is caused by inactivating mutations in the CLCN5 gene which encodes the voltage-gated ClC-5 chloride/proton antiporter. Currently, the treatment of DD-1 is only supportive and focused on delaying the progression of the disease. Here, we generated and characterized a Clcn5 knock-in mouse model that carries a pathogenic CLCN5 variant, c. 1566_1568delTGT; p.Val523del, which has been previously detected in several DD-1 unrelated patients, and presents the main clinical manifestations of DD-1 such as high levels of urinary b2-microglobulin, phosphate and calcium. Mutation p.Val523del causes partial ClC-5 retention in the endoplasmic reticulum. Additionally, we assessed the ability of sodium 4-phenylbutyrate, a small chemical chaperone, to ameliorate DD-1 symptoms in this mouse model. The proposed model would be of significant value in the investigation of the fundamental pathological processes underlying DD-1 and in the development of effective therapeutic strategies for this rare condition.
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Canales de Cloruro , Modelos Animales de Enfermedad , Técnicas de Sustitución del Gen , Fenilbutiratos , Proteinuria , Animales , Canales de Cloruro/genética , Canales de Cloruro/metabolismo , Ratones , Proteinuria/tratamiento farmacológico , Fenilbutiratos/farmacología , Fenilbutiratos/uso terapéutico , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/tratamiento farmacológico , Mutación , Masculino , Humanos , Enfermedad de Dent/tratamiento farmacológico , Enfermedad de Dent/genética , NefrolitiasisRESUMEN
Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a rare disease first reported in 2020, most commonly seen in men aged 56-75 years old. Common clinical features include skin lesions (83.5%), fever (63.6%), relapsing chondritis (36.4%), venous thrombosis (34.7%) and lymph node enlargement (33.9%). The patient is a man in his 40s who presented with testicular and lower extremity pain, followed by a rash and bicytopenia. He was initiated on corticosteroids and sulfasalazine. He was found to have mediastinal lymphadenopathy and underwent an endobronchial ultrasound and transbronchial needle aspiration followed by a video-assisted thoracic surgery biopsy which were unrevealing. Eventually, an ubiquitin-like modifier activating enzyme (UBA-1) gene analysis was performed that was consistent with VEXAS syndrome. Patients with VEXAS syndrome usually present with a red or violaceous rash and dyspnoea. Laboratory abnormalities include anaemia, elevated mean corpuscular volume, thrombocytopenia and elevated inflammatory markers. Diagnosis is based on the genetic mutation and associated symptoms. The treatment includes steroids and Janus kinase (JAK) inhibitors, specifically ruxolitinib.
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Linfadenopatía , Humanos , Masculino , Linfadenopatía/etiología , Adulto , Enzimas Activadoras de Ubiquitina/genética , Enfermedades del Mediastino/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Enfermedades Autoinflamatorias Hereditarias/genética , Diagnóstico Diferencial , Síndrome , Nitrilos , Pirazoles , PirimidinasRESUMEN
Autosomal recessive agammaglobulinemia is a severe primary antibody deficiency disorder typically presenting in infancy. We present a rare case of an 8-year-old boy with AR agammaglobulinemia due to a homozygous splice site variant (c.499-1G > A) in the CD79A gene. Despite monthly intravenous immunoglobulin replacement and prophylactic antibiotics, he developed refractory Helicobacter bilis leg ulcers. Helicobacter species are known for extracellular colonization and are challenging to culture, necessitating molecular diagnostics for identification. The patient required prolonged treatment with intravenous meropenem followed by oral metronidazole and doxycycline for resolution of the ulcers over two years. The patient also exhibited persistent asymptomatic thrombocytopenia, an atypical finding in CD79A mutation cases. This case underscores the importance of genetic diagnosis and targeted antimicrobial therapy in managing rare infections associated with primary immunodeficiencies like autosomal recessive agammaglobulinemia due to CD79A mutation.
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Agammaglobulinemia , Antígenos CD79 , Infecciones por Helicobacter , Mutación , Fenotipo , Humanos , Masculino , Niño , Mutación/genética , Infecciones por Helicobacter/diagnóstico , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/genética , Agammaglobulinemia/genética , Agammaglobulinemia/diagnóstico , Antígenos CD79/genética , Antibacterianos/uso terapéutico , Helicobacter/genética , Inmunoglobulinas Intravenosas/uso terapéutico , Enfermedades Genéticas Ligadas al Cromosoma XRESUMEN
X-linked dystonia-parkinsonism (XDP) is a severe neurodegenerative disorder resulting from an inherited intronic SINE-Alu-VNTR (SVA) retrotransposon in the TAF1 gene that causes dysregulation of TAF1 transcription. The specific mechanism underlying this dysregulation remains unclear, but it is hypothesized to involve the formation of G-quadruplexes (G4) structures within the XDP-SVA that impede transcription. In this study, we show that ZNF91, a critical repressor of SVA retrotransposons, specifically binds to G4-forming DNA sequences. Further, we found that genetic deletion of ZNF91 exacerbates the molecular phenotype associated with the XDP-SVA insertion in patient cells, while no difference was observed when ZNF91 was deleted from isogenic control cells. Additionally, we observed a significant age-related reduction in ZNF91 expression in whole blood and brain, indicating a progressive loss of repression of the XDP-SVA in XDP. These findings indicate that ZNF91 plays a crucial role in controlling the molecular phenotype associated with XDP. Since ZNF91 binds to G4-forming DNA sequences in SVAs, this suggests that interactions between ZNF91 and G4-forming sequences in the XDP-SVA minimize the severity of the molecular phenotype. Our results showing that ZNF91 expression levels significantly decrease with age provide a potential explanation for the age-related progressive neurodegenerative character of XDP. Collectively, our study provides important insights into the protective role of ZNF91 in XDP pathogenesis and suggests that restoring ZNF91 expression, destabilization of G4s, or targeted repression of the XDP-SVA could be future therapeutic strategies to prevent or treat XDP.
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Trastornos Distónicos , Enfermedades Genéticas Ligadas al Cromosoma X , Fenotipo , Humanos , Trastornos Distónicos/genética , Trastornos Distónicos/metabolismo , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/metabolismo , G-Cuádruplex , Factores Asociados con la Proteína de Unión a TATA/genética , Factores Asociados con la Proteína de Unión a TATA/metabolismo , Masculino , Factor de Transcripción TFIID/genética , Factor de Transcripción TFIID/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Retroelementos/genética , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismoRESUMEN
The clinical presentation, treatment, and follow-up of two boys with type 1 Dent disease who exhibited a Bartter-like phenotype were retropectively analysed. The related literature of pediatric patients with type 1 Dent disease who had hypokalemia and metabolic alkalosis was screened through databases such as PubMed, CNKI, and Wanfang until February 1, 2024, and common features among these patients were summarized through literature review. A total of 7 literatures were included, and 9 children were included in the analysis. All patients were male, presenting with significant low molecular weight proteinuria and hypercalciuria. Other prominent characteristic phenotypes included short stature (7/8), hypophosphatemia (8/9), and rickets (6/8). Seven previously reported patients had missense or nonsense mutations, while 2 patients in this study carried possible pathogenic mutations in the CLCN5 gene, c.315+2T>A (p.?) and c.584dupT (p.I196Yfs*6), respectively. Five patients were able to maintain blood potassium levels around 3 mmol/L with oral potassium chloride solution combined with non-steroidal anti-inflammatory drugs (ibuprofen or indomethacin). The follow-up showed that 2 patients developed chronic kidney disease stage 4 and stage 3 at the age of 13 and 21 years, respectively. The phenotypic overlap between Dent disease and Batter syndrome is considerable,with the distinguishing feature being the presence of significant low molecular weight proteinuria. Patients with type 1 Dent disease presenting with the Bartter-like phenotype have a high prevalence of short stature, hypophosphatemia, and rickets. Non-steroidal anti-inflammatory drugs can be used to correct hypokalemia in patients under periodic renal function assessment.
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Enfermedades Genéticas Ligadas al Cromosoma X , Nefrolitiasis , Niño , Humanos , Masculino , Síndrome de Bartter/genética , Síndrome de Bartter/diagnóstico , Canales de Cloruro/genética , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Hipercalciuria/diagnóstico , Hipercalciuria/genética , Hipopotasemia/diagnóstico , Hipopotasemia/genética , Hipofosfatemia/diagnóstico , Hipofosfatemia/genética , Mutación , Nefrolitiasis/diagnóstico , Nefrolitiasis/genética , Fenotipo , Proteinuria/diagnóstico , Proteinuria/genética , Raquitismo/diagnósticoRESUMEN
INTRODUCTION: In X-linked agammaglobulinemia (XLA), the diversity of BTK variants complicates the study of genotype-phenotype correlations. Since BTK negatively regulates toll-like receptors (TLRs), we investigated if distinct BTK mutation types selectively modulate TLR pathways, affecting disease expression. METHODS: Using reverse transcription-quantitative polymerase chain reaction, we quantified ten TLR signaling-related genes in XLA patients with missense (n = 3) and nonsense (n = 5) BTK mutations and healthy controls (n = 17). RESULTS: BTK, IRAK2, PIK3R4, REL, TFRC, and UBE2N were predominantly downregulated, while RIPK2, TLR3, TLR10, and TLR6 showed variable regulation. The missense XLA group exhibited significant downregulation of IRAK2, PIK3R4, REL, and TFRC and upregulation of TLR3 and/or TLR6. CONCLUSION: Hypo-expression of TLR3, TLR6, and TLR10 may increase susceptibility to infections, while hyper-expression might contribute to chronic inflammatory conditions like arthritis or inflammatory bowel disease. Our findings shed light on the important inflammatory component characteristic of some XLA patients, even under optimal therapeutic conditions.
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Agammaglobulinemia Tirosina Quinasa , Agammaglobulinemia , Estudios de Asociación Genética , Enfermedades Genéticas Ligadas al Cromosoma X , Transducción de Señal , Receptores Toll-Like , Humanos , Agammaglobulinemia/genética , Agammaglobulinemia/inmunología , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Agammaglobulinemia Tirosina Quinasa/genética , Transducción de Señal/genética , Masculino , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Adolescente , Niño , Regulación de la Expresión Génica , Adulto , Preescolar , Adulto Joven , Femenino , MutaciónRESUMEN
A significant source of risk for neurodevelopmental disorders (NDDs), including intellectual disability (ID) and autism spectrum disorder (ASD), lies in genes located on the X chromosome. Males can be particularly vulnerable to X-linked variation because of hemizygosity, and male-specific segregation in pedigrees has guided earlier gene discovery for X-linked recessive conditions. More recently, X-linked disorders disproportionally affecting females, with complex inheritance patterns and/or presenting with sex differences, have surfaced. Here, we discuss the genetics and neurobiology of X-linked genes that are paradigmatic to understand NDDs in females. Integrating genetic, clinical, and functional data will be key to understand how X-linked variation contributes to the risk architecture of NDDs.
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Genes Ligados a X , Trastornos del Neurodesarrollo , Humanos , Trastornos del Neurodesarrollo/genética , Genes Ligados a X/genética , Femenino , Animales , Cromosomas Humanos X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Predisposición Genética a la Enfermedad/genéticaRESUMEN
ABSTRACT: X-linked myopathy with excessive autophagy is a rare disorder caused by a mutation in the vacuolar ATPase assembly factor gene which causes slowly progressive early onset proximal weakness and loss of ambulation by the age of 50-70 years. Electrodiagnostic (EDx) testing usually shows widespread complex repetitive and myotonic discharges, even in muscles unaffected clinically. We report a 65-year-old man who presented with progressive proximal weakness since his teenage years. Extensive workup over 30 years revealed inconclusive EDx and muscle histopathology findings. The diagnosis was finally made with genetic testing. Subsequent neuromuscular ultrasound was more informative of disease severity than repeat EDx and directed a muscle biopsy that showed an autophagic vacuolar myopathy and the novel identification of vacuoles in capillary endothelial cells. Although genetic testing is required for confirmation, in milder cases of X-linked myopathy with excessive autophagy, neuromuscular ultrasound may aid in diagnosis even when EDx findings are inconclusive.
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Enfermedades Genéticas Ligadas al Cromosoma X , Músculo Esquelético , Enfermedades Musculares , Ultrasonografía , Humanos , Masculino , Anciano , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico por imagen , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Musculares/genética , Enfermedades Musculares/diagnóstico por imagen , Enfermedades Musculares/diagnóstico , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Electrodiagnóstico , Autofagia/genética , Pruebas GenéticasRESUMEN
Inactivating mutations of Foxp3, the master regulator of regulatory T cell development and function, lead to immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome in mice and humans. IPEX is a fatal autoimmune disease, with allogeneic stem cell transplant being the only available therapy. In this study, we report that a single dose of adeno-associated virus (AAV)-IL-27 to young mice with naturally occurring Foxp3 mutation (Scurfy mice) substantially ameliorates clinical symptoms, including growth retardation and early fatality. Correspondingly, AAV-IL-27 gene therapy significantly prevented naive T cell activation, as manifested by downregulation of CD62L and upregulation of CD44, and immunopathology typical of IPEX. Because IL-27 is known to induce IL-10, a key effector molecule of regulatory T cells, we evaluated the contribution of IL-10 induction by crossing IL-10-null allele to Scurfy mice. Although IL-10 deficiency does not affect the survival of Scurfy mice, it largely abrogated the therapeutic effect of AAV-IL-27. Our study revealed a major role for IL-10 in AAV-IL-27 gene therapy and demonstrated that IPEX is amenable to gene therapy.
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Factores de Transcripción Forkhead , Enfermedades Genéticas Ligadas al Cromosoma X , Terapia Genética , Mutación de Línea Germinal , Interleucina-10 , Linfocitos T Reguladores , Animales , Factores de Transcripción Forkhead/genética , Ratones , Interleucina-10/genética , Interleucina-10/inmunología , Terapia Genética/métodos , Linfocitos T Reguladores/inmunología , Enfermedades Genéticas Ligadas al Cromosoma X/terapia , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Interleucinas/inmunología , Interleucinas/genética , Diarrea/genética , Diarrea/terapia , Diarrea/inmunología , Enfermedades Intestinales/inmunología , Enfermedades Intestinales/genética , Enfermedades Intestinales/terapia , Dependovirus/genética , Ratones Endogámicos C57BL , Enfermedades del Sistema Inmune/inmunología , Enfermedades del Sistema Inmune/terapia , Enfermedades del Sistema Inmune/genética , Enfermedades del Sistema Inmune/congénito , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/congénito , Ratones Noqueados , Activación de Linfocitos/inmunología , Humanos , Interleucina-27/genéticaRESUMEN
CDKL5 deficiency disorder (CDD) is an X-linked dominant epileptic encephalopathy, characterized by early-onset and drug-resistant seizures, psychomotor delay, and slight facial features. Genomic variants inactivating CDKL5 or impairing its protein product kinase activity have been reported, making next-generation sequencing (NGS) and chromosomal microarray analysis (CMA) the standard diagnostic tests. We report a suspicious case of CDD in a female child who tested negative upon NGS and CMA and harbored an X chromosome de novo pericentric inversion. The use of recently developed genomic techniques (optical genome mapping and whole-genome sequencing) allowed us to finely characterize the breakpoints, with one of them interrupting CDKL5 at intron 1. This is the fifth case of CDD reported in the scientific literature harboring a structural rearrangement on the X chromosome, providing evidence for the hypothesis that this type of anomaly can represent a recurrent pathogenic mechanism, whose frequency is likely underestimated, with it being overlooked by standard techniques. The identification of the molecular etiology of the disorder is extremely important in evaluating the pathological outcome and to better investigate the mechanisms associated with drug resistance, paving the way for the development of specific therapies. Karyotype and genomic techniques should be considered in all cases presenting with CDD without molecular confirmation.
Asunto(s)
Cromosomas Humanos X , Proteínas Serina-Treonina Quinasas , Humanos , Femenino , Cromosomas Humanos X/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/deficiencia , Inversión Cromosómica , Síndromes Epilépticos/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Espasmos InfantilesRESUMEN
PURPOSE: To define the clinical and histological characteristics of nephritis in patients with X-linked agammaglobulinemia (XLA) and their immunological profiles. METHODS: The clinical, immunological, and histological findings of nine patients with XLA and nephritis were retrospectively analyzed. RESULTS: Based on kidney histological findings, patients with XLA and nephritis could be divided into two groups, viz., chronic glomerulonephritis (CGN) and tubulointerstitial nephritis (TIN). The two groups showed different immunological profiles. Patients in the CGN group exhibited an atypical immunological profile of XLA, with pathogenic leaky B cells producing immunoglobulins that may play a role in forming immune complexes and causing immune-mediated glomerulonephritis. In contrast, patients in the TIN group exhibited a typical immunological profile of XLA, suggesting that antibody-independent/other BTK-dependent mechanisms, or immunoglobulin replacement therapy (IgRT)-related immune/nonimmune-mediated nephrotoxicity causes TIN. CONCLUSION: Nephritis occurring in patients with XLA could have links between their renal pathology and immunological status. Careful observation is recommended to detect kidney pathology in patients with XLA on IgRT.