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1.
Medicine (Baltimore) ; 99(40): e22640, 2020 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-33019488

RESUMEN

INTRODUCTION: Danon disease is a rare X-linked dominant genetic disorder caused by defects in the lysosome-associated membrane protein 2 (LAMP2) gene. Unless treated, cardiogenic death is the main cause of mortality. This case report describes a 19-year-old man who was diagnosed with Danon disease and survived for 3 years from symptom onset to death. The mutation in his LAMP2 gene (p.Gly221Ilefs*19) had not been previously reported. PATIENT CONCERNS: A 19-year-old man patient was hospitalized for intermittent palpitations. He had no family history of cardiomyopathy, arrhythmia, or sudden cardiac death, but his sister had died of cirrhosis at age 12 years, but the exact cause of cirrhosis was unknown. DIAGNOSIS: Exome sequencing and Sanger sequencing identified a novel missense mutation (p.Gly221Ilefs*19) in the LAMP2 gene of the proband. This mutation was also detected in his mother, confirming the diagnosis of Danon disease. INTERVENTIONS: The patient experienced various types of arrhythmia throughout the clinical process, including Wolff-Parkinson-White syndrome, non-sustained atrial tachycardia, atrial flutter, and third-degree atrioventricular block. He was therefore treated with cardiac ablation procedures and cardiac resynchronization therapy. OUTCOMES: The period from the onset of symptoms to the onset of heart failure was 2 years. The patient died of cardiogenic death during the third year, at age 22 years. LESSONS: Danon disease is a rare disease that is difficult to recognize because of its hidden early manifestations. Early identification of its clinical symptoms can lead to early diagnosis and treatment.


Asunto(s)
Enfermedad por Depósito de Glucógeno de Tipo IIb/genética , Enfermedad por Depósito de Glucógeno de Tipo IIb/terapia , Proteína 2 de la Membrana Asociada a los Lisosomas/genética , Arritmias Cardíacas/etiología , Terapia de Resincronización Cardíaca/métodos , Ablación por Catéter/métodos , Resultado Fatal , Enfermedad por Depósito de Glucógeno de Tipo IIb/complicaciones , Enfermedad por Depósito de Glucógeno de Tipo IIb/diagnóstico , Insuficiencia Cardíaca/etiología , Humanos , Masculino , Mutación Missense/genética , Secuenciación del Exoma Completo/métodos , Síndrome de Wolff-Parkinson-White/genética , Síndrome de Wolff-Parkinson-White/terapia , Adulto Joven
2.
Sci Rep ; 10(1): 17492, 2020 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-33060796

RESUMEN

The novel SARS-CoV-2 outbreak has swiftly spread worldwide. The rapid genome sequencing of SARS-CoV-2 strains has become a helpful tool for better understanding the genomic characteristics and origin of the virus. To obtain virus whole-genome sequences directly from clinical specimens, we performed nanopore sequencing using a modified ARTIC protocol in a portable nanopore sequencer and validated a routine 8-h workflow and a 5-h rapid pipeline. We conducted some optimization to improve the genome sequencing workflow. The sensitivity of the workflow was also tested by serially diluting RNA from clinical samples. The optimized pipeline was finally applied to obtain the whole genomes of 29 clinical specimens collected in Hangzhou from January to March 2020. In the 29 obtained complete genomes of SARS-CoV-2, 33 variations were identified and analyzed. The genomic variations and phylogenetic analysis hinted at multiple sources and different transmission patterns during the COVID-19 epidemic in Hangzhou, China. In conclusion, the genomic characteristics and origin of the virus can be quickly determined by nanopore sequencing following our workflows.


Asunto(s)
Betacoronavirus/genética , Genoma Viral , Secuenciación de Nanoporos/métodos , Adolescente , Adulto , Betacoronavirus/clasificación , Betacoronavirus/aislamiento & purificación , Niño , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/virología , Femenino , Variación Genética , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Pandemias , Filogenia , Neumonía Viral/diagnóstico , Neumonía Viral/virología , Análisis de Secuencia de ADN , Adulto Joven
3.
BMC Bioinformatics ; 21(1): 452, 2020 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-33050876

RESUMEN

BACKGROUND: Any two unrelated people differ by about 20,000 missense mutations (also referred to as SAVs: Single Amino acid Variants or missense SNV). Many SAVs have been predicted to strongly affect molecular protein function. Common SAVs (> 5% of population) were predicted to have, on average, more effect on molecular protein function than rare SAVs (< 1% of population). We hypothesized that the prevalence of effect in common over rare SAVs might partially be caused by common SAVs more often occurring at interfaces of proteins with other proteins, DNA, or RNA, thereby creating subgroup-specific phenotypes. We analyzed SAVs from 60,706 people through the lens of two prediction methods, one (SNAP2) predicting the effects of SAVs on molecular protein function, the other (ProNA2020) predicting residues in DNA-, RNA- and protein-binding interfaces. RESULTS: Three results stood out. Firstly, SAVs predicted to occur at binding interfaces were predicted to more likely affect molecular function than those predicted as not binding (p value < 2.2 × 10-16). Secondly, for SAVs predicted to occur at binding interfaces, common SAVs were predicted more strongly with effect on protein function than rare SAVs (p value < 2.2 × 10-16). Restriction to SAVs with experimental annotations confirmed all results, although the resulting subsets were too small to establish statistical significance for any result. Thirdly, the fraction of SAVs predicted at binding interfaces differed significantly between tissues, e.g. urinary bladder tissue was found abundant in SAVs predicted at protein-binding interfaces, and reproductive tissues (ovary, testis, vagina, seminal vesicle and endometrium) in SAVs predicted at DNA-binding interfaces. CONCLUSIONS: Overall, the results suggested that residues at protein-, DNA-, and RNA-binding interfaces contributed toward predicting that common SAVs more likely affect molecular function than rare SAVs.


Asunto(s)
Aminoácidos/genética , Variación Genética , Ácidos Nucleicos/metabolismo , Proteínas/genética , Proteínas/metabolismo , Secuencia de Bases , Femenino , Humanos , Sustancias Macromoleculares/metabolismo , Masculino , Modelos Moleculares , Mutación Missense/genética , Unión Proteica , Reproducibilidad de los Resultados
4.
Commun Biol ; 3(1): 641, 2020 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-33110195

RESUMEN

The emergence of SARS-CoV-2 has caused over a million human deaths and massive global disruption. The viral infection may also represent a threat to our closest living relatives, nonhuman primates. The contact surface of the host cell receptor, ACE2, displays amino acid residues that are critical for virus recognition, and variations at these critical residues modulate infection susceptibility. Infection studies have shown that some primate species develop COVID-19-like symptoms; however, the susceptibility of most primates is unknown. Here, we show that all apes and African and Asian monkeys (catarrhines), exhibit the same set of twelve key amino acid residues as human ACE2. Monkeys in the Americas, and some tarsiers, lemurs and lorisoids, differ at critical contact residues, and protein modeling predicts that these differences should greatly reduce SARS-CoV-2 binding affinity. Other lemurs are predicted to be closer to catarrhines in their susceptibility. Our study suggests that apes and African and Asian monkeys, and some lemurs, are likely to be highly susceptible to SARS-CoV-2. Urgent actions have been undertaken to limit the exposure of great apes to humans, and similar efforts may be necessary for many other primate species.


Asunto(s)
Betacoronavirus/patogenicidad , Infecciones por Coronavirus/veterinaria , Especificidad del Huésped/genética , Pandemias/veterinaria , Peptidil-Dipeptidasa A/genética , Neumonía Viral/veterinaria , Enfermedades de los Primates/enzimología , Primates/genética , Receptores Virales/genética , Secuencia de Aminoácidos , Sustitución de Aminoácidos , Animales , Betacoronavirus/fisiología , Evolución Biológica , Quirópteros/genética , Secuencia Conservada , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/transmisión , Predisposición Genética a la Enfermedad , Mamíferos/genética , Modelos Moleculares , Mutación Missense , Peptidil-Dipeptidasa A/química , Filogenia , Neumonía Viral/epidemiología , Neumonía Viral/transmisión , Mutación Puntual , Enfermedades de los Primates/virología , Unión Proteica , Conformación Proteica , Riesgo , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Especificidad de la Especie , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/metabolismo
5.
Nat Commun ; 11(1): 5414, 2020 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-33110075

RESUMEN

The neoplastic stromal cells of giant cell tumor of bone (GCTB) carry a mutation in H3F3A, leading to a mutant histone variant, H3.3-G34W, as a sole recurrent genetic alteration. We show that in patient-derived stromal cells H3.3-G34W is incorporated into the chromatin and associates with massive epigenetic alterations on the DNA methylation, chromatin accessibility and histone modification level, that can be partially recapitulated in an orthogonal cell line system by the introduction of H3.3-G34W. These epigenetic alterations affect mainly heterochromatic and bivalent regions and provide possible explanations for the genomic instability, as well as the osteolytic phenotype of GCTB. The mutation occurs in differentiating mesenchymal stem cells and associates with an impaired osteogenic differentiation. We propose that the observed epigenetic alterations reflect distinct differentiation stages of H3.3 WT and H3.3 MUT stromal cells and add to H3.3-G34W-associated changes.


Asunto(s)
Neoplasias Óseas/genética , Tumor Óseo de Células Gigantes/genética , Histonas/genética , Osteogénesis , Neoplasias Óseas/metabolismo , Neoplasias Óseas/fisiopatología , Metilación de ADN , Epigénesis Genética , Epigenómica , Tumor Óseo de Células Gigantes/metabolismo , Tumor Óseo de Células Gigantes/fisiopatología , Histonas/metabolismo , Humanos , Mutación Missense
6.
Medicine (Baltimore) ; 99(43): e22936, 2020 Oct 23.
Artículo en Inglés | MEDLINE | ID: mdl-33120852

RESUMEN

RATIONALE: Kallmann syndrome (KS) is a rare inherited genetic disorder characterized by hypogonadotropic hypogonadism and hyposmia/anosmia. Early diagnosis is the key to timely treatment and improvement of prognosis in patients with KS. As the most common complication of KS, renal agenesis can provide clues to early diagnosis and treatment for KS. In this article, we report a case of KS with 8 rare urinary disorders for the first time. PATIENT CONCERNS: A 19-year-old Chinese man presented with 8 rare urinary disorders and a history of bilateral cryptorchidism came to us for micropenis, hyposmia, and delayed puberty. DIAGNOSIS: The patient presented with hyposmia, low levels of sex hormones and showed a weak response to the GnRH stimulation test leading to a diagnosis of KS. Two missense mutations were found in further whole-exome sequencing: 1) Kallmann syndrome 1 (KAL1) gene in exon11, c.1600G > A, p. Val534Ile; 2) Prokineticin receptor 2 (PROKR2) gene in exon 2, c.533G > A, p. Trp178Ser. which led to a diagnosis of KS. INTERVENTIONS: The patient underwent replacement therapy of human chorionic gonadotropin (HCG) and human menopausal gonadotropin (HMG). The patient had previously undergone six surgeries for cryptorchidism and urinary disorders. OUTCOMES: The patient's puberty retardation was effectively alleviated. His serum testosterone (T) reached a normal level (8.280 nmol/mL). During the follow-up period, he presented with Tanner stage II pubic hair development. CONCLUSION: In this article, we report 8 rare urinary disorders with missense mutations of KAL1 and PROKR2 in a case of KS. Among them, bilateral giant kidneys, urinary extravasation of right renal, bilateral megalo-ureters, left ureteral terminal obstruction, bilateral renal cyst and bladder emptying disorder are reported for the first time, which enrich the integrity of urinary disorder types and provide clues to genetic counseling in patients with KS.


Asunto(s)
Síndrome de Kallmann/diagnóstico , Síndrome de Kallmann/genética , Enfermedades Urológicas/etiología , Criptorquidismo/diagnóstico , Criptorquidismo/etiología , Criptorquidismo/cirugía , Exones , Proteínas de la Matriz Extracelular/genética , Enfermedades de los Genitales Masculinos/diagnóstico , Enfermedades de los Genitales Masculinos/etiología , Terapia de Reemplazo de Hormonas/métodos , Humanos , Síndrome de Kallmann/tratamiento farmacológico , Masculino , Mutación Missense/genética , Proteínas del Tejido Nervioso/genética , Trastornos del Olfato/diagnóstico , Trastornos del Olfato/etiología , Pene/anomalías , Pubertad Tardía/diagnóstico , Pubertad Tardía/etiología , Enfermedades Raras , Receptores Acoplados a Proteínas G/genética , Receptores de Péptidos/genética , Resultado del Tratamiento , Secuenciación del Exoma Completo/métodos , Adulto Joven
7.
BMC Med Genet ; 21(1): 195, 2020 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-33008311

RESUMEN

BACKGROUND: Alagille syndrome is an autosomal dominant disorder usually caused by pathogenic variants of the JAG1 gene. In the past, cholestasis was a condition sine qua non for diagnosis of the syndrome. However, recent advancements in genetic testing have revealed that clinical presentations vary from lack of symptoms, to multiorgan involvement. Tetralogy of Fallot, the most frequent complex congenital heart defect in Alagille Syndrome, very rarely leads to renal failure requiring dialysis - there are only single reports of such cases in the literature, with none of them in Alagille Syndrome. CASE PRESENTATION: A 41-year-old woman suffering from cyanosis, dyspnea and plethora was admitted to the hospital. The patient suffered from chronic kidney disease and tetralogy of Fallot and had been treated palliatively with Blalock-Taussig shunts in the past; at admission, only minimal flow through the left shunt was preserved. These symptoms, together with impaired mental status and dysmorphic facial features, led to extensive clinical and genetic testing including whole exome sequencing. A previously unknown missense variant c.587G > A within the JAG1 gene was identified. As there were no signs of cholestasis, and subclinical liver involvement was only suggested by elevated alkaline phosphatase levels, the patient was diagnosed with incomplete Alagille Syndrome. End-stage renal disease required introduction of renal replacement therapy. Continuous ambulatory peritoneal dialysis was chosen and the patient's quality of life significantly increased. However, after refusal of further treatment, the patient died at the age of 45. CONCLUSIONS: Tetralogy of Fallot should always urge clinicians to evaluate for Alagille Syndrome and offer patients early nephrological care. Although tetralogy of Fallot rarely leads to end-stage renal disease requiring dialysis, if treated palliatively and combined with renal dysplasia (typical of Alagille Syndrome), it can result in severe renal failure as in the presented case. There is no standard treatment for such cases, but based on our experience, peritoneal dialysis is worth consideration. Finally, clinical criteria for the diagnosis of Alagille Syndrome require revision. Previously, diagnosis was based on cholestasis - however, cardiovascular anomalies are found to be more prevalent. Furthermore, the criteria do not include renal impairment, which is also common.


Asunto(s)
Síndrome de Alagille/terapia , Proteína Jagged-1/genética , Mutación Missense , Diálisis Peritoneal/métodos , Insuficiencia Renal Crónica/terapia , Tetralogía de Fallot/terapia , Adulto , Síndrome de Alagille/diagnóstico , Síndrome de Alagille/genética , Resultado Fatal , Femenino , Pruebas Genéticas , Humanos , Cuidados Paliativos/métodos , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/genética , Tetralogía de Fallot/diagnóstico , Tetralogía de Fallot/genética
8.
BMC Med Genet ; 21(1): 196, 2020 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-33032550

RESUMEN

BACKGROUND: Juvenile polyposis syndrome (JPS) is a rare autosomal dominant hereditary disorder characterized by the development of multiple distinct juvenile polyps in the gastrointestinal tract with an increased risk of colorectal cancer. Germline mutations in two genes, SMAD4 and BMPR1A, have been identified to cause JPS. CASE PRESENTATION: Here, we report a germline heterozygous missense variant (c.299G > A) in exon 3 BMPR1A gene in a family with juvenile polyposis. This variant was absent from the population database, and concluded as de novo compared with the parental sequencing. Further sequencing of the proband's children confirmed the segregation of this variant with the disease, while the variant was also predicted to have damaging effect based on online prediction tools. Therefore, this variant was classified as likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines. CONCLUSIONS: Germline genetic testing revealed a de novo germline missense variant in BMPR1A gene in a family with juvenile polyposis. Identification of the pathogenic variant facilitates the cancer risk management of at-risk family members, and endoscopic surveillance is recommended for mutation carriers.


Asunto(s)
Poliposis Adenomatosa del Colon/genética , Receptores de Proteínas Morfogenéticas Óseas de Tipo 1/genética , Mutación de Línea Germinal , Poliposis Intestinal/congénito , Mutación Missense , Síndromes Neoplásicos Hereditarios/genética , Poliposis Adenomatosa del Colon/diagnóstico , Adulto , Salud de la Familia , Femenino , Pruebas Genéticas , Heterocigoto , Humanos , Poliposis Intestinal/diagnóstico , Poliposis Intestinal/genética , Masculino , Síndromes Neoplásicos Hereditarios/diagnóstico , Linaje , Proteína Smad4/genética
9.
Nat Commun ; 11(1): 5168, 2020 10 14.
Artículo en Inglés | MEDLINE | ID: mdl-33057011

RESUMEN

The potassium ion (K+) channel plays a fundamental role in controlling K+ permeation across the cell membrane and regulating cellular excitabilities. Mutations in the transmembrane pore reportedly affect the gating transitions of K+ channels, and are associated with the onset of neural disorders. However, due to the lack of structural and dynamic insights into the functions of K+ channels, the structural mechanism by which these mutations cause K+ channel dysfunctions remains elusive. Here, we used nuclear magnetic resonance spectroscopy to investigate the structural mechanism underlying the decreased K+-permeation caused by disease-related mutations, using the prokaryotic K+ channel KcsA. We demonstrated that the conformational equilibrium in the transmembrane region is shifted toward the non-conductive state with the closed intracellular K+-gate in the disease-related mutant. We also demonstrated that this equilibrium shift is attributable to the additional steric contacts in the open-conductive structure, which are evoked by the increased side-chain bulkiness of the residues lining the transmembrane helix. Our results suggest that the alteration in the conformational equilibrium of the intracellular K+-gate is one of the fundamental mechanisms underlying the dysfunctions of K+ channels caused by disease-related mutations.


Asunto(s)
Proteínas Bacterianas/metabolismo , Activación del Canal Iónico/genética , Canales de Potasio/metabolismo , Potasio/metabolismo , Alanina/genética , Ataxia/genética , Proteínas Bacterianas/genética , Proteínas Bacterianas/aislamiento & purificación , Epilepsia/genética , Humanos , Síndrome de QT Prolongado/genética , Espectroscopía de Resonancia Magnética , Simulación de Dinámica Molecular , Mutación Missense , Canales de Potasio/genética , Canales de Potasio/aislamiento & purificación , Conformación Proteica en Hélice alfa/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/metabolismo , Streptomyces lividans , Valina/genética
10.
Medicine (Baltimore) ; 99(39): e21941, 2020 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-32991402

RESUMEN

INTRODUCTION: Diffuse pulmonary lymphangiomatosis (DPL) is a rare condition. Most patients with DPL present dyspnea, cough, expectoration, and hemoptysis. There are few reports of DPL accompanied by thrombocytopenia, whose cause remains unknown. PATIENT CONCERNS: An 18-year-old male patient presented with recurrent cough, expectoration, and dyspnea for 5 years, and thrombocytopenia was observed during a 2-month follow-up. DIAGNOSIS: Chest computed tomography showed diffuse patchy shadows in both lungs, and pleural and pericardial effusions. Immunohistochemical lung tissue staining showed lymphatic and vascular endothelial cells positive for D2-40, CD31 and CD34. Routine blood test revealed platelets at 62 × 10 cells/L during follow-up. Bone marrow biopsy was normal. Ultrasound revealed no hepatosplenomegaly. Finally, the patient was diagnosed with DPL accompanied by thrombocytopenia. INTERVENTIONS: He was treated by subtotal pericardial resection, thoracocentesis, and anti-infective therapy. Oral prednisone was administered for 2 months. OUTCOMES: The symptoms of cough and shortness of breath were improved, but thrombocytopenia persisted. We investigated the cause of thrombocytopenia. Whole-exome sequencing identified a mutation in exon 3 of the TNFRSF13B gene in this patient. CONCLUSION: DPL may present with thrombocytopenia and DIC. Patients with thrombocytopenia but not DIC and splenomegaly should be screened for gene mutations.


Asunto(s)
Enfermedades Pulmonares/congénito , Linfangiectasia/congénito , Trombocitopenia/complicaciones , Adolescente , Niño , Humanos , Enfermedades Pulmonares/complicaciones , Enfermedades Pulmonares/diagnóstico por imagen , Enfermedades Pulmonares/genética , Enfermedades Pulmonares/patología , Linfangiectasia/complicaciones , Linfangiectasia/diagnóstico por imagen , Linfangiectasia/genética , Linfangiectasia/patología , Masculino , Mutación Missense , Trombocitopenia/diagnóstico , Tomografía Computarizada por Rayos X , Proteína Activadora Transmembrana y Interactiva del CAML , Secuenciación del Exoma Completo
11.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(10): 1128-1131, 2020 Oct 10.
Artículo en Chino | MEDLINE | ID: mdl-32924117

RESUMEN

OBJECTIVE: To analyze the clinical characteristics and genetic variation in a child with acrodysostosis type 2. METHODS: The child has undergone history taking and physical examination. Genome DNA was extracted from peripheral blood samples from him and his parents. High-throughput sequencing was carried out. The result was verified by Sanger sequencing. RESULTS: The 8-year-old boy presented with midface hypoplasia, hypertelorism, prominent nasal bridge, small and upturned nostrils, broad thumb and great toes, and brachydactyly of remaining fingers and toes. Genetic testing revealed that the child has carried a heterozygous c.1813T>C (p.Tyr605His) missense mutation of the PDE4D gene. The same mutation was not found in either parent and was unreported previously. CONCLUSION: The child was diagnosed with acrodysostosis type 2 due to the novel mutation of the PDE4D gene.


Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/genética , Disostosis/genética , Discapacidad Intelectual/genética , Osteocondrodisplasias/genética , Niño , Pruebas Genéticas , Humanos , Masculino , Mutación Missense
12.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(10): 1154-1157, 2020 Oct 10.
Artículo en Chino | MEDLINE | ID: mdl-32924124

RESUMEN

OBJECTIVE: To explore the genetic basis for a child with mental retardation. METHODS: The child was subjected to next generation sequencing (NGS). Candidate variant was analyzed with bioinformatic software. RESULTS: NGS revealed that the child has carried a de novo heterozygous c.4035G>C (p.Gln1345His) variant of the ARID1B gene. The variant was unreported previously and may cause instability of the protein structure. CONCLUSION: The de novo missense variant of ARID1B gene may underlie the mental retardation in the child. Above result has enabled genetic counseling and prenatal diagnosis for her family.


Asunto(s)
Proteínas de Unión al ADN/genética , Discapacidad Intelectual , Mutación Missense , Factores de Transcripción/genética , Niño , Femenino , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Discapacidad Intelectual/genética
13.
PLoS Pathog ; 16(8): e1008775, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32866218

RESUMEN

Small RNA viruses only have a very limited coding capacity, thus most viral proteins have evolved to fulfill multiple functions. The highly conserved matrix protein 1 (M1) of influenza A viruses is a prime example for such a multifunctional protein, as it acts as a master regulator of virus replication whose different functions have to be tightly regulated. The underlying mechanisms, however, are still incompletely understood. Increasing evidence points towards an involvement of posttranslational modifications in the spatio-temporal regulation of M1 functions. Here, we analyzed the role of M1 tyrosine phosphorylation in genuine infection by using recombinant viruses expressing M1 phosphomutants. Presence of M1 Y132A led to significantly decreased viral replication compared to wildtype and M1 Y10F. Characterization of phosphorylation dynamics by mass spectrometry revealed the presence of Y132 phosphorylation in M1 incorporated into virions that is most likely mediated by membrane-associated Janus kinases late upon infection. Molecular dynamics simulations unraveled a potential phosphorylation-induced exposure of the positively charged linker domain between helices 4 and 5, supposably acting as interaction platform during viral assembly. Consistently, M1 Y132A showed a defect in lipid raft localization due to reduced interaction with viral HA protein resulting in a diminished structural stability of viral progeny and the formation of filamentous particles. Importantly, reduced M1-RNA binding affinity resulted in an inefficient viral genome incorporation and the production of non-infectious virions that interferes with virus pathogenicity in mice. This study advances our understanding of the importance of dynamic phosphorylation as a so far underestimated level of regulation of multifunctional viral proteins and emphasizes the potential feasibility of targeting posttranslational modifications of M1 as a novel antiviral intervention.


Asunto(s)
Virus de la Influenza A/metabolismo , Mutación Missense , Proteínas de la Matriz Viral/metabolismo , Células A549 , Sustitución de Aminoácidos , Animales , Perros , Femenino , Células HEK293 , Humanos , Virus de la Influenza A/genética , Células de Riñón Canino Madin Darby , Masculino , Ratones , Ratones Transgénicos , Fosforilación , Proteínas de la Matriz Viral/genética
14.
BMC Med Genet ; 21(1): 180, 2020 09 11.
Artículo en Inglés | MEDLINE | ID: mdl-32917147

RESUMEN

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal-dominant hereditary disease characterized by hamartomas of multiple organ systems, including the brain, skin, heart, kidney and lung. Genetically, TSC is caused by pathogenic variants in the TSC1 or TSC2 gene. CASE PRESENTATION: We reported a sporadic case of a 32-year-old Han Chinese male diagnosed with TSC, whose spouse had a history of two spontaneous miscarriages and an induced abortion of a 30-week fetus identified with cardiac rhabdomyoma by ultrasound. A novel heterozygous missense variant in the TSC2 gene (Exon35:c.4511 T > C:p.L1504P) was identified in the male patient and the aborted fetus by next-generation sequencing, but not in his wife or both his parents. According to the ACMG/AMP criteria, this variant was classified as a "likely pathogenic" variant. CONCLUSION: The novel TSC2:c.4511 T > C variant identified was highly likely associated with TSC and could potentially lead to adverse reproductive outcomes. IVF-ET and pre-implantation genetic diagnosis for TSC are recommended for this patient in the future to prevent fetal TSC.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Mutación Missense , Proteína 2 del Complejo de la Esclerosis Tuberosa/genética , Esclerosis Tuberosa/genética , Adulto , Secuencia de Bases , Bandeo Cromosómico , Salud de la Familia , Femenino , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Masculino , Linaje , Esclerosis Tuberosa/diagnóstico
15.
BMC Med Genet ; 21(1): 185, 2020 09 22.
Artículo en Inglés | MEDLINE | ID: mdl-32962661

RESUMEN

BACKGROUND: Genetic eye diseases constitute a large and heterogeneous group of childhood ocular morbidity. Individual diseases may cause multiple structural anomalies and developmental features. Nepal Pediatric Ocular Disease Study (NPODS) was a population-based epidemiological study conducted across three ecological regions of Nepal to determine the prevalence and etiology of childhood ocular morbidity and blindness. In Phase II of this study, genetic analysis was performed for children who were found to have congenital ocular anomalies. METHOD: It was a cross sectional descriptive study. A total of 10,270 children across three different ecological regions in Nepal (Low lands, hills, and mountains) underwent ocular examinations in NPODS. Out of 374 (3.6%) of children with ocular abnormalities, 30 were thought to be congenital in nature. Targeted genetic analysis, including genotyping for genes specific to presenting phenotype, was performed for 25 children using serum samples. RESULTS: Out of 25 children, 18 had meaningful genetic results. Analysis revealed one missense alteration G12411T of Zinc Finger Homeobox 4 (ZFHX4) gene in one participant among 10 with congenital ptosis and another missense variation T > C P. Y374 C of Signaling Receptor and Transporter Retinol 6 (STRA6) gene in one participant among 3 with microphthalmos. CONCLUSION: The study is first of its kind from Nepal and mutant genes were unique to Nepalese Population. Further analysis of genetic factors is crucial to better understand genetic association with ocular diseases and conditions. This helps further in genetic counseling and probably gene therapy to prevent blindness from these conditions.


Asunto(s)
Ceguera/genética , Anomalías Congénitas/genética , Oftalmopatías/genética , Predisposición Genética a la Enfermedad/genética , Mutación Missense , Adolescente , Altitud , Ceguera/diagnóstico , Ceguera/epidemiología , Niño , Preescolar , Anomalías Congénitas/diagnóstico , Anomalías Congénitas/epidemiología , Estudios Transversales , Oftalmopatías/diagnóstico , Oftalmopatías/epidemiología , Femenino , Proteínas de Homeodominio/genética , Humanos , Lactante , Recién Nacido , Masculino , Proteínas de la Membrana/genética , Nepal/epidemiología , Prevalencia , Factores de Transcripción/genética
16.
Medicine (Baltimore) ; 99(31): e21438, 2020 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-32756155

RESUMEN

RATIONALE: Mutations in the hepatocyte nuclear factor-1-beta (HNF1B) gene result in a very variable presentation, including maturity onset diabetes of the young (MODY), renal cysts, renal dysplasia, and autosomal dominant tubulointerstitial kidney disease (ADTKD), which is characterized by tubular damage, renal fibrosis, and progressive renal dysfunction. PATIENT CONCERNS: A 22-year-old man came to the hospital presenting with hyperglycemia, hyperuricemia and elevated serum creatinine. His urine protein was within the normal range. The ultrasound examination revealed shrunken kidneys with renal cysts. The patient's mother was diagnosed with diabetes mellitus when she was 25 years old. Her laboratory results showed elevated serum creatinine. Her ultrasonography revealed shrunken kidneys with renal cysts and hydronephrosis without kidney stones. The next-generation sequencing revealed that the proband and his mother held the same heterozygous missense mutation (c.530G>A, NM_000458, p.R177Q) in the HNF1B gene. Bioinformatic analyses predicted that the mutation was likely pathogenic. DIAGNOSIS: The patient and his mother were diagnosed as ADTKD and MODY5 due to HNF1B mutation. INTERVENTION: The proband was administered metformin at a dose of 500 mg/day. OUTCOMES: The patient had well-controlled blood glucose levels and a stable renal function at his 12-month follow-up. LESSONS: We should take into account the diagnoses of ADTKD and MODY5 if patients present with early onset diabetes and multiple renal cysts or evidence of renal tubulointerstitial dysplasia, especially those with negative proteinuria results. Genetic testing helps detect the HNF1B gene mutations.


Asunto(s)
Enfermedades del Sistema Nervioso Central/genética , Esmalte Dental/anomalías , Diabetes Mellitus Tipo 2/genética , Factor Nuclear 1-beta del Hepatocito/genética , Enfermedades Renales Quísticas/genética , Nefritis Intersticial/genética , Cuidados Posteriores , Enfermedades del Sistema Nervioso Central/complicaciones , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Hiperglucemia/etiología , Hiperuricemia/etiología , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/uso terapéutico , Riñón/diagnóstico por imagen , Riñón/patología , Riñón/fisiopatología , Enfermedades Renales Quísticas/complicaciones , Enfermedades Renales Quísticas/tratamiento farmacológico , Enfermedades Renales Quísticas/patología , Masculino , Metformina/administración & dosificación , Metformina/uso terapéutico , Mutación Missense , Nefritis Intersticial/complicaciones , Nefritis Intersticial/patología , Linaje , Ultrasonografía/métodos , Adulto Joven
17.
J Transl Med ; 18(1): 321, 2020 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-32831104

RESUMEN

BACKGROUND: The outbreak of coronavirus disease (COVID-19) was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), through its surface spike glycoprotein (S-protein) recognition on the receptor Angiotensin-converting enzyme 2 (ACE2) in humans. However, it remains unclear how genetic variations in ACE2 may affect its function and structure, and consequently alter the recognition by SARS-CoV-2. METHODS: We have systemically characterized missense variants in the gene ACE2 using data from the Genome Aggregation Database (gnomAD; N = 141,456). To investigate the putative deleterious role of missense variants, six existing functional prediction tools were applied to evaluate their impact. We further analyzed the structural flexibility of ACE2 and its protein-protein interface with the S-protein of SARS-CoV-2 using our developed Legion Interfaces Analysis (LiAn) program. RESULTS: Here, we characterized a total of 12 ACE2 putative deleterious missense variants. Of those 12 variants, we further showed that p.His378Arg could directly weaken the binding of catalytic metal atom to decrease ACE2 activity and p.Ser19Pro could distort the most important helix to the S-protein. Another seven missense variants may affect secondary structures (i.e. p.Gly211Arg; p.Asp206Gly; p.Arg219Cys; p.Arg219His, p.Lys341Arg, p.Ile468Val, and p.Ser547Cys), whereas p.Ile468Val with AF = 0.01 is only present in Asian. CONCLUSIONS: We provide strong evidence of putative deleterious missense variants in ACE2 that are present in specific populations, which could disrupt the function and structure of ACE2. These findings provide novel insight into the genetic variation in ACE2 which may affect the SARS-CoV-2 recognition and infection, and COVID-19 susceptibility and treatment.


Asunto(s)
Betacoronavirus/fisiología , Mutación Missense , Peptidil-Dipeptidasa A/genética , Dominios y Motivos de Interacción de Proteínas/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo , Sustitución de Aminoácidos , Betacoronavirus/metabolismo , Sitios de Unión/genética , Infecciones por Coronavirus/etnología , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/virología , Análisis Mutacional de ADN/métodos , Bases de Datos Genéticas , Predisposición Genética a la Enfermedad/etnología , Variación Genética , Geografía , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Pandemias , Peptidil-Dipeptidasa A/química , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/etnología , Neumonía Viral/genética , Neumonía Viral/virología , Polimorfismo de Nucleótido Simple , Unión Proteica , Estructura Secundaria de Proteína/genética , Glicoproteína de la Espiga del Coronavirus/química , Internalización del Virus
18.
PLoS Genet ; 16(8): e1008941, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32760060

RESUMEN

Apolipoprotein B-containing lipoproteins (B-lps) are essential for the transport of hydrophobic dietary and endogenous lipids through the circulation in vertebrates. Zebrafish embryos produce large numbers of B-lps in the yolk syncytial layer (YSL) to move lipids from yolk to growing tissues. Disruptions in B-lp production perturb yolk morphology, readily allowing for visual identification of mutants with altered B-lp metabolism. Here we report the discovery of a missense mutation in microsomal triglyceride transfer protein (Mtp), a protein that is essential for B-lp production. This mutation of a conserved glycine residue to valine (zebrafish G863V, human G865V) reduces B-lp production and results in yolk opacity due to aberrant accumulation of cytoplasmic lipid droplets in the YSL. However, this phenotype is milder than that of the previously reported L475P stalactite (stl) mutation. MTP transfers lipids, including triglycerides and phospholipids, to apolipoprotein B in the ER for B-lp assembly. In vitro lipid transfer assays reveal that while both MTP mutations eliminate triglyceride transfer activity, the G863V mutant protein unexpectedly retains ~80% of phospholipid transfer activity. This residual phospholipid transfer activity of the G863V mttp mutant protein is sufficient to support the secretion of small B-lps, which prevents intestinal fat malabsorption and growth defects observed in the mttpstl/stl mutant zebrafish. Modeling based on the recent crystal structure of the heterodimeric human MTP complex suggests the G865V mutation may block triglyceride entry into the lipid-binding cavity. Together, these data argue that selective inhibition of MTP triglyceride transfer activity may be a feasible therapeutic approach to treat dyslipidemia and provide structural insight for drug design. These data also highlight the power of yolk transport studies to identify proteins critical for B-lp biology.


Asunto(s)
Proteínas Portadoras/genética , Lípidos/genética , Lipoproteínas/genética , Triglicéridos/genética , Animales , Hígado Graso/genética , Hígado Graso/patología , Tracto Gastrointestinal/metabolismo , Humanos , Inmunoprecipitación , Gotas Lipídicas/metabolismo , Lipoproteínas/metabolismo , Mutación Missense/genética , Mutación Puntual/genética , Transporte de Proteínas/genética , Triglicéridos/metabolismo , Pez Cebra/genética
19.
Nat Commun ; 11(1): 4287, 2020 08 27.
Artículo en Inglés | MEDLINE | ID: mdl-32855419

RESUMEN

Warsaw Breakage Syndrome (WABS) is a rare disorder related to cohesinopathies and Fanconi anemia, caused by bi-allelic mutations in DDX11. Here, we report multiple compound heterozygous WABS cases, each displaying destabilized DDX11 protein and residual DDX11 function at the cellular level. Patient-derived cell lines exhibit sensitivity to topoisomerase and PARP inhibitors, defective sister chromatid cohesion and reduced DNA replication fork speed. Deleting DDX11 in RPE1-TERT cells inhibits proliferation and survival in a TP53-dependent manner and causes chromosome breaks and cohesion defects, independent of the expressed pseudogene DDX12p. Importantly, G-quadruplex (G4) stabilizing compounds induce chromosome breaks and cohesion defects which are strongly aggravated by inactivation of DDX11 but not FANCJ. The DNA helicase domain of DDX11 is essential for sister chromatid cohesion and resistance to G4 stabilizers. We propose that DDX11 is a DNA helicase protecting against G4 induced double-stranded breaks and concomitant loss of cohesion, possibly at DNA replication forks.


Asunto(s)
Anomalías Múltiples/etiología , ARN Helicasas DEAD-box/genética , ARN Helicasas DEAD-box/metabolismo , ADN Helicasas/genética , ADN Helicasas/metabolismo , G-Cuádruplex , Intercambio de Cromátides Hermanas , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Proliferación Celular , ARN Helicasas DEAD-box/química , ADN Helicasas/química , Proteínas del Grupo de Complementación de la Anemia de Fanconi/genética , Proteínas del Grupo de Complementación de la Anemia de Fanconi/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Mutación Missense , Estabilidad Proteica , Seudogenes , ARN Helicasas/genética , ARN Helicasas/metabolismo , Recombinasa Rad51/genética , Recombinasa Rad51/metabolismo , Síndrome , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo
20.
Ann Hematol ; 99(10): 2295-2301, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32844323

RESUMEN

Early detection of individuals with hereditary hemochromatosis (HH) is important to manage iron levels and prevent future organ damage. Although the HFE mutations that cause most cases of HH have been identified, their geographic distribution is highly variable, and their contribution to iron overload is not fully understood. All new registered blood donors at the Sahlgrenska University hospital between 1998 and 2015 were included in the study. Donors with signs of iron overload at baseline and subsequent follow-up testing were recommended genotyping of the HFE gene. Of the 50,493 donors that were included in the study, 950 (1.9%) had signs of iron overload on both test occasions. Of the 840 donors with iron overload that performed HFE genotyping, 117 were homozygous for C282Y, and 97 were compound heterozygotes. The prevalence of C282Y homozygosity was 0.23%. Iron overload screening effectively detects individuals at risk of carrying the C282Y mutation of the HFE gene and enables early treatment to prevent HH complications.


Asunto(s)
Donantes de Sangre , Selección de Donante/métodos , Proteína de la Hemocromatosis/genética , Hemocromatosis/diagnóstico , Mutación Missense , Adulto , Diagnóstico Precoz , Femenino , Ferritinas/sangre , Frecuencia de los Genes , Genotipo , Hemocromatosis/sangre , Hemocromatosis/genética , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Programas y Proyectos de Salud , Suecia/epidemiología , Adulto Joven
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