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1.
Medicine (Baltimore) ; 100(25): e26382, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160414

RESUMO

RATIONALE: Multiple endocrine neoplasia type 1 (MEN1) is a rare tumor syndrome with an autosomal dominant inheritance, and genetic testing for MEN1 gene is important for both affected individuals and their relatives. We present a 2-person family affected by a germline c.1546dupC MEN1 mutation, and one of them had a full-spectrum of MEN-related endocrine tumors. PATIENT CONCERNS: A female patient aged 32 years presented with jejunal ulcer perforation due to gastrinoma. DIAGNOSES: We conducted genetic analysis and extensive biochemical/radiological evaluation for detecting other endocrine tumors. Multiple pancreatic neuroendocrine tumors (NETs), prolactinoma and primary hyperparathyroidism were diagnosed, and a frame-shift mutation, NM_130799.1:c.1546dupC (p.Arg516Profs∗15), was detected. One daughter of the proband, aged 12 years, had the same mutation for MEN1. INTERVENTION: She underwent pancreatic surgery for pancreatic NETs and total parathyroidectomy for primary hyperparathyroidism. OUTCOMES: After pancreatic surgery, long-term symptoms of epigastric soreness, acid belching, sweating, and palpitation in fasting were improved. Hypercalcemia was improved after parathyroidectomy and she was supplemented with oral calcium and vitamin D. Her daughter showed normal biochemical surveillance until 15 years of age. LESSONS: We report 2 people in a family affected by MEN1 with the heterozygous germline c.1546dupC mutation, a variant that should be surveilled for early development of full-blown MEN1-associated endocrine tumors.


Assuntos
Neoplasia Endócrina Múltipla Tipo 1/diagnóstico , Neoplasias Primárias Múltiplas/diagnóstico , Tumores Neuroendócrinos/diagnóstico , Proteínas Proto-Oncogênicas/genética , Adenoma/diagnóstico , Adenoma/genética , Adenoma/cirurgia , Adulto , Criança , Feminino , Mutação da Fase de Leitura , Gastrinoma/diagnóstico , Gastrinoma/genética , Gastrinoma/cirurgia , Testes Genéticos , Mutação em Linhagem Germinativa , Glucagonoma , Heterozigoto , Humanos , Hiperparatireoidismo Primário/diagnóstico , Hiperparatireoidismo Primário/genética , Hiperparatireoidismo Primário/cirurgia , Insulinoma , Neoplasia Endócrina Múltipla Tipo 1/complicações , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/cirurgia , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/cirurgia , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirurgia , Neoplasias das Paratireoides/diagnóstico , Neoplasias das Paratireoides/genética , Neoplasias das Paratireoides/cirurgia , Paratireoidectomia , Prolactinoma/diagnóstico , Prolactinoma/genética , Prolactinoma/cirurgia
2.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(5): 789-792, 2021 May 20.
Artigo em Chinês | MEDLINE | ID: mdl-34134969

RESUMO

OBJECTIVE: To investigate the pathogenic gene in a child with optic atrophy and analyze the influence of this gene mutation on protein structure. OBJECTIVE: We collected the clinical record of the 13-year-old girl and her relatives. The child received examinations of the visual acuity, visual field, fundus, OCT, visual-evoked potential (VEP) and the nerve system, underwent brain MRI and was followed up for 1 year. Genomic DNA was extracted from the peripheral blood of the child and her parents for next-generation sequencing of the whole exon. The pathogenic gene mutation was identified and the resultant changes in the protein structure was analyzed. OBJECTIVE: The patient presented with impaired vision and optic nerve atrophy in both eyes with low amplitude of VEP, but did not show dystonia or pyramidal tract symptom. Brain MRI detected no leukodystrophy. Genetic analysis suggested a heterozygous c.53_54delTG mutation in exon 1 in the NDUFV1 gene of complex I, which caused a frameshift starting with the codon valine 18, thus changing the amino acid to an Alanine residue and creating a premature stop codon at position 20 of the new reading frame (p.Val18AlafsX20). A heterozygous for c.1162+4A>C: IVS8 + 4A>C in intron 8 was also found. Protein structure analysis showed the missing of important structure of NDUFV1 subunit in complex I. OBJECTIVE: We identified a novel NDUFV1 mutation in a child with optic nerve atrophy. This finding may provide further insight into the genotype-phenotype correlations for NDUFV1 gene.


Assuntos
Atrofia Óptica , Adolescente , Atrofia/patologia , Criança , Complexo I de Transporte de Elétrons , Feminino , Mutação da Fase de Leitura , Humanos , Mutação , Atrofia Óptica/genética , Atrofia Óptica/patologia , Nervo Óptico/diagnóstico por imagem , Nervo Óptico/patologia , Fenótipo
3.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070492

RESUMO

Inherited retinal dystrophies (IRDs) are rare but highly heterogeneous genetic disorders that affect individuals and families worldwide. However, given its wide variability, its analysis of the driver genes for over 50% of the cases remains unexplored. The present study aims to identify novel driver genes, disease-causing variants, and retinitis pigmentosa (RP)-associated pathways. Using family-based whole-exome sequencing (WES) to identify putative RP-causing rare variants, we identified a total of five potentially pathogenic variants located in genes OR56A5, OR52L1, CTSD, PRF1, KBTBD13, and ATP2B4. Of the variants present in all affected individuals, genes OR56A5, OR52L1, CTSD, KBTBD13, and ATP2B4 present as missense mutations, while PRF1 and CTSD present as frameshift variants. Sanger sequencing confirmed the presence of the novel pathogenic variant PRF1 (c.124_128del) that has not been reported previously. More causal-effect or evidence-based studies will be required to elucidate the precise roles of these SNPs in the RP pathogenesis. Taken together, our findings may allow us to explore the risk variants based on the sequencing data and upgrade the existing variant annotation database in Taiwan. It may help detect specific eye diseases such as retinitis pigmentosa in East Asia.


Assuntos
Catepsina D/genética , Predisposição Genética para Doença , Distrofias Retinianas/genética , Adulto , Idoso , Catepsina D/sangue , Feminino , Mutação da Fase de Leitura , Ontologia Genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Musculares/genética , Mutação de Sentido Incorreto , Linhagem , Perforina/genética , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Polimorfismo de Nucleotídeo Único , Mapas de Interação de Proteínas , Distrofias Retinianas/congênito , Distrofias Retinianas/patologia , Retinite Pigmentosa/congênito , Retinite Pigmentosa/diagnóstico por imagem , Retinite Pigmentosa/genética , Retinite Pigmentosa/patologia , Fatores de Risco , Tomografia de Coerência Óptica , Sequenciamento Completo do Exoma
4.
Biochim Biophys Acta Mol Basis Dis ; 1867(8): 166154, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: covidwho-1209165

RESUMO

BACKGROUND: Severe acute respiratory syndrome-2 (SARS-CoV-2) exhibits a broad spectrum of clinical manifestations. Despite the fact that SARS-CoV-2 has slower evolutionary rate than other coronaviruses, different mutational hotspots have been identified along the SARS-CoV-2 genome. METHODS: We performed whole-genome high throughput sequencing on isolates from 50 Egyptian patients to see if the variation in clinical symptoms was related to mutations in the SARS-CoV-2 genome. Then, we investigated the relationship between the observed mutations and the clinical characteristics of the patients. RESULTS: Among the 36 most common mutations, we found two frameshift deletions linked to an increased risk of shortness of breath, a V6 deletion in the spike glycoprotein's signal peptide region linked to an increased risk of fever, longer fever duration and nasal congestion, and L3606-nsp6 deletion linked to a higher prevalence of cough and conjunctival congestion. S5398L nsp13-helicase was linked to an increased risk of fever duration and progression. The most common mutations (241, 3037, 14,408, and 23,403) were not linked to clinical variability. However, the E3909G-nsp7 variant was more common in children (2-13 years old) and was associated with a shorter duration of symptoms. The duration of fever was significantly reduced with E1363D-nsp3 and E3073A-nsp4. CONCLUSIONS: The most common mutations, D614G/spike-glycoprotein and P4715L/RNA-dependent-RNA-polymerase, were linked to transmissibility regardless of symptom variability. E3909G-nsp7 could explain why children recover so quickly. Nsp6-L3606fs, spike-glycoprotein-V6fs, and nsp13-S5398L variants may be linked to clinical symptom worsening. These variations related to host-virus interactions might open new therapeutic avenues for symptom relief and disease containment.


Assuntos
COVID-19/virologia , Mutação , SARS-CoV-2/genética , Adolescente , Adulto , COVID-19/epidemiologia , COVID-19/patologia , Criança , Pré-Escolar , Egito/epidemiologia , Feminino , Mutação da Fase de Leitura , Genoma Viral , Humanos , Masculino , Pessoa de Meia-Idade , Deleção de Sequência , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/genética , Adulto Jovem
5.
Gene ; 790: 145698, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-33964374

RESUMO

Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive retinal dystrophy which is caused by the mutations of CYP4V2, usually progressing to legal blindness by the 5th or 6th decade of life. Here we identified CYP4V2 compound heterozygous mutations in two female siblings with BCD without subjective symptoms. After 381 pathogenic genes related to retinal diseases were screened by targeted sequence capture array techniques and confirmed by Sanger sequencing, two compound heterozygous mutations in CYP4V2 were found. One was missense mutation c.1198C>T (p.R400C) and the other was frameshift mutation c.802-8_810delinsGC (p.V268_E329del). Optical coherence tomography (OCT) showed that the ellipsoid zone was absent in the macular regions and electroretinogram (ERG) revealed poor cone and rod responses. Compound heterozygous mutations in CYP4V2 are related to the BCD. Our study expands our knowledge of heterogenic phenotypes and genotypes through genetic diagnosis of the BCD patients.


Assuntos
Distrofias Hereditárias da Córnea/patologia , Família 4 do Citocromo P450/genética , Mutação da Fase de Leitura , Mutação de Sentido Incorreto , Doenças Retinianas/patologia , Adulto , Distrofias Hereditárias da Córnea/genética , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Linhagem , Doenças Retinianas/genética
6.
BMC Bioinformatics ; 22(1): 251, 2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34000995

RESUMO

BACKGROUND: RNA viruses possess remarkable evolutionary versatility driven by the high mutability of their genomes. Frameshifting nucleotide insertions or deletions (indels), which cause the premature termination of proteins, are frequently observed in the coding sequences of various viral genomes. When a secondary indel occurs near the primary indel site, the open reading frame can be restored to produce functional proteins, a phenomenon known as the compensatory frameshift. RESULTS: In this study, we systematically analyzed publicly available viral genome sequences and identified compensatory frameshift events in hundreds of viral protein-coding sequences. Compensatory frameshift events resulted in large-scale amino acid differences between the compensatory frameshift form and the wild type even though their nucleotide sequences were almost identical. Phylogenetic analyses revealed that the evolutionary distance between proteins with and without a compensatory frameshift were significantly overestimated because amino acid mismatches caused by compensatory frameshifts were counted as substitutions. Further, this could cause compensatory frameshift forms to branch in different locations in the protein and nucleotide trees, which may obscure the correct interpretation of phylogenetic relationships between variant viruses. CONCLUSIONS: Our results imply that the compensatory frameshift is one of the mechanisms driving the rapid protein evolution of RNA viruses and potentially assisting their host-range expansion and adaptation.


Assuntos
Mutação da Fase de Leitura , Vírus de RNA , Sequência de Aminoácidos , Genoma Viral , Filogenia , RNA , Vírus de RNA/genética , RNA Viral
7.
Biochim Biophys Acta Mol Basis Dis ; 1867(8): 166154, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33932525

RESUMO

BACKGROUND: Severe acute respiratory syndrome-2 (SARS-CoV-2) exhibits a broad spectrum of clinical manifestations. Despite the fact that SARS-CoV-2 has slower evolutionary rate than other coronaviruses, different mutational hotspots have been identified along the SARS-CoV-2 genome. METHODS: We performed whole-genome high throughput sequencing on isolates from 50 Egyptian patients to see if the variation in clinical symptoms was related to mutations in the SARS-CoV-2 genome. Then, we investigated the relationship between the observed mutations and the clinical characteristics of the patients. RESULTS: Among the 36 most common mutations, we found two frameshift deletions linked to an increased risk of shortness of breath, a V6 deletion in the spike glycoprotein's signal peptide region linked to an increased risk of fever, longer fever duration and nasal congestion, and L3606-nsp6 deletion linked to a higher prevalence of cough and conjunctival congestion. S5398L nsp13-helicase was linked to an increased risk of fever duration and progression. The most common mutations (241, 3037, 14,408, and 23,403) were not linked to clinical variability. However, the E3909G-nsp7 variant was more common in children (2-13 years old) and was associated with a shorter duration of symptoms. The duration of fever was significantly reduced with E1363D-nsp3 and E3073A-nsp4. CONCLUSIONS: The most common mutations, D614G/spike-glycoprotein and P4715L/RNA-dependent-RNA-polymerase, were linked to transmissibility regardless of symptom variability. E3909G-nsp7 could explain why children recover so quickly. Nsp6-L3606fs, spike-glycoprotein-V6fs, and nsp13-S5398L variants may be linked to clinical symptom worsening. These variations related to host-virus interactions might open new therapeutic avenues for symptom relief and disease containment.


Assuntos
COVID-19/virologia , Mutação , SARS-CoV-2/genética , Adolescente , Adulto , COVID-19/epidemiologia , COVID-19/patologia , Criança , Pré-Escolar , Egito/epidemiologia , Feminino , Mutação da Fase de Leitura , Genoma Viral , Humanos , Masculino , Pessoa de Meia-Idade , Deleção de Sequência , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/genética , Adulto Jovem
8.
Arch Virol ; 166(7): 2059-2062, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33983504

RESUMO

China rose (Rosa chinensis Jacq.) is an important ornamental plant grown widely in China. In May 2019, we sampled and analyzed a China rose plant by high-throughput sequencing using small RNAs. A luteovirus, rose spring dwarf-associated virus (RSDaV), was detected in this plant, and its complete nucleotide sequence of 5816 nucleotides was determined. The China rose isolate of RSDaV contains five major open reading frames (ORFs) and three putative small ORFs, typical of members of the genus Luteovirus. It shares 94.4% nt sequence identity with the Californian (USA) isolate of the virus. Genomic analysis revealed a deletion of a single U at nt position 5295, which introduced a frameshift mutation, and an insertion of nine nucleotides (AUAAAUGAU) at position 5706-5714, which did not change the reading frame. The aa sequence in that portion of the protein was 90.5% identical to that of the Californian isolate. This is the first report on the occurrence of RSDaV infecting rose plants in China.


Assuntos
Genoma Viral/genética , Luteovirus/genética , Doenças das Plantas/virologia , Rosa/virologia , Sequência de Bases , China , Mutação da Fase de Leitura/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Fases de Leitura Aberta/genética , Filogenia , RNA Viral/genética
9.
Medicina (Kaunas) ; 57(3)2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33803538

RESUMO

Restrictive cardiomyopathy (RCM) is one of the rarest cardiac disorders, with a very poor prognosis, and heart transplantation is the only long-term treatment of choice. We reported that a Korean family presented different cardiomyopathies, such as idiopathic RCM and hypertrophic cardiomyopathy (HCM), caused by the same MYBPC3 mutation in different individuals. A 74-year-old male was admitted for the evaluation of exertional dyspnea, palpitations, and pitting edema in both legs for several months. Transthoracic echocardiography (TTE) showed RCM with biatrial enlargement and pericardial effusion. Cardiac magnetic resonance (CMR) images revealed normal left ventricular chamber size, borderline diffuse left ventricular hypertrophy and very large atria. In contrast to the proband, CMR images showed asymmetric septal hypertrophy of the left ventricle, consistent with a diagnosis of HCM in the proband's two daughters. Of the five heterozygous variants identified as candidate causes of inherited cardiomyopathy by whole exome sequencing in the proband, Sanger sequencing confirmed the presence of a heterozygous frameshift mutation (NM_000256.3:c.3313_3314insGG; p.Ala1105Glyfs*85) in MYBPC3 in the proband and his affected daughters, but not in his unaffected granddaughter. There is clinical and genetic overlap of HCM with restrictive physiology and RCM, especially when HCM is combined with severe myocardial fibrosis. Family screening with genetic testing and CMR imaging could be excellent tools for the evaluation of idiopathic RCM.


Assuntos
Cardiomiopatia Hipertrófica Familiar , Mutação da Fase de Leitura , Idoso , Proteínas de Transporte/genética , Humanos , Masculino , Mutação , Linhagem , Fenótipo , República da Coreia
10.
Am J Hematol ; 96(6): 698-707, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33761144

RESUMO

Myeloproliferative neoplasms (MPNs) are characterized by a pathologic expansion of myeloid lineages. Mutations in JAK2, CALR and MPL genes are known to be three prominent MPN disease drivers. Mutant CALR (mutCALR) is an oncoprotein that interacts with and activates the thrombopoietin receptor (MPL) and represents an attractive target for targeted therapy of CALR mutated MPN. We generated a transgenic murine model with conditional expression of the human mutant exon 9 (del52) from the murine endogenous Calr locus. These mice develop essential thrombocythemia like phenotype with marked thrombocytosis and megakaryocytosis. The disease exacerbates with age showing prominent signs of splenomegaly and anemia. The disease is transplantable and mutCALR stem cells show proliferative advantage when compared to wild type stem cells. Transcriptome profiling of hematopoietic stem cells revealed oncogenic and inflammatory gene expression signatures. To demonstrate the applicability of the transgenic animals for immunotherapy, we treated mice with monoclonal antibody raised against the human mutCALR. The antibody treatment lowered platelet and stem cell counts in mutant mice. Secretion of mutCALR did not constitute a significant antibody sink. This animal model not only recapitulates human MPN but also serves as a relevant model for testing immunotherapeutic strategies targeting epitopes of the human mutCALR.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Calreticulina/antagonistas & inibidores , Modelos Animais de Doenças , Células-Tronco Hematopoéticas/metabolismo , Terapia de Alvo Molecular , Trombocitemia Essencial/terapia , Animais , Anticorpos Monoclonais/imunologia , Plaquetas/imunologia , Plaquetas/metabolismo , Calreticulina/genética , Calreticulina/imunologia , Calreticulina/fisiologia , Éxons/genética , Mutação da Fase de Leitura , Técnicas de Introdução de Genes , Imunoterapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Quimera por Radiação , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Deleção de Sequência , Esplenomegalia/etiologia , Trombocitemia Essencial/sangue , Trombocitemia Essencial/complicações , Trombocitemia Essencial/genética , Transcriptoma
11.
Medicine (Baltimore) ; 100(12): e24804, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33761640

RESUMO

RATIONALE: The etiology of non-immune hydrops fetalis is complex, and its prognosis is poor. One of its main causes is anemia. There are few reports on hydrops fetalis due to anemia caused by hereditary spherocytosis (HS), especially regarding its occurrence in the neonatal period. Thus, we report on a case of neonatal HS caused by a new SPTB gene mutation that was characterized by hydrops fetalis. PATIENT CONCERNS: A neonate with intrauterine hydrops fetalis showed severe hyperbilirubinemia and anemia, reticulocytosis, and hepatosplenomegaly. Laboratory examination findings were normal. DIAGNOSES: Gene sequencing of the patient and his parents showed a de novo frameshift mutation in the patient's SPTB gene. Ultimately, the patient was diagnosed with HS. INTERVENTIONS: Exchange and red blood cell transfusions were performed in the neonatal period. OUTCOMES: The child was discharged from the hospital 14 days postnatal because his hemoglobin and bilirubin levels were stable. Red blood cell transfusion was performed once in infancy; however, no further red blood cell transfusions were required within 2 years of age. LESSONS: Hydrops fetalis can be a manifestation of HS. Genetic detection can help confirm the diagnosis of suspected neonatal HS undocumented by other laboratory examinations.


Assuntos
Hidropisia Fetal/genética , Espectrina/genética , Esferocitose Hereditária/diagnóstico , Análise Mutacional de DNA , Transfusão de Eritrócitos , Mutação da Fase de Leitura , Hemoglobinas/análise , Humanos , Hidropisia Fetal/sangue , Hidropisia Fetal/terapia , Recém-Nascido , Masculino , Esferocitose Hereditária/complicações , Esferocitose Hereditária/genética , Esferocitose Hereditária/terapia , Resultado do Tratamento
12.
Int J Mol Sci ; 22(5)2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33668121

RESUMO

The frameshift mutants K192Sfs*7 and R153Sfs*41, of the polyglutamine tract-binding protein 1 (PQBP-1), are stable intrinsically disordered proteins (IDPs). They are each associated with the severe cognitive disorder known as the Renpenning syndrome, a form of X-linked intellectual disability (XLID). Relative to the monomeric wild-type protein, these mutants are dimeric, contain more folded contents, and have higher thermal stabilities. Comparisons can be drawn to the toxic oligomerisation in the "conformational diseases", which collectively describe medical conditions involving a substantial protein structural transition in the pathogenic mechanism. At the molecular level, the end state of these diseases is often cytotoxic protein aggregation. The conformational disease proteins contain varying extents of intrinsic disorder, and the consensus pathogenesis includes an early oligomer formation. We reviewed the experimental characterisation of the toxic oligomers in representative cases. PQBP-1 mutant dimerisation was then compared to the oligomerisation of the conformational disease proteins. The PQBP-1 mutants are unique in behaving as stable soluble dimers, which do not further develop into higher oligomers or aggregates. The toxicity of the PQBP-1 mutant dimers lies in the native functions (in transcription regulation and possibly, RNA splicing) being compromised, rather than proceeding to aggregation. Other examples of stable IDP dimers were discussed and we speculated on the roles of IDP dimerisation in protein evolution.


Assuntos
Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Mutação da Fase de Leitura , Genes Ligados ao Cromossomo X , Deficiência Intelectual/patologia , Proteínas Mutantes/química , Proteínas de Ligação a DNA/metabolismo , Humanos , Deficiência Intelectual/genética , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Conformação Proteica , Multimerização Proteica , Splicing de RNA
13.
Genet Med ; 23(6): 1158-1162, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33531666

RESUMO

PURPOSE: The endoplasmic reticulum membrane complex (EMC) is a highly conserved, multifunctional 10-protein complex related to membrane protein biology. In seven families, we identified 13 individuals with highly overlapping phenotypes who harbor a single identical homozygous frameshift variant in EMC10. METHODS: Using exome, genome, and Sanger sequencing, a recurrent frameshift EMC10 variant was identified in affected individuals in an international cohort of consanguineous families. Multiple families were independently identified and connected via Matchmaker Exchange and internal databases. We assessed the effect of the frameshift variant on EMC10 RNA and protein expression and evaluated EMC10 expression in normal human brain tissue using immunohistochemistry. RESULTS: A homozygous variant EMC10 c.287delG (Refseq NM_206538.3, p.Gly96Alafs*9) segregated with affected individuals in each family, who exhibited a phenotypic spectrum of intellectual disability (ID) and global developmental delay (GDD), variable seizures and variable dysmorphic features (elongated face, curly hair, cubitus valgus, and arachnodactyly). The variant arose on two founder haplotypes and results in significantly reduced EMC10 RNA expression and an unstable truncated EMC10 protein. CONCLUSION: We propose that a homozygous loss-of-function variant in EMC10 causes a novel syndromic neurodevelopmental phenotype. Remarkably, the recurrent variant is likely the result of a hypermutable site and arose on distinct founder haplotypes.


Assuntos
Deficiências do Desenvolvimento , Deficiência Intelectual , Criança , Deficiências do Desenvolvimento/genética , Mutação da Fase de Leitura , Homozigoto , Humanos , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Linhagem , Fenótipo , Convulsões/genética
15.
Genet Test Mol Biomarkers ; 25(2): 145-151, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33596140

RESUMO

Aim: To detect mutations in the EXT1 and EXT2 genes in four Chinese families with hereditary multiple osteochondromas (HMO). HMO is an autosomal dominant disorder characterized by the overgrowth of multiple cartilage-capped bones in the metaphysis of long bones and flat bones. Methods: Polymerase chain reaction-based amplification followed by DNA sequencing of the complete coding sequences of EXT1 and EXT2 was performed for four Chinese families with HMO. Results: The mutant allele was found in six patients: three mutations were found in EXT1 and two in EXT2. A novel frameshift mutation, which generates a premature stop codon at codon 586 and causes partial loss of the glycosyltransferase domain, was detected in exon 9 of EXT1 (F579Yfs*8). We hypothesize that F579Yfs*8 is a pathogenic mutation. Two novel missense mutations (G339S and V545D) were found in EXT1. The variant c.1634T>A (V545D) is apparently benign. In addition we found a novel deletion mutation in EXT2, c.856_864 del TTCCTCCTG, which results in the deletion of 286Phe, 287Leu, and 288Leu, that is likely pathogenic. Finally, we identified a likely benign variant in exon 13 of EXT2. c.2035-41T>C (rs3740878). Conclusions: We found three novel, potentially pathogenic mutations in EXT1 and EXT2, including a novel frameshift mutation. More importantly, our study results have expanded the spectrum of EXT mutations conducive to the genetic diagnosis and counseling of patients with HMO.


Assuntos
Exostose Múltipla Hereditária/genética , N-Acetilglucosaminiltransferases/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Sequência de Bases/genética , Criança , Pré-Escolar , China , Éxons/genética , Exostose Múltipla Hereditária/metabolismo , Família , Feminino , Mutação da Fase de Leitura/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Mutação de Sentido Incorreto/genética , N-Acetilglucosaminiltransferases/metabolismo , Linhagem
16.
Artigo em Inglês | MEDLINE | ID: mdl-33538231

RESUMO

This study investigated the atopic march on the basis of genetics. This research detected 227 variants in the filaggrin gene (FLG gene). Missense, silent, non-sense, frame-shift and non-coding mutations were detected in exon 3 of the FLG gene in patients with bronchial asthma, atopic dermatitis, allergic rhinitis and mixed atopy. Missense mutation was detected at c.8343 G > C (p. Asp2781Glu) in all adult asthmatic and allergic rhinitis patients. Whereas, mutation at c.8360 C > T/A (p. Arg2787 His/Leu) was detected in all childhood asthmatic and mixed atopic patients. A non-coding mutation was detected at c.12365 in atopic dermatitis and bronchial asthma patients. Furthermore, DNA sequencing of asthmatic and mixed atopic patients showed missense mutations at c.6073 C > T (p. Gly2025Glu) and a silent mutation at c. 8341 G > A (p. Asp2781Asp).


Assuntos
Asma/genética , Dermatite Atópica/genética , Éxons/genética , Proteínas de Filamentos Intermediários/genética , Mutação , Rinite Alérgica/genética , Adulto , Códon sem Sentido , Feminino , Mutação da Fase de Leitura , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto
19.
Gene ; 778: 145464, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33524517

RESUMO

BACKGROUND: Hearing loss is the most common sensory disorder worldwide, affecting about 1 out of every 1000 newborns. The disease has major genetic components, and can be inherited as a single gene disorder either in autosomal dominant or recessive fashions. Due to the high rate of consanguineous unions, Iran has one of the highest prevalence of autosomal recessive nonsyndromic deafness (ARNSD) in the world. METHODS: We carried out a genetic screening of ten Iranian kindreds with more than one offspring affected by ARNSD caused by consanguineous unions. Sanger sequencing and whole exome sequencing together with in silico 3D structure modeling and protein stability prediction were used to identify the underlying disease causing genes. CONCLUSION: We identified the causes of deafness in all 10 kindred. In six kindreds homozygous mutations were identified in GJB2 gene by Sanger sequencing. By using whole exome sequencing (WES), a homozygous missense mutation was identified in ESRRB gene as the first ever reported disease gene in Iran. Also two novel homozygous frameshift and missense mutations were identified in MYO15A gene and one previously reported mutation in TMC1 gene in three independent kindred. Our study shows the efficacy of WES for unraveling new pathogenic mutations in ARNSD patients and expands the spectrum of genes contributing to ARNSD in the Iranian population. The findings of our study can facilitate future genetic screening of patients with ARNSD , early screening and optimal design of novel therapeutics.


Assuntos
Mutação da Fase de Leitura , Predisposição Genética para Doença/genética , Perda Auditiva/genética , Mutação de Sentido Incorreto , Conexina 26/química , Conexina 26/genética , Consanguinidade , Feminino , Homozigoto , Humanos , Irã (Geográfico) , Masculino , Proteínas de Membrana/química , Proteínas de Membrana/genética , Modelos Moleculares , Miosinas/química , Miosinas/genética , Linhagem , Estabilidade Proteica , Receptores de Estrogênio/química , Receptores de Estrogênio/genética , Sequenciamento Completo do Exoma
20.
Eur J Med Genet ; 64(3): 104144, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33486103

RESUMO

BACKGROUND: Mutations in NFKB1(nuclear factor of kappa light polypeptide gene enhancer in B-cells 1) are associated with a variety of clinical symptoms, including lymphadenopathy, splenomegaly, hepatomegaly, autoimmune haemolytic anaemia, arthralgia, recurrent respiratory tract infections and post-operative necrotizing cellulitis. CASE PRESENTATION: We describe a case of a 47-year-old man, who presented with deep necrotizing cellulitis after incision of a submucous abscess by a dentist. Surgical intervention led to a massive progress. Pyoderma gangraenosum (PG) was diagnosed clinically and confirmed histopathologically. High dose corticosteroids and intravenous immunoglobulins (IVIG) improved wound healing dramatically. Until now, immune mediated inflammation events not only affected the skin, but also multiple inner organs, i.e. the heart, lungs and gut. Sequencing of all coding exons of NFKB1 revealed a heterozygous 1bp deletion in exon 23 predicting a frameshift starting at codon Ala891 and resulting in a subsequent stop codon at position 6 in the new reading frame: NM_003998.4: c.2671del; p.(Ala891Glnfs*6) Acute episodes were always successfully treated with corticosteroids, IVIG and concomitant antibiotics. To prevent further exacerbations, the patient receives IVIG once a month, low-dose corticosteroids and methotrexate. CONCLUSION: This is the first case of a patient with recurrent necrotizing cellulitis and immune mediated multi-organ involvement (heart, lungs, intestine) carrying the novel frameshift mutation c.2671del (p.Ala891Glnfs*6) in NFKB1 effectively treated with IVIG, low-dose corticosteroids and methotrexate.


Assuntos
Doenças Autoimunes/genética , Celulite (Flegmão)/genética , Mutação da Fase de Leitura , Subunidade p50 de NF-kappa B/genética , Doenças da Imunodeficiência Primária/genética , Pioderma Gangrenoso/genética , Doenças Autoimunes/diagnóstico , Celulite (Flegmão)/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Doenças da Imunodeficiência Primária/diagnóstico , Pioderma Gangrenoso/diagnóstico , Síndrome
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