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1.
Medicine (Baltimore) ; 98(42): e17594, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626133

RESUMO

RATIONALE: Idiopathic pulmonary arterial hypertension (IPAH) is characterized by intense remodeling of small pulmonary arteries. Loss-of-function mutation of bone morphogenetic protein receptor II (BMPR2) gene and exaggerated activation of transforming growth factor (TGF)-ß signaling play a critical role in this process. PATIENT CONCERNS AND DIAGNOSIS: We report a novel frameshift mutation (c.117InsT, p.Y40fsX48) of the BMPR2 gene identified in a 19-year-old IPAH patient with syncope. Despite BMPR2 mutation, the phosphorylation of Smad2/3 and Samd1/5/8 was increased in the patient's peripheral blood mononuclear cells, and this event was accompanied by the upregulation of bone morphogenetic protein (BMP) signaling target genes, but not TGF-ß signaling target genes. Moreover, we observed an increased expression of other BMPRs, that is, anti-Mullerian hormone type-2 receptor and the activin receptor-like kinases (ALK) 1, ALK3, and ALK6. INTERVENTIONS AND OUTCOMES: The patient was prescribed a combination of macitentan, sildenafil, and nifedipine, which successfully controlled her symptom of syncope and normalized N-terminal pro-brain natriuretic peptide level after 3 months of medication. LESSONS: In light of these results, we propose a new pathogenetic mechanism for IPAH, based on enhanced BMP signaling via the functional replacement of mutated BMPR2 by other BMP receptors.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Proteínas Morfogenéticas Ósseas/genética , DNA/genética , Hipertensão Pulmonar Primária Familiar/genética , Mutação da Fase de Leitura , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Análise Mutacional de DNA , Hipertensão Pulmonar Primária Familiar/metabolismo , Feminino , Humanos , Transdução de Sinais , Adulto Jovem
2.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(10): 993-995, 2019 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-31598943

RESUMO

OBJECTIVE: To explore the genetic etiology of a pedigree affected with tricho-rhino-phalangeal syndrome. METHODS: Next-generation sequencing (NGS) using a gene panel for hereditary osteopathies was carried out for the proband. Suspected mutation was validated in the proband and her parents by Sanger sequencing. RESULTS: A heterozygous frameshift variation c.1995dupA (p.Gly666Argfs*20) of the TRPS1 gene was detected in the proband but not in her parents. CONCLUSION: The novel c.1995dupA (p.Gly666Argfs*20) mutation of the TRPS1 gene probably underlies the disease in the proband.


Assuntos
Proteínas de Ligação a DNA/genética , Dedos/anormalidades , Mutação da Fase de Leitura , Doenças do Cabelo/genética , Síndrome de Langer-Giedion/genética , Nariz/anormalidades , Fatores de Transcrição/genética , Feminino , Humanos , Linhagem
3.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(10): 1019-1021, 2019 Oct 10.
Artigo em Chinês | MEDLINE | ID: mdl-31598950

RESUMO

OBJECTIVE: To identify pathogenic mutation of TSC1 and TSC2 genes in a patient with long-time misdiagnosis of epilepsy. METHODS: Peripheral blood samples and clinical data of the patient and her 2 parents were collected. Potential mutation of TSC1 and TSC2 genes were detected by direct sequencing. RESULTS: The patient had frequent episodes of epilepsy in addition with Shagreen patches for 10 years. A frame-shifting mutation c.2509_2512delAACA was detected in exon 20 of the TSC1 gene. This same mutation was not found in her unaffected parents. CONCLUSION: The recurrent frame-shifting mutation c.2509_2512delAACA (p.Asn837ValfsX11) of the TSC1 gene probably underlies the disease in this patient.


Assuntos
Epilepsia/diagnóstico , Epilepsia/genética , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/genética , Erros de Diagnóstico , Feminino , Mutação da Fase de Leitura , Humanos , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética
4.
J Cancer Res Clin Oncol ; 145(12): 2891-2899, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31617076

RESUMO

PURPOSE: Microsatellites are widely distributed repetitive DNA motifs, accounting for approximately 3% of the genome. Due to mismatch repair system deficiency, insertion or deletion of repetitive units often occurs, leading to microsatellite instability. In this review, we aimed to explore the relationship between MSI and biological behaviour of colorectal carcinoma, gastric carcinoma, lymphoma/leukaemia and endometrial carcinoma, as well as the application of frameshift peptide vaccines in cancer therapy. METHODS: The relevant literature from PubMed and Baidu Xueshu were reviewed in this article. The ClinicalTrials.gov database was searched for clinical trials related to the specific topic. RESULTS: Microsatellite instability is divided into three subtypes: high-level, low-level microsatellite instability, and stable microsatellites. The majority of tumour patients with high-level microsatellite instability often show a better efficacy and prognosis than those with low-level microsatellite instability or stable microsatellites. In coding regions, especially for genes involved in tumourigenesis, microsatellite instability often results in inactivation of proteins and contributes to tumourigenesis. Moreover, the occurrence of microsatellite instability in coding regions can also cause the generation of frameshift peptides that are thought to be unknown and novel to the individual immune system. Thus, these frameshift peptides have the potential to be biomarkers to raise tumour-specific immune responses. CONCLUSION: MSI has the potential to become a key predictor for evaluating the degree of malignancy, efficacy and prognosis of tumours. Clinically, MSI patterns will provide more valuable information for clinicians to create optimal individualized treatment strategies based on frameshift peptides vaccines.


Assuntos
Mutação da Fase de Leitura/genética , Repetições de Microssatélites/genética , Neoplasias/genética , Animais , Carcinogênese/genética , Ensaios Clínicos como Assunto , Reparo de Erro de Pareamento de DNA/genética , Humanos , Instabilidade de Microssatélites , Prognóstico
5.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(8): 757-760, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31400121

RESUMO

OBJECTIVE: To identify pathogenic variations of EXT1 and EXT2 genes in two Chinese pedigrees affected with hereditary multiple exostosis (HME). METHODS: Genomic DNA was extracted from peripheral blood samples using a phenol-chloroform method. PCR and Sanger sequencing was conducted to amplify the exons and the flanking intronic regions of the EXT1 and EXT2 genes. RESULTS: DNA sequencing has revealed a heterozygous missense variation c.812A>G (p.Tyr271Cys) in the exon 1 of EXT1 in pedigree 1, and a heterozygous frameshift variation c.1431dup (p.Ser478Leufs*43) in the exon 6 of EXT1 in the proband from pedigree 2. Both variations have co-segregated with the disease phenotype, which was also consistent with previous report. CONCLUSION: Two heterozygous pathogenic variations underlying HME have been identified. The result has facilitated genetic counseling and prenatal diagnosis for the affected pedigrees.


Assuntos
Exostose Múltipla Hereditária/genética , N-Acetilglucosaminiltransferases/genética , Grupo com Ancestrais do Continente Asiático , Sequência de Bases , Análise Mutacional de DNA , Exostose Múltipla Hereditária/patologia , Mutação da Fase de Leitura , Humanos , Mutação de Sentido Incorreto , Linhagem
6.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(8): 834-836, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31400140

RESUMO

OBJECTIVE: To explore the clinical features and mutations of the TRPM6 gene in an infant featuring hypomagnesemia and secondary hypocalcemia. METHODS: Clinical data of the patient was collected. Genomic DNA was extracted from peripheral blood samples from the patient and her parents. Targeted exome sequencing was carried out to screen the potential mutations. Suspected mutations were verified by Sanger sequencing. RESULTS: A novel homozygous c.5538delA (p.Q1846Qfs*2) mutation in the TRPM6 gene was identified in the proband, for which both of her parents were heterozygous carriers. CONCLUSION: The homozygous frameshift mutation of TRPM6 gene (c.5538delA) probably underlies the disease in the proband. The finding has expanded the mutation spectrum of TRPM6 gene.


Assuntos
Hipocalcemia/genética , Deficiência de Magnésio/congênito , Canais de Cátion TRPM/genética , Análise Mutacional de DNA , Feminino , Mutação da Fase de Leitura , Humanos , Lactente , Deficiência de Magnésio/genética
7.
Medicine (Baltimore) ; 98(33): e16899, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415434

RESUMO

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive multisystem disorder characterized by oculocutaneous albinism (OCA) and bleeding diathesis, although it displays both genetic and phenotypic heterogeneity. Several genetic subtypes of HPS have been identified in human; however, the characterizations of HPS type 4 (HPS-4) genotype and phenotype remain unclear. This study was aimed to identify gene mutation responsible for HPS-4 with pulmonary fibrosis (PF).Two Chinese siblings in their 50 s afflicted with OCA and progressive dyspnea were recruited and underwent clinical and genetic examinations. In both patients, chest high-resolution computerized tomography showed severe interstitial PF in bilateral lung fields, and the pulmonary function test indicated restrictive lung disease. A novel homozygous frameshift mutation (NM_022081: c.630dupC; p.A211fs) in the HPS4 gene was identified by whole-exome sequencing analysis followed by Sanger DNA sequencing, and it segregated with the phenotypes. The c.630dupC mutation was not found in unaffected healthy controls. The patients were considered as HPS-4 with interstitial PF and eventually died of respiratory failure.This is the first report on the genotype and clinical phenotype of HPS-4 in China. Our results demonstrate the association between a novel frameshift mutation in HPS4 and severe PF with poor prognosis in HPS is presented.


Assuntos
Mutação da Fase de Leitura , Síndrome de Hermanski-Pudlak/genética , Fibrose Pulmonar Idiopática/genética , Proteínas/genética , Adulto , China , Testes Genéticos , Humanos , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA , Irmãos
8.
Nat Commun ; 10(1): 3086, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300655

RESUMO

Mammalian fertilisation begins when sperm interacts with the egg zona pellucida (ZP), whose ZP1 subunit is important for fertility by covalently cross-linking ZP filaments into a three-dimensional matrix. Like ZP4, a structurally-related component absent in the mouse, ZP1 is predicted to contain an N-terminal ZP-N domain of unknown function. Here we report a characterisation of ZP1 proteins carrying mutations from infertile patients, which suggests that, in human, filament cross-linking by ZP1 is crucial to form a stable ZP. We map the function of ZP1 to its ZP-N1 domain and determine crystal structures of ZP-N1 homodimers from a chicken homolog of ZP1. These reveal that ZP filament cross-linking is highly plastic and can be modulated by ZP1 fucosylation and, potentially, zinc sparks. Moreover, we show that ZP4 ZP-N1 forms non-covalent homodimers in chicken but not in human. Together, these data identify human ZP1 cross-links as a promising target for non-hormonal contraception.


Assuntos
Infertilidade Feminina/genética , Domínios Proteicos/fisiologia , Glicoproteínas da Zona Pelúcida/metabolismo , Zona Pelúcida/metabolismo , Animais , Galinhas , Cristalografia por Raios X , Feminino , Fertilização/fisiologia , Mutação da Fase de Leitura , Humanos , Simulação de Dinâmica Molecular , Multimerização Proteica , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/ultraestrutura , Alinhamento de Sequência , Glicoproteínas da Zona Pelúcida/genética , Glicoproteínas da Zona Pelúcida/isolamento & purificação , Glicoproteínas da Zona Pelúcida/ultraestrutura
10.
Gene ; 715: 143957, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31276734

RESUMO

MPIG6B has orthologous physiological effects in human and mice, which regulates platelet production and function. For this reason, germline loss-of-function mutations in this gene cause congenital thrombocytopenia that is associated with bone marrow fibrosis, organomegaly and subsequent anemia. This was described in a consanguineous Arabian family with a novel truncation mutation (p.C108*) in chromosome 6, open reading frame 25 gene, also known as MPIG6B. In our case, we identified a homozygous frameshift variation (c.392delC,p.P134Lfs*10) in a ten-month-old boy presenting with signs of pallor, splenomegaly and resistant hemocytopenia. Interestingly, this is a new form of a MPIG6B variation, which could disrupt the effector protein for the key hematopoiesis regulators. This report adds to the growing number of mutations causing complex clinical manifestations associated with pancytopenia and splenomegaly in children.


Assuntos
Cromossomos Humanos Par 6/genética , Mutação da Fase de Leitura , Fases de Leitura Aberta , Pancitopenia/genética , Esplenomegalia/genética , Grupo com Ancestrais do Continente Asiático , Humanos , Lactente , Masculino , Pancitopenia/patologia , Esplenomegalia/patologia
11.
J Dermatol ; 46(8): 731-733, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31241787

RESUMO

Hypohidrotic ectodermal dysplasia (HED) is a rare hereditary disorder that affects tissues derived from the ectoderm including hair, teeth and sweat glands. EDA is the major causative gene of HED. This study recruited a Chinese family with HED, including a male proband and his mother with a fetus. The proband had typical clinical features of HED and the mother had identical but milder features. Interestingly, some phenotypes of the mother appeared asymmetrically between the right and left side of the body that were not reported in previous studies. Targeted sequencing was performed in the proband and a novel frame-shift mutation (NM_001399.4: c.381_382delinsG, p.Q128Rfs*9) in EDA was found. Sanger sequencing validated the mutation and identified the same mutation in the mother. Our study expands the clinical and genetic spectrum of EDA-related disorders and reports new asymmetrical phenotypes in a female.


Assuntos
Displasia Ectodérmica Anidrótica Tipo 1/genética , Ectodisplasinas/genética , Genes Ligados ao Cromossomo X/genética , Fenótipo , Adulto , Criança , Análise Mutacional de DNA , Displasia Ectodérmica Anidrótica Tipo 1/diagnóstico , Feminino , Mutação da Fase de Leitura , Aconselhamento Genético , Hemizigoto , Heterozigoto , Humanos , Masculino
12.
Hum Genet ; 138(10): 1071-1075, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31175426

RESUMO

While the importance of tight junctions in hearing is well established, the role of Claudin- 9 (CLDN9), a tight junction protein, in human hearing and deafness has not been explored. Through whole-genome sequencing, we identified a one base pair deletion (c.86delT) in CLDN9 in a consanguineous family from Turkey with autosomal recessive nonsyndromic hearing loss. Three affected members of the family had sensorineural hearing loss (SNHL) ranging from moderate to profound in severity. The variant is predicted to cause a frameshift and produce a truncated protein (p.Leu29ArgfsTer4) in this single-exon gene. It is absent in public databases as well as in over 1000 Turkish individuals, and co-segregates with SNHL in the family. Our in vitro studies demonstrate that the mutant protein does not localize to cell membrane as demonstrated for the wild-type protein. Mice-lacking Cldn9 have been shown to develop SNHL. We conclude that CLDN9 is essential for proper audition in humans and its disruption leads to SNHL in humans.


Assuntos
Claudinas/genética , Surdez/diagnóstico , Surdez/genética , Genes Recessivos , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Claudinas/química , Claudinas/metabolismo , Biologia Computacional/métodos , Análise Mutacional de DNA , Feminino , Mutação da Fase de Leitura , Humanos , Mutação , Linhagem , Polimorfismo Genético , Transporte Proteico , Turquia , Sequenciamento Completo do Genoma
13.
BMC Med Genet ; 20(1): 105, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31185933

RESUMO

BACKGROUND: Axenfeld-Rieger syndrome (ARS) is an autosomal dominant genetic disorder that is characterized by specific abnormalities of the anterior segment of the eye. Heterozygous mutations in two developmental transcription factor genes PITX2 and FOXC1 have been identified within ARS patients, accounting for 40 to 70% of cases. Our purpose is to describe clinical and genetic findings in a Chinese family with ARS. METHODS: An ARS family with three affected members was recruited. The patients underwent a series of complete ophthalmologic examinations, general physical examination and dental radiography. DNA samples of proband II-1 were used for targeted exome sequencing of the FOXC1 and PITX2 genes. Sanger sequencing was used to validate the variation in PITX2. Quantitative real-time PCR was carried out to detect the expression of PITX2 in patients and normal controls. RESULTS: All affected members showed iris atrophy, corectopia, shallow anterior chamber, complete or partial angle closure, and advanced glaucoma. In addition, they revealed systemic anomalies, including microdontia, hypodontia, and redundant periumbilical skin. A novel heterozygous frameshift variation, c.515delA, in PITX2 was found in the proband, which might lead to a truncated PITX2 protein (p.Gln172ArgfsX36). Sanger sequencing validated that the variation completely cosegregated with the ARS phenotype among this family, but was absent in 100 unrelated controls. Quantitative real-time PCR analysis revealed that the mRNA expression of PITX2 was significantly decreased in patients compared with that in unrelated normal controls. CONCLUSIONS: PITX2 c.515delA (p.Gln172ArgfsX36) was the genetic etiology of our pedigree. The mutation led to decreased PITX2 gene expression and a truncated mRNA transcript.


Assuntos
Segmento Anterior do Olho/anormalidades , Anormalidades do Olho/genética , Oftalmopatias Hereditárias/genética , Mutação da Fase de Leitura , Predisposição Genética para Doença/genética , Proteínas de Homeodomínio/genética , Fatores de Transcrição/genética , Sequenciamento Completo do Exoma/métodos , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático , China , Anormalidades do Olho/etnologia , Oftalmopatias Hereditárias/etnologia , Saúde da Família , Feminino , Predisposição Genética para Doença/etnologia , Humanos , Masculino , Linhagem , Adulto Jovem
14.
Biochem Mol Biol Educ ; 47(5): 573-580, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31225941

RESUMO

The CRISPR/Cas9 system is a powerful tool for gene editing and it has become increasingly important for biology students to understand this emerging technique. Most CRISPR laboratory teaching modules use complex metazoan systems or mammalian cell culture which can be expensive. Here, we present a lab module that engages students in learning the fundamentals of CRISPR/Cas9 methodology using the simple and inexpensive model system, Saccharomyces cerevisiae. Students use CRISPR/Cas9 and nonhomologous end joining to generate frameshift insertion and deletion mutations in the CAN1 gene, which are easily selected for using media plates that have canavanine. DNA sequencing is also performed to determine what type of mutation occurred in gene-edited cells. This easy to implement set of experiments has been run as both a 5-week and a shorter 3-week lab module. Learning assessments demonstrate increased understanding in CRISPR-related concepts as well as increased confidence using molecular techniques. Thus, this CRISPR/Cas9 lab module can be added to an existing Genetics, Microbiology, or Molecular Biology lab course to help undergraduate students learn current gene editing techniques with limited effort and cost. © 2019 International Union of Biochemistry and Molecular Biology, 47(5):573-580, 2019.


Assuntos
Sistemas CRISPR-Cas/genética , Mutação da Fase de Leitura/genética , Laboratórios , Saccharomyces cerevisiae/genética , Humanos , Aprendizagem , Estudantes , Universidades
15.
Genet Test Mol Biomarkers ; 23(6): 423-427, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31063410

RESUMO

Aim: The aim of this study was to report a novel POU Class 3 Homeobox 4 (POU3F4) variant and to provide further guidance on genetic counseling for incomplete partition (IP) type III families in the Korean population by showing two new contrasting cases in terms of genotypes and inheritance. Materials and Methods: Two consecutively recruited hearing-impaired probands with seemingly nonsyndromic features and their biological mothers were included in this study. Sanger sequencing and quantitative polymerase chain reaction (PCR) assays were performed for POU3F4. Results: A novel frameshift variant of POU3F4, c.852delC (p.Ile285Serfs*3), was identified in one of the patients. This mutation is predicted to truncate the protein within the POU homeodomain, resulting in the complete loss of the last nucleus localization signal. The proband's biological mother was also shown to be a carrier of this c.852delC (p.Ile285Serfs*3) mutant allele. A de novo genomic deletion on chromosome Xq21.2 was confirmed in another subject via quantitative PCR. This subject's biological mother, however, was not a carrier of this deletion. This indicates that the large upstream deletion of POU3F4 in the second proband occurred de novo. This finding is compatible with the previously proposed tendency for a high de novo rate of large genomic deletions involving the X-linked deafness-2 (DFNX2) locus. Conclusion: This study adds a novel, probably pathogenic POU3F4 truncation variant to the literature and provides guidance toward effective genetic counseling for IP III subjects based on more frequent de novo occurrence of POU3F4 deletions than POU3F4 point variants.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/genética , Perda Auditiva Neurossensorial/genética , Fatores do Domínio POU/genética , Adulto , Criança , Surdez/genética , Família , Feminino , Mutação da Fase de Leitura/genética , Aconselhamento Genético/métodos , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Genótipo , Perda Auditiva/genética , Perda Auditiva Neurossensorial/metabolismo , Humanos , Masculino , Mutação , Linhagem , República da Coreia
16.
Int J Mol Sci ; 20(10)2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-31130602

RESUMO

Leaf blade width, curvature, and cuticular wax are important agronomic traits of rice. Here, we report the rice Oschr4-5 mutant characterized by pleiotropic phenotypes, including narrow and rolled leaves, enhanced cuticular wax deposition and reduced plant height and tiller number. The reduced leaf width is caused by a reduced number of longitudinal veins and increased auxin content. The cuticular wax content was significantly higher in the Oschr4-5 mutant, resulting in reduced water loss rate and enhanced drought tolerance. Molecular characterization reveals that a single-base deletion results in a frame-shift mutation from the second chromodomain of OsCHR4, a CHD3 (chromodomain helicase DNA-binding) family chromatin remodeler, in the Oschr4-5 mutant. Expressions of seven wax biosynthesis genes (GL1-4, WSL4, OsCER7, LACS2, LACS7, ROC4 and BDG) and four auxin biosynthesis genes (YUC2, YUC3, YUC5 and YUC6) was up-regulated in the Oschr4-5 mutant. Chromatin immunoprecipitation assays revealed that the transcriptionally active histone modification H3K4me3 was increased, whereas the repressive H3K27me3 was reduced in the upregulated genes in the Oschr4-5 mutant. Therefore, OsCHR4 regulates leaf morphogenesis and cuticle wax formation by epigenetic modulation of auxin and wax biosynthetic genes expression.


Assuntos
DNA Helicases/genética , Regulação da Expressão Gênica de Plantas , Oryza/genética , Proteínas de Plantas/genética , Plantas Geneticamente Modificadas/genética , Montagem e Desmontagem da Cromatina , Secas , Epigênese Genética , Mutação da Fase de Leitura , Oryza/fisiologia , Oryza/ultraestrutura , Fenótipo , Folhas de Planta/genética , Folhas de Planta/fisiologia , Folhas de Planta/ultraestrutura , Plantas Geneticamente Modificadas/fisiologia , Plantas Geneticamente Modificadas/ultraestrutura , Estresse Fisiológico , Ceras/análise , Ceras/metabolismo
17.
Cytogenet Genome Res ; 158(1): 1-9, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31129666

RESUMO

X-linked hypohidrotic ectodermal dysplasia (XLHED; OMIM 305100) is the most common form of ectodermal dysplasia, presenting with the triad of hypotrichosis, hypodontia, and hypohidrosis. This disorder is caused by mutations in EDA, which encodes ectodysplasin A, a member of the tumor necrosis factor superfamily. In this study, we describe clinical and genetic characteristics of 10 Korean XLHED patients (9 males, 1 female) from 9 families. Nine out of the 10 patients manifested the cardinal triad of symptoms. Six patients had a positive family history, while 2 patients were brothers. The most common initial presentation was hypotrichosis or hypodontia, while 1 patient presented with recurrent high fever in early infancy. Sanger sequencing of the EDA gene was performed and revealed 9 different mutations. Three had been reported previously, and 6 were novel mutations. One female patient, carrying a previously reported missense mutation, might be affected by skewed X-inactivation. This is the first observational study investigating genetically confirmed XLHED patients in Korea. To provide appropriate supportive care and genetic counseling, clinicians should consider the possibility of XLHED in the differential diagnosis of recurrent fever in infants, as well as recognize the typical triad of symptoms.


Assuntos
Displasia Ectodérmica Anidrótica Tipo 1/genética , Ectodisplasinas/genética , Mutação , Adolescente , Substituição de Aminoácidos , Criança , Pré-Escolar , Displasia Ectodérmica Anidrótica Tipo 1/etnologia , Ectodisplasinas/química , Feminino , Mutação da Fase de Leitura , Estudos de Associação Genética , Triagem de Portadores Genéticos , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , Linhagem , República da Coreia/epidemiologia
18.
PLoS Genet ; 15(5): e1008130, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31048900

RESUMO

Nanophthalmos is a rare, potentially devastating eye condition characterized by small eyes with relatively normal anatomy, a high hyperopic refractive error, and frequent association with angle closure glaucoma and vision loss. The condition constitutes the extreme of hyperopia or farsightedness, a common refractive error that is associated with strabismus and amblyopia in children. NNO1 was the first mapped nanophthalmos locus. We used combined pooled exome sequencing and strong linkage data in the large family used to map this locus to identify a canonical splice site alteration upstream of the last exon of the gene encoding myelin regulatory factor (MYRF c.3376-1G>A), a membrane bound transcription factor that undergoes autoproteolytic cleavage for nuclear localization. This variant produced a stable RNA transcript, leading to a frameshift mutation p.Gly1126Valfs*31 in the C-terminus of the protein. In addition, we identified an early truncating MYRF frameshift mutation, c.769dupC (p.S264QfsX74), in a patient with extreme axial hyperopia and syndromic features. Myrf conditional knockout mice (CKO) developed depigmentation of the retinal pigment epithelium (RPE) and retinal degeneration supporting a role of this gene in retinal and RPE development. Furthermore, we demonstrated the reduced expression of Tmem98, another known nanophthalmos gene, in Myrf CKO mice, and the physical interaction of MYRF with TMEM98. Our study establishes MYRF as a nanophthalmos gene and uncovers a new pathway for eye growth and development.


Assuntos
Glaucoma de Ângulo Fechado/genética , Hiperopia/genética , Proteínas de Membrana/genética , Microftalmia/genética , Degeneração Retiniana/genética , Fatores de Transcrição/genética , Adulto , Animais , Criança , Pré-Escolar , Éxons , Família , Feminino , Mutação da Fase de Leitura/genética , Variação Genética/genética , Glaucoma de Ângulo Fechado/metabolismo , Humanos , Hiperopia/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microftalmia/metabolismo , Pessoa de Meia-Idade , Linhagem , Sítios de Splice de RNA/genética , Erros de Refração/genética , Fatores de Transcrição/metabolismo
19.
Orphanet J Rare Dis ; 14(1): 109, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31092259

RESUMO

OBJECTIVE: The importance of late-onset cobalamin C (cblC) disorder is underestimated in adults. Improved awareness on its clinical and neuroimaging features helps timely diagnosis and appropriate treatment. METHODS: Totally 16 late-onset cblC cases were diagnosed based on clinical, biochemical findings and MMAHC gene mutation analysis. Clinical presentations, neuroimaging features and mutational spectrum were reviewed. RESULTS: The case series included 10 males and 6 females, with average age of 22 (range 13-40) years. All the 16 patients displayed bilateral pyramidal tract signs, and most of the cases (13) had cognitive impairment. Other symptoms included psychiatric symptoms (6), epilepsy (6), peripheral nerve damage (5), ocular symptoms (4) and lower-limb thrombosis (1). The neuroimaging findings were dominated by cerebral atrophy (11/16), followed by white matter lesions (4), cerebellar lesions/atrophy (2) and spinal cord lesions (1). There were also 2 patients with normal imaging. All the MMACHC mutations were compound heterozygous, of which the most and second frequent was c.482G > A (p.R161Q; 15/16 case; allele frequency: 46.88%) and c.609G > A(p.W203X; 6/16 case; allele frequency: 18.75%). In addition, patients carrying frameshift mutations (deletion/duplication) presented more frequently with psychiatric symptoms (57.1%) and optic nerve damages (42.9%) than those carrying point mutations (22.2 and 11.1%, respectively). In contrast, peripheral nerve (44.4%) and white matter lesions (33.3%) were more frequently identified in point mutation- carriers. However, the differences did not achieve statistical significance (all p > 0.05). CONCLUSION: Compared to the early-onset form, late-onset cblC displayed some clinical, neuroimaging and mutational profiles, which warrants particular attention in adult neurologic practice. These findings not only broaden our insights into the genotypes and phenotypes of the disease, but highlight the importance of early diagnosis and initiation of appropriate treatments.


Assuntos
Neuroimagem/métodos , Deficiência de Vitamina B 12/diagnóstico por imagem , Deficiência de Vitamina B 12/genética , Adolescente , Adulto , Proteínas de Transporte , Feminino , Mutação da Fase de Leitura , Testes Genéticos , Heterozigoto , Humanos , Transtornos de Início Tardio , Masculino , Mutação , Fenótipo , Vitamina B 12/sangue , Deficiência de Vitamina B 12/sangue , Adulto Jovem
20.
Cell Physiol Biochem ; 52(5): 970-983, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30977983

RESUMO

BACKGROUND/AIMS: Regulation of mRNA translation is central to protein homeostasis and is optimized for speed and accuracy. Spontaneous recoding events occur virtually at any codon but at very low frequency and are commonly assumed to increase as the cell ages. METHODS: Here, we leveraged the polyglutamine(polyQ)-frameshifting model of huntingtin exon 1 with CAG repeat length in the pathological range (Htt51Q), which undergoes enhanced non-programmed translational -1 frameshifting. RESULTS: In body muscle cells of Caenorhabditis elegans, -1 frameshifting occured at the onset of expression of the zero-frame product, correlated with mRNA level of the non-frameshifted expression and formed aggregates correlated with reduced motility in C. elegans. Spontaneous frameshifting was modulated by IFG-1, the homologue of the nutrient-responsive eukaryotic initiation factor 4G (eIF4G), under normal growth conditions and NSUN-5, a conserved ribosomal RNA methyltransferase, under osmotic stress. CONCLUSION: Our results suggest that frameshifting and aggregation occur at even early stages of development and, because of their intrinsic stability, may persist and accelerate the onset of age-related proteinopathies.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Mutação da Fase de Leitura , Proteína Huntingtina , Doença de Huntington , Expansão das Repetições de Trinucleotídeos , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animais de Doenças , Éxons , Humanos , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/genética , Doença de Huntington/metabolismo , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/metabolismo
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