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1.
Mol Genet Genomic Med ; 7(5): e621, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30884204

RESUMO

BACKGROUND: X-linked myotubular myopathy (XLMTM) is a form of the severest congenital muscle diseases characterized by marked muscle weakness, hypotonia, and feeding and breathing difficulties in male infants. It is caused by mutations in the myotubularin gene (MTM1). METHODS: Evaluation of clinical history and examination of muscle pathology of three patients and comprehensive genome analysis on our original targeted gene panel system for muscular diseases. RESULTS: We report three patients, each of whom presents distinct muscle pathological features. The three patients have novel hemizygous MTM1 variants, including c.527A>G (p.Gln176Arg), c.595C>G (p.Pro199Ala), or c.688T>C (p.Trp230Arg). CONCLUSIONS: All variants were assessed as "Class 4 (likely pathogenic)" on the basis of the guideline of American College of Medical Genetics and Genomics. These distinct pathological features among the patients with variants in the second cluster of PTP domain in MTM1 provides an insight into microheterogeneities in disease phenotypes in XLMTM.


Assuntos
Mutação de Sentido Incorreto , Miopatias Congênitas Estruturais/genética , Proteínas Tirosina Fosfatases não Receptoras/genética , Adolescente , Criança , Hemizigoto , Humanos , Lactente , Recém-Nascido , Masculino , Miopatias Congênitas Estruturais/patologia , Proteínas Tirosina Fosfatases não Receptoras/química , Proteínas Tirosina Fosfatases não Receptoras/metabolismo
2.
Cancer Invest ; 37(1): 46-65, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30599775

RESUMO

The c-Myb gene encodes a transcription factor that regulates cell proliferation, differentiation, and apoptosis through protein-protein interaction and transcriptional regulation of signaling pathways. The protein is frequently overexpressed in human leukemias, breast cancers, and other solid tumors suggesting that it is a bona fide oncogene. c-MYB is often overexpressed by translocation in human tumors with t(6;7)(q23;q34) resulting in c-MYB-TCRß in T cell ALL, t(X;6)(p11;q23) with c-MYB-GATA1 in acute basophilic leukemia, and t(6;9)(q22-23;p23-24) with c-MYB-NF1B in adenoid cystic carcinoma. Antisense oligonucleotides to c-MYB were developed to purge bone marrow cells to eliminate tumor cells in leukemias. Recently, small molecules that inhibit c-MYB activity have been developed to disrupt its interaction with p300. The Dmp1 (cyclin D binding myb-like protein 1; Dmtf1) gene was isolated through its virtue for binding to cyclin D2. It is a transcription factor that has a Myb-like repeat for DNA binding. The Dmtf1 protein directly binds to the Arf promoter for transactivation and physically interacts with p53 to activate the p53 pathway. The gene is hemizygously deleted in 35-42% of human cancers and is associated with longer survival. The significances of aberrant expression of c-MYB and DMTF1 proteins in human cancers and their clinical significances are discussed.


Assuntos
Fatores de Ribosilação do ADP/genética , Neoplasias/genética , Proteínas Proto-Oncogênicas c-myb/genética , Fatores de Transcrição/genética , Regulação Neoplásica da Expressão Gênica , Hemizigoto , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-myb/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Análise de Sobrevida , Fatores de Transcrição/metabolismo , Translocação Genética , Regulação para Cima
3.
J Mol Neurosci ; 67(3): 418-423, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30618027

RESUMO

In this report, we described a large Han-Chinese family which presents with various phenotypes from unaffected to manifested nystagmus in females. Infantile nystagmus (IN) is characterized by bilateral, involuntary, and periodic eyeball oscillation, occurring at birth or within the first 6 months. The most common inheritance pattern of IN is an X-linked form with incomplete penetrance among females, and the FERM domain containing 7 gene (FRMD7) is a main disease-causing gene. A combination of exome sequencing and Sanger sequencing, as well as detailed clinical examinations were performed on the Chinese IN family. An FRMD7 c.47T>C (p.Phe16Ser) variant was proposed as the disease-causing variant. Incomplete penetrance was found in females with the FRMD7 c.47T>C variant, and hemizygous male affected subjects presented more severe manifestations compared to heterozygous female affected subjects. These findings could enhance genetic counseling and antenatal diagnosis of IN.


Assuntos
Proteínas do Citoesqueleto/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Proteínas de Membrana/genética , Nistagmo Congênito/genética , Polimorfismo de Nucleotídeo Único , Adulto , Proteínas do Citoesqueleto/química , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Hemizigoto , Humanos , Masculino , Proteínas de Membrana/química , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Nistagmo Congênito/patologia , Linhagem , Penetrância
4.
Mol Med Rep ; 19(3): 1716-1720, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30628680

RESUMO

Endometriosis is an enigmatic condition with an unknown etiology and a poorly understood pathogenesis. It is considered to appear from the interplay of many genetic and environmental factors, affecting up to 10% of women and represents a major cause of pain and infertility. The familial association of endometriosis, as demonstrated through monozygotic twin and family studies suggests a genetic contribution to the disease, with further case­control and genome­wide association studies (GWAS) detecting various endometriosis risk factors. In a recent study, we described a unique, three­generation family of Cretan origin (Greece) with 7 females with surgically confirmed endometriosis (grandmother, 3 daughters and 3 granddaughters). All the affected members of this family displayed a variety of clinical manifestations and complications. In the present study, to further analyze the genetic variants conferring the risk of developing endometriosis, whole exome sequencing (WES) was performed, using the AmpliSeq technology on the Ion Proton platform. An initial analysis of 64 variants that were detected across the 14 genes previously confirmed to be associated with endometriosis, did not identify any deleterious exonic variants in these genes. However, further analysis revealed 2 hemizygous deletions in the grandmother that segregate in several of her affected offspring. The first deletion was found in the UGT2B28 locus, spanning 7 informative sequence variants across at least 14 kb. The second deletion, located in USP17L2, spans 3 informative variants across at least 2 kb. On the whole, the findings of the presents study implicate 2 additional genes in the pathogenesis of endometriosis, apart from those already identified by GWAS.


Assuntos
Endometriose/genética , Endopeptidases/genética , Glucuronosiltransferase/genética , Deleção de Sequência/genética , Adulto , Endometriose/fisiopatologia , Endometriose/cirurgia , Exoma/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Hemizigoto , Humanos , Pessoa de Meia-Idade , Mutação , Linhagem , Sequenciamento Completo do Exoma
5.
Int J Mol Sci ; 20(3)2019 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-30691124

RESUMO

Kidney injury due to focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disorder causing end-stage renal disease. Homozygous mutations in either glomerular basement membrane or slit diaphragm genes cause early renal failure. Heterozygous carriers develop renal symptoms late, if at all. In contrast to mutations in slit diaphragm genes, hetero- or hemizygous mutations in the X-chromosomal COL4A5 Alport gene have not yet been recognized as a major cause of kidney injury by FSGS. We identified cases of FSGS that were unexpectedly diagnosed: In addition to mutations in the X-chromosomal COL4A5 type IV collagen gene, nephrin and podocin polymorphisms aggravated kidney damage, leading to FSGS with ruptures of the basement membrane in a toddler and early renal failure in heterozygous girls. The results of our case series study suggest a synergistic role for genes encoding basement membrane and slit diaphragm proteins as a cause of kidney injury due to FSGS. Our results demonstrate that the molecular genetics of different players in the glomerular filtration barrier can be used to evaluate causes of kidney injury. Given the high frequency of X-chromosomal carriers of Alport genes, the analysis of genes involved in the organization of podocyte architecture, the glomerular basement membrane, and the slit diaphragm will further improve our understanding of the pathogenesis of FSGS and guide prognosis of and therapy for hereditary glomerular kidney diseases.


Assuntos
Lesão Renal Aguda/etiologia , Colágeno Tipo IV/genética , Glomerulosclerose Segmentar e Focal/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Nefrite Hereditária/genética , Polimorfismo de Nucleotídeo Único , Lesão Renal Aguda/genética , Adulto , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Glomerulosclerose Segmentar e Focal/complicações , Hemizigoto , Heterozigoto , Humanos , Lactente , Masculino , Mutação , Linhagem
6.
EBioMedicine ; 39: 422-435, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30555043

RESUMO

BACKGROUND: Progression of Alzheimer's disease is thought initially to depend on rising amyloidß and its synaptic interactions. Transgenic mice (TASTPM; APPSwe/PSEN1M146V) show altered synaptic transmission, compatible with increased physiological function of amyloidß, before plaques are detected. Recently, the importance of microglia has become apparent in the human disease. Similarly, TASTPM show a close association of plaque load with upregulated microglial genes. METHODS: CA1 synaptic transmission and plasticity were investigated using in vitro electrophysiology. Microglial relationship to plaques was examined with immunohistochemistry. Behaviour was assessed with a forced-alternation T-maze, open field, light/dark box and elevated plus maze. FINDINGS: The most striking finding is the increase in microglial numbers in TASTPM, which, like synaptic changes, begins before plaques are detected. Further increases and a reactive phenotype occur later, concurrent with development of larger plaques. Long-term potentiation is initially enhanced at pre-plaque stages but decrements with the initial appearance of plaques. Finally, despite altered plasticity, TASTPM have little cognitive deficit, even with a heavy plaque load, although they show altered non-cognitive behaviours. INTERPRETATION: The pre-plaque synaptic changes and microglial proliferation are presumably related to low, non-toxic amyloidß levels in the general neuropil and not directly associated with plaques. However, as plaques grow, microglia proliferate further, clustering around plaques and becoming phagocytic. Like in humans, even when plaque load is heavy, without development of neurofibrillary tangles and neurodegeneration, these alterations do not result in cognitive deficits. Behaviours are seen that could be consistent with pre-diagnosis changes in the human condition. FUNDING: GlaxoSmithKline; BBSRC; UCL; ARUK; MRC.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Cognição/fisiologia , Hipocampo/fisiologia , Microglia/fisiologia , Presenilina-1/genética , Animais , Comportamento Animal , Modelos Animais de Doenças , Hemizigoto , Hipocampo/metabolismo , Humanos , Masculino , Aprendizagem em Labirinto , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , Transmissão Sináptica
7.
Toxicol Pathol ; 47(1): 82-92, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30585133

RESUMO

The 6-month Tg.rasH2 mouse carcinogenicity model provides an acceptable alternative to the 2-year carcinogenicity study in CD-1 mice. However, key questions related to the use of this model for testing antisense oligonucleotides (ASOs) include the similarity in the biologic response between mouse strains and the feasibility of using data from the CD-1 mouse to set doses and dose schedules for a Tg.rasH2 carcinogenicity study. To evaluate the potential strain differences, four distinct 2'- O-(2-methoxyethyl) ASOs were administered to CByB6F1 (wild type), Tg.rasH2 (hemizygous), and CD-1 mice. There were no meaningful differences in clinical signs, body weight, food consumption, or serum chemistry and hematology parameters. Histopathology evaluation indicated little to no difference in the spectrum or magnitude of changes present. The cytokine/chemokine response was also not appreciably different between the strains. This was consistent with the similarity in ASO concentration in the liver between the mouse strains tested. As the class effects of the ASOs were not meaningfully different between CD-1, CByB6F1, or Tg.rasH2 mice, data from nonclinical studies in CD-1 mice can be used for dose selection and expectation of effect in the Tg.rasH2 mouse.


Assuntos
Carcinógenos/toxicidade , Genes ras , Oligonucleotídeos Antissenso/toxicidade , Oligorribonucleotídeos/toxicidade , Testes de Toxicidade , Animais , Sequência de Bases , Carcinógenos/classificação , Carcinógenos/farmacocinética , Citocinas/sangue , Feminino , Hemizigoto , Masculino , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Oligonucleotídeos Antissenso/classificação , Oligonucleotídeos Antissenso/farmacocinética , Oligorribonucleotídeos/classificação , Oligorribonucleotídeos/farmacocinética , Tamanho do Órgão/efeitos dos fármacos , Especificidade de Órgãos , Especificidade da Espécie , Fatores de Tempo , Distribuição Tecidual , Testes de Toxicidade/métodos , Testes de Toxicidade/normas
8.
Proc Natl Acad Sci U S A ; 115(40): 10172-10177, 2018 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-30232263

RESUMO

Alzheimer's disease (AD), the most common form of dementia, is characterized by the abnormal accumulation of amyloid plaques and hyperphosphorylated tau aggregates, as well as microgliosis. Hemizygous missense variants in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) are associated with elevated risk for developing late-onset AD. These variants are hypothesized to result in loss of function, mimicking TREM2 haploinsufficiency. However, the consequences of TREM2 haploinsufficiency on tau pathology and microglial function remain unknown. We report the effects of partial and complete loss of TREM2 on microglial function and tau-associated deficits. In vivo imaging revealed that microglia from aged TREM2-haploinsufficient mice show a greater impairment in their injury response compared with microglia from aged TREM2-KO mice. In transgenic mice expressing mutant human tau, TREM2 haploinsufficiency, but not complete loss of TREM2, increased tau pathology. In addition, whereas complete TREM2 deficiency protected against tau-mediated microglial activation and atrophy, TREM2 haploinsufficiency elevated expression of proinflammatory markers and exacerbated atrophy at a late stage of disease. The differential effects of partial and complete loss of TREM2 on microglial function and tau pathology provide important insights into the critical role of TREM2 in AD pathogenesis.


Assuntos
Doença de Alzheimer , Haploinsuficiência , Hemizigoto , Glicoproteínas de Membrana , Microglia/metabolismo , Mutação de Sentido Incorreto , Receptores Imunológicos , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Microglia/patologia , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo
9.
Genome Biol ; 19(1): 106, 2018 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-30086769

RESUMO

BACKGROUND: CTCF binding to DNA helps partition the mammalian genome into discrete structural and regulatory domains. Complete removal of CTCF from mammalian cells causes catastrophic genome dysregulation, likely due to widespread collapse of 3D chromatin looping and alterations to inter- and intra-TAD interactions within the nucleus. In contrast, Ctcf hemizygous mice with lifelong reduction of CTCF expression are viable, albeit with increased cancer incidence. Here, we exploit chronic Ctcf hemizygosity to reveal its homeostatic roles in maintaining genome function and integrity. RESULTS: We find that Ctcf hemizygous cells show modest but robust changes in almost a thousand sites of genomic CTCF occupancy; these are enriched for lower affinity binding events with weaker evolutionary conservation across the mouse lineage. Furthermore, we observe dysregulation of the expression of several hundred genes, which are concentrated in cancer-related pathways, and are caused by changes in transcriptional regulation. Chromatin structure is preserved but some loop interactions are destabilized; these are often found around differentially expressed genes and their enhancers. Importantly, the transcriptional alterations identified in vitro are recapitulated in mouse tumors and also in human cancers. CONCLUSIONS: This multi-dimensional genomic and epigenomic profiling of a Ctcf hemizygous mouse model system shows that chronic depletion of CTCF dysregulates steady-state gene expression by subtly altering transcriptional regulation, changes which can also be observed in primary tumors.


Assuntos
Neoplasias da Mama/genética , Fator de Ligação a CCCTC/genética , Cromatina/química , DNA de Neoplasias/genética , Regulação Neoplásica da Expressão Gênica , Genoma , Neoplasias Hepáticas Experimentais/genética , Neoplasias Uterinas/genética , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Fator de Ligação a CCCTC/deficiência , Linhagem Celular , Cromatina/metabolismo , DNA de Neoplasias/metabolismo , Elementos Facilitadores Genéticos , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Hemizigoto , Homeostase , Humanos , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ligação Proteica , Transdução de Sinais , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia
10.
J Hum Genet ; 63(7): 847-850, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29717186

RESUMO

Intellectual disability (ID) and autism spectrum disorders are complex neurodevelopmental disorders occurring among all ethnic and socioeconomic groups. Pathogenic variants in the neurite extension and migration factor (NEXMIF) gene (formerly named KIAA2022) on the X chromosome are responsible for ID, autistic behavior, epilepsy, or dysmorphic features in males. Most affected females described had a milder phenotype or were asymptomatic obligate carriers. We report here for the first time mother-to-son transmission of a novel NEXMIF truncating variant without X-inactivation skewing in the blood. Truncating gene variant leads to symptomatic mother to severely affected son transmission. Our findings emphasize that NEXMIF sequencing should be strongly considered in patients with unexplained autism spectrum disorder, ID, and epilepsy, irrespective of gender. Such testing could increase our knowledge of the pathogenicity of NEXMIF variants and improve genetic counseling.


Assuntos
Transtorno do Espectro Autista/genética , Sequência de Bases , Epilepsia/genética , Deficiência Intelectual/genética , Proteínas do Tecido Nervoso/genética , Deleção de Sequência , Adulto , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/fisiopatologia , Criança , Epilepsia/diagnóstico , Epilepsia/fisiopatologia , Feminino , Expressão Gênica , Hemizigoto , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/fisiopatologia , Masculino , Herança Materna , Linhagem , Índice de Gravidade de Doença , Inativação do Cromossomo X
11.
Genet Sel Evol ; 50(1): 7, 2018 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-29566646

RESUMO

BACKGROUND: Sex-linked slow (SF) and fast (FF) feathering rates at hatch have been widely used in poultry breeding for autosexing at hatch. In chicken, the sex-linked K (SF) and k+ (FF) alleles are responsible for the feathering rate phenotype. Allele K is dominant and a partial duplication of the prolactin receptor gene has been identified as the causal mutation. Interestingly, some domesticated turkey lines exhibit similar slow- and fast-feathering phenotypes, but the underlying genetic components and causal mutation have never been investigated. In this study, our aim was to investigate the molecular basis of feathering rate at hatch in domestic turkey. RESULTS: We performed a sequence-based case-control association study and detected a genomic region on chromosome Z, which is statistically associated with rate of feathering at hatch in turkey. We identified a 5-bp frameshift deletion in the prolactin receptor (PRLR) gene that is responsible for slow feathering at hatch. All female cases (SF turkeys) were hemizygous for this deletion, while 188 controls (FF turkeys) were hemizygous or homozygous for the reference allele. This frameshift mutation introduces a premature stop codon and six novel amino acids (AA), which results in a truncated PRLR protein that lacks 98 C-terminal AA. CONCLUSIONS: We present the causal mutation for feathering rate in turkey that causes a partial C-terminal loss of the prolactin receptor, and this truncated PRLR protein is strikingly similar to the protein encoded by the slow feathering K allele in chicken.


Assuntos
Galinhas/genética , Mutação da Fase de Leitura , Receptores da Prolactina/genética , Análise de Sequência de DNA/veterinária , Perus/genética , Alelos , Sequência de Aminoácidos , Animais , Galinhas/metabolismo , Duplicação Cromossômica , Plumas , Feminino , Estudos de Associação Genética/veterinária , Hemizigoto , Masculino , Fenótipo , Receptores da Prolactina/metabolismo , Perus/metabolismo
12.
Eur J Haematol ; 100(3): 294-303, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29240263

RESUMO

BACKGROUND: Medicines that exert oxidative pressure on red blood cells (RBC) can cause severe hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Due to X-chromosome inactivation, females heterozygous for G6PD with 1 allele encoding a G6PD-deficient protein and the other a normal protein produce 2 RBC populations each expressing exclusively 1 allele. The G6PD mosaic is not captured with routine G6PD tests. METHODS: An open-source software tool for G6PD cytofluorometric data interpretation is described. The tool interprets data in terms of % bright RBC, or cells with normal G6PD activity in specimens collected from 2 geographically and ethnically distinct populations, an African American cohort (USA) and a Karen and Burman ethnic cohort (Thailand) comprising 242 specimens including 89 heterozygous females. RESULTS: The tool allowed comparison of data across 2 laboratories and both populations. Hemizygous normal or deficient males and homozygous normal or deficient females cluster at narrow % bright cells with mean values of 96%, or 6% (males) and 97%, or 2% (females), respectively. Heterozygous females show a distribution of 10-85% bright cells and a mean of 50%. The distributions are associated with the severity of the G6PD mutation. CONCLUSIONS: Consistent cytofluorometric G6PD analysis facilitates interlaboratory comparison of cellular G6PD profiles and contributes to understanding primaquine-associated hemolytic risk.


Assuntos
Antimaláricos/efeitos adversos , Eritrócitos/efeitos dos fármacos , Deficiência de Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/genética , Mosaicismo , Mutação , Primaquina/efeitos adversos , Afro-Americanos , Alelos , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Contraindicações de Medicamentos , Eritrócitos/enzimologia , Eritrócitos/patologia , Feminino , Citometria de Fluxo/métodos , Regulação da Expressão Gênica , Glucosefosfato Desidrogenase/metabolismo , Deficiência de Glucosefosfato Desidrogenase/enzimologia , Deficiência de Glucosefosfato Desidrogenase/etnologia , Deficiência de Glucosefosfato Desidrogenase/patologia , Hemizigoto , Heterozigoto , Humanos , Masculino , Índice de Gravidade de Doença , Software , Tailândia , Estados Unidos
13.
Mol Vis ; 24: 847-852, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30713423

RESUMO

Purpose: To identify the genetic variation in two unrelated probands with congenital cataract and to perform functional analysis of the detected variants. Methods: Clinical examination and phenotyping, segregation, and functional analysis were performed for the two studied pedigrees. Results: A novel OCRL gene variant (c.1964A>T, p. (Asp655Val)) was identified. This variant causes defects in OCRL protein folding and mislocalization to the cytoplasm. In addition, the variant's location close to the Rab binding site is likely to be associated with membrane targeting abnormalities. Conclusions: The results highlight the importance of early genetic diagnosis in infants with congenital cataract and show that mutations in the OCRL gene can present as apparently isolated congenital cataract.


Assuntos
Catarata/genética , Síndrome Oculocerebrorrenal/genética , Monoéster Fosfórico Hidrolases/genética , Mutação Puntual , Proteínas rab de Ligação ao GTP/genética , Substituição de Aminoácidos , Sítios de Ligação , Catarata/congênito , Catarata/metabolismo , Catarata/patologia , Criança , Expressão Gênica , Hemizigoto , Humanos , Masculino , Síndrome Oculocerebrorrenal/metabolismo , Síndrome Oculocerebrorrenal/patologia , Linhagem , Fenótipo , Monoéster Fosfórico Hidrolases/química , Monoéster Fosfórico Hidrolases/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Dobramento de Proteína , Domínios e Motivos de Interação entre Proteínas , Proteínas rab de Ligação ao GTP/química , Proteínas rab de Ligação ao GTP/metabolismo
14.
Pediatr Hematol Oncol ; 34(5): 286-291, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29200320

RESUMO

BACKGROUND: The Wiskott-Aldrich syndrome (WAS) is X-linked recessive disorder associated with microplatelet thrombocytopenia, eczema, infections, and an increased risk of autoimmunity and lymphoid neoplasia. The originally described features of WAS include susceptibility to infections, microthrombocytopenia, and eczema. AIM: In this case report, we present our experience about two cases diagnosed with a new mutation. METHODS: We report phenotypical and laboratory description of two cases with WAS. RESULTS: We, for the first time, detected a new hemizygote mutation of WAS gene (NM_000377.2 p.M393lfs*102 (c.1178dupT)) in two patients. The first case was an 11-month-old boy presenting with complaints of recurrent soft tissue infection, ear infection, anemia, and thrombocytopenia with a low platelet volume. The second case was a 2-month-old boy presenting with thrombocytopenia and a low platelet volume. Both cases were the first-degree relatives: they were cousins and their mothers were sisters. CONCLUSION: Herein, we report two cases of WAS and a new gene mutation which would disrupt the WAS protein function within the Polyproline (PPP) domain. This report adds to the growing number of mutations which cause complex clinical manifestations associated with WAS.


Assuntos
Hemizigoto , Mutação , Proteína da Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/genética , Humanos , Lactente , Masculino , Domínios Proteicos , Síndrome de Wiskott-Aldrich/patologia
15.
Fetal Pediatr Pathol ; 36(6): 432-436, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29206494

RESUMO

INTRODUCTION AND AIMS: Androgen insensitivity syndrome (AIS) is an X-linked recessive genetic disorder caused by mutations in the androgen receptor (AR) gene. Only a few cases of AIS with AR gene mutations have been diagnosed prenatally. This study aimed to investigate the gene mutation in a Chinese complete androgen insensitivity syndrome family and perform prenatal diagnosis for twin fetuses. CASE REPORT: We evaluated the AR gene of the child proband in a Chinese CAIS family, and detected a novel mutation c.3864T>C (p. Phe917Leu). Amniocentesis was performed when the mother presented to our hospital with a subsequent twin pregnancy. Mutation analysis revealed that both fetuses were hemizygous for this mutation. The aborted fetuses had typical female external genitalia and bilateral testes in abdomen. CONCLUSION: The c.3864T>C AR novel mutation is responsible for complete androgen insensitivity syndrome, and its identification was subsequently used for a subsequent successful prenatal diagnosis.


Assuntos
Síndrome de Resistência a Andrógenos/genética , Doenças em Gêmeos , Mutação , Diagnóstico Pré-Natal , Fatores de Transcrição/genética , Amniocentese , China , Análise Mutacional de DNA , Feminino , Hemizigoto , Humanos , Cariotipagem , Masculino , Linhagem , Fenótipo , Gravidez , Gravidez de Gêmeos
16.
Brain ; 140(12): 3139-3152, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29136088

RESUMO

Cerebral X-linked adrenoleukodystrophy is a devastating neurodegenerative disorder caused by mutations in the ABCD1 gene, which lead to a rapidly progressive cerebral inflammatory demyelination in up to 60% of affected males. Selective brain endothelial dysfunction and increased permeability of the blood-brain barrier suggest that white matter microvascular dysfunction contributes to the conversion to cerebral disease. Applying a vascular model to conventional dynamic susceptibility contrast magnetic resonance perfusion imaging, we demonstrate that lack of ABCD1 function causes increased capillary flow heterogeneity in asymptomatic hemizygotes predominantly in the white matter regions and developmental stages with the highest probability for conversion to cerebral disease. In subjects with ongoing inflammatory demyelination we observed a sequence of increased capillary flow heterogeneity followed by blood-brain barrier permeability changes in the perilesional white matter, which predicts lesion progression. These white matter microvascular alterations normalize within 1 year after treatment with haematopoietic stem cell transplantation. For the first time in vivo, our studies unveil a model to assess how ABCD1 alters white matter microvascular function and explores its potential as an earlier biomarker for monitoring disease progression and response to treatment.


Assuntos
Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP/genética , Adrenoleucodistrofia/diagnóstico por imagem , Microcirculação , Substância Branca/irrigação sanguínea , Adolescente , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/terapia , Doenças Assintomáticas , Barreira Hematoencefálica/metabolismo , Estudos de Casos e Controles , Circulação Cerebrovascular , Criança , Pré-Escolar , Transplante de Células-Tronco Hematopoéticas , Hemizigoto , Humanos , Angiografia por Ressonância Magnética , Imagem por Ressonância Magnética , Masculino , Mutação , Permeabilidade , Substância Branca/diagnóstico por imagem , Adulto Jovem
17.
J Clin Immunol ; 37(8): 801-810, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28993958

RESUMO

Hypomorphic IKBKG mutations in males are typically associated with anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID). Some mutations cause immunodeficiency without EDA (NEMO-ID). The immunological profile associated with these NEMO-ID variants is not fully documented. We present a 2-year-old patient with suspected immunodeficiency in which a hemizygous p.Glu57Lys IKBKG variant was identified. At the age of 1 year, he had an episode of otitis media that evolved into a bilateral mastoiditis (Pseudomonas spp). Hypogammaglobulinemia, specific (polysaccharide) antibody deficiency, and low switched memory B cell subsets were noticed. The mother was heterozygous for the variant but had no signs of incontinentia pigmenti. Patient peripheral blood mononuclear cells produced low amounts of IL-6 after stimulation with IL-1ß, Pam3CSK4, and FSL-1. In patient fibroblasts, IκB-α was degraded normally upon stimulation with IL-1ß or TNF-α. Transduction of wild-type and variant NEMO in NEMO-/- deficient SV40 fibroblasts revealed a slight but significant reduction of IL-6 production upon stimulation with IL-1ß and TNF-α. In conclusion, we demonstrated that p.Glu57Lys leads to specific immunological defects in vitro. No other pathogenic PID variants were identified through whole exome sequencing. As rare polymorphisms have been described in IKBKG and polygenic inheritance remains an option in the presented case, this study emphasizes the need for thorough functional and genetic evaluation when encountering and interpreting suspected disease-causing NEMO-ID variants.


Assuntos
Imunodeficiência de Variável Comum/genética , Displasia Ectodérmica/genética , Fibroblastos/fisiologia , Quinase I-kappa B/genética , Mutação/genética , Infecções por Pseudomonas/diagnóstico , Pseudomonas/fisiologia , Agamaglobulinemia , Células Cultivadas , Pré-Escolar , Imunodeficiência de Variável Comum/diagnóstico , Displasia Ectodérmica/diagnóstico , Hemizigoto , Humanos , Quinase I-kappa B/metabolismo , Interleucina-6/metabolismo , Masculino , Mastoidite , Otite , Polimorfismo Genético
18.
JAMA Neurol ; 74(12): 1464-1472, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29059326

RESUMO

Importance: Accumulation of the protein tau is a defining characteristic of several neurodegenerative diseases. Thorough assessment of transgenic (Tg) mouse lines that replicate this process is critical for establishing the models used for testing anti-tau therapeutics in vivo. Objective: To define a consistent mouse model of disease for use in future compound efficacy studies. Design, Setting, and Participants: In this time course study, cohorts of Tg and control mice were euthanized at defined intervals. Collected brains were bisected down the midline. One half was frozen and used to measure the tau prion content, while the other half was fixed for immunostaining with anti-tau antibodies. All mice were maintained at the Hunters Point Animal Facility at the University of California, San Francisco, and all experiments were performed at the Mission Bay Campus of the University of California, San Francisco. Study animals were PS19, homozygous and hemizygous Tg(MAPT*P301S), and B6/J mice. The study dates were August 9, 2010, to October 3, 2016. Main Outcomes and Measures: Tau prions were measured using a cell-based assay. Neuropathology was measured by determining the percentage area positive for immunostaining in defined brain regions. A separate cohort of mice was aged until each mouse developed neurological signs as determined by trained animal technicians to assess mortality. Results: A total of 1035 mice were used in this time course study. These included PS19 mice (51.2% [126 of 246] male and 48.8% [120 of 246] female), Tg(MAPT*P301S+/+) mice (52.3% [216 of 413] male, 43.8% [181 of 413] female, and 3.9% [16 of 413] undetermined), Tg(MAPT*P301S+/-) mice (51.8% [101 of 195] male and 48.2% [94 of 195] female), and B6/J mice (49.7% [90 of 181] male and 50.3% [91 of 181] female). While considerable interanimal variability in neuropathology, disease onset, and tau prion formation in the PS19 mice was observed, all 3 measures of disease were more uniform in the Tg(MAPT*P301S+/+) mice. Comparing tau prion formation in Tg(MAPT*P301S+/+) mice with B6/J controls, the 95% CIs for the 2 mouse lines diverged before age 5 weeks, and significant (P < .05) neuropathology in the hindbrain of 24-week-old mice was quantifiable. Conclusions and Relevance: The assessment of disease progression using 3 criteria showed that disease onset in PS19 mice is too variable to obtain reliable measurements for drug discovery research. However, the reproducibility of tau prion formation in young Tg(MAPT*P301S+/+) mice establishes a rapid assay for compound efficacy in vivo.


Assuntos
Encéfalo/metabolismo , Modelos Animais de Doenças , Camundongos , Príons/metabolismo , Tauopatias/genética , Proteínas tau/genética , Animais , Feminino , Hemizigoto , Homozigoto , Humanos , Cinética , Masculino , Camundongos Transgênicos , Mutação , Reprodutibilidade dos Testes , Tauopatias/metabolismo , Proteínas tau/metabolismo
19.
Cytogenet Genome Res ; 152(3): 111-116, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28877528

RESUMO

We described a 5-year-old male with hypodontia, hypohidrosis, and facial dysmorphisms characterized by a depressed nasal bridge, maxillary hypoplasia, and protuberant lips. Chromosomal analysis revealed a normal 46,XY male karyotype. Due to the presence of clinical features of hypohidrotic ectodermal dysplasia (HED), the EDA gene, located at Xq12q13.1, of the patient and his family was sequenced. Analysis of the proband's sequence revealed a missense mutation (T to A transversion) in hemizygosity state at nucleotide position 158 in exon 1 of the EDA gene, which changes codon 53 from leucine to histidine, while heterozygosity at this position was detected in the slightly affected mother; moreover, this mutation was not found in the publically available Human Gene Mutation Database. To date, our findings indicate that a novel mutation in EDA is associated with X-linked HED, adding it to the repertoire of EDA mutations.


Assuntos
Displasia Ectodérmica Anidrótica Tipo 1/genética , Ectodisplasinas/genética , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Anodontia/genética , Anodontia/patologia , Pré-Escolar , Códon , Análise Mutacional de DNA , Displasia Ectodérmica Anidrótica Tipo 1/patologia , Feminino , Genes Ligados ao Cromossomo X , Hemizigoto , Heterozigoto , Histidina/genética , Humanos , Hipo-Hidrose/genética , Hipo-Hidrose/patologia , Leucina/genética , Lábio/anormalidades , Masculino , Maxila/anormalidades , Osso Nasal/anormalidades
20.
Genome Biol Evol ; 9(9): 2461-2476, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28961969

RESUMO

Many animals with genetic sex determination harbor heteromorphic sex chromosomes, where the heterogametic sex has half the gene dose of the homogametic sex. This imbalance, if reflected in the abundance of transcripts or proteins, has the potential to deleteriously disrupt interactions between X-linked and autosomal loci in the heterogametic sex. Classical theory predicts that molecular mechanisms will evolve to provide dosage compensation that recovers expression levels comparable to ancestral expression prior to sex chromosome divergence. Such dosage compensating mechanisms may also, secondarily, result in balanced sex-linked gene expression between males and females. However, numerous recent studies addressing sex chromosome dosage compensation (SCDC) in a diversity of animals have yielded a surprising array of patterns concerning dosage compensation in the heterogametic sex, as well as dosage balance between sexes. These results substantially contradict longstanding theory, catalyzing both novel perspectives and new approaches in dosage compensation research. In this review, we summarize the theory, analytical approaches, and recent results concerning evolutionary patterns of SCDC in animals. We also discuss methodological challenges and discrepancies encountered in this research, which often underlie conflicting results. Finally, we discuss what outstanding questions and opportunities exist for future research on SCDC.


Assuntos
Compensação de Dosagem (Genética) , Evolução Molecular , Cromossomos Sexuais/genética , Animais , Feminino , Hemizigoto , Masculino
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