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1.
Cell Mol Life Sci ; 76(10): 1935-1945, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30830238

RESUMO

Rab18 is one of the small number of conserved Rab proteins which have been traced to the last eukaryotic common ancestor. It is found in organisms ranging from humans to trypanosomes, and localizes to multiple organelles, including most notably endoplasmic reticulum and lipid droplets. In humans, absence of Rab18 leads to a severe illness known as Warburg-Micro syndrome. Despite this evidence that Rab18 is essential, its role in cells remains mysterious. However, recent studies identifying effectors and interactors of Rab18, are now shedding light on its mechanism of action, suggesting functions related to organelle tethering and to autophagy. In this review, we examine the variety of roles proposed for Rab18 with a focus on new evidence giving insights into the molecular mechanisms it utilizes. Based on this summary of our current understanding, we identify priority areas for further research.


Assuntos
Retículo Endoplasmático/metabolismo , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos , Proteínas rab de Ligação ao GTP/metabolismo , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Animais , Autofagia/genética , Catarata/congênito , Catarata/genética , Catarata/metabolismo , Córnea/anormalidades , Córnea/metabolismo , Humanos , Hipogonadismo/genética , Hipogonadismo/metabolismo , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Microcefalia/genética , Microcefalia/metabolismo , Modelos Biológicos , Mutação , Atrofia Óptica/genética , Atrofia Óptica/metabolismo , Proteínas rab de Ligação ao GTP/genética
2.
Nat Rev Genet ; 20(5): 299-309, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30760854

RESUMO

Many recent advances have emerged in the telomere and telomerase fields. This Timeline article highlights the key advances that have expanded our views on the mechanistic underpinnings of telomeres and telomerase and their roles in ageing and disease. Three decades ago, the classic view was that telomeres protected the natural ends of linear chromosomes and that telomerase was a specific telomere-terminal transferase necessary for the replication of chromosome ends in single-celled organisms. While this concept is still correct, many diverse fields associated with telomeres and telomerase have substantially matured. These areas include the discovery of most of the key molecular components of telomerase, implications for limits to cellular replication, identification and characterization of human genetic disorders that result in premature telomere shortening, the concept that inhibiting telomerase might be a successful therapeutic strategy and roles for telomeres in regulating gene expression. We discuss progress in these areas and conclude with challenges and unanswered questions in the field.


Assuntos
Envelhecimento/genética , Genômica/história , Neoplasias/genética , Telomerase/genética , Telômero/química , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Envelhecimento/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , DNA/química , DNA/genética , DNA/metabolismo , Regulação da Expressão Gênica , Genômica/métodos , História do Século XX , História do Século XXI , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Progéria/genética , Progéria/metabolismo , Progéria/patologia , Ribonucleoproteínas Nucleares Pequenas/genética , Ribonucleoproteínas Nucleares Pequenas/metabolismo , Ribonucleoproteínas Nucleolares Pequenas/genética , Ribonucleoproteínas Nucleolares Pequenas/metabolismo , Telomerase/metabolismo , Telômero/metabolismo , Homeostase do Telômero , Proteínas de Ligação a Telômeros/genética , Proteínas de Ligação a Telômeros/metabolismo
3.
Nat Commun ; 10(1): 605, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30723199

RESUMO

Nuclear envelopathies comprise a heterogeneous group of diseases caused by mutations in genes encoding nuclear envelope proteins. Mutations affecting lamina-associated polypeptide 1 (LAP1) result in two discrete phenotypes of muscular dystrophy and progressive dystonia with cerebellar atrophy. We report 7 patients presenting at birth with severe progressive neurological impairment, bilateral cataract, growth retardation and early lethality. All the patients are homozygous for a nonsense mutation in the TOR1AIP1 gene resulting in the loss of both protein isoforms LAP1B and LAP1C. Patient-derived fibroblasts exhibit changes in nuclear envelope morphology and large nuclear-spanning channels containing trapped cytoplasmic organelles. Decreased and inefficient cellular motility is also observed in these fibroblasts. Our study describes the complete absence of both major human LAP1 isoforms, underscoring their crucial role in early development and organogenesis. LAP1-associated defects may thus comprise a broad clinical spectrum depending on the availability of both isoforms in the nuclear envelope throughout life.


Assuntos
Anormalidades Múltiplas/genética , Predisposição Genética para Doença/genética , Proteínas de Membrana/genética , Mutação , Membrana Nuclear/genética , Proteínas Nucleares/genética , Anormalidades Múltiplas/metabolismo , Sequência de Bases , Criança , Pré-Escolar , Análise Mutacional de DNA , Evolução Fatal , Feminino , Humanos , Masculino , Proteínas de Membrana/metabolismo , Microscopia Eletrônica de Transmissão , Membrana Nuclear/metabolismo , Membrana Nuclear/ultraestrutura , Proteínas Nucleares/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo
4.
J Hum Genet ; 64(5): 467-471, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30796325

RESUMO

Spondylocarpotarsal synostosis syndrome, a rare syndromic skeletal disorder characterized by disrupted vertebral segmentation with vertebral fusion, scoliosis, short stature, and carpal/tarsal synostosis, has been associated with biallelic truncating mutations in the filamin B gene or monoallelic mutations in the myosin heavy chain 3 gene. We herein report the case of a patient with a typical phenotype of spondylocarpotarsal synostosis syndrome who had a homozygous frameshift mutation in the refilin A gene (RFLNA) [c.241delC, p.(Leu81Cysfs*111)], which encodes one of the filamin-binding proteins. Refilins, filamins, and myosins play critical roles in forming perinuclear actin caps, which change the nuclear morphology during cell migration and differentiation. The present study implies that RFLNA is an additional causative gene for spondylocarpotarsal synostosis syndrome in humans and a defect in forming actin bundles and perinuclear actin caps may be a critical mechanism for the development of spondylocarpotarsal synostosis syndrome.


Assuntos
Anormalidades Múltiplas/genética , Biomarcadores Tumorais/genética , Mutação da Fase de Leitura , Homozigoto , Vértebras Lombares/anormalidades , Doenças Musculoesqueléticas/genética , Escoliose/congênito , Sinostose/genética , Vértebras Torácicas/anormalidades , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Biomarcadores Tumorais/metabolismo , Humanos , Lactente , Vértebras Lombares/metabolismo , Vértebras Lombares/patologia , Masculino , Doenças Musculoesqueléticas/metabolismo , Doenças Musculoesqueléticas/patologia , Escoliose/genética , Escoliose/metabolismo , Escoliose/patologia , Sinostose/metabolismo , Sinostose/patologia , Vértebras Torácicas/metabolismo , Vértebras Torácicas/patologia
6.
Skelet Muscle ; 8(1): 17, 2018 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-29855340

RESUMO

BACKGROUND: Transport protein particle (TRAPP) is a supramolecular protein complex that functions in localizing proteins to the Golgi compartment. The TRAPPC11 subunit has been implicated in muscle disease by virtue of homozygous and compound heterozygous deleterious mutations being identified in individuals with limb girdle muscular dystrophy and congenital muscular dystrophy. It remains unclear how this protein leads to muscle disease. Furthermore, a role for this protein, or any other membrane trafficking protein, in the etiology of the dystroglycanopathy group of muscular dystrophies has yet to be found. Here, using a multidisciplinary approach including genetics, immunofluorescence, western blotting, and live cell analysis, we implicate both TRAPPC11 and another membrane trafficking protein, GOSR2, in α-dystroglycan hypoglycosylation. CASE PRESENTATION: Subject 1 presented with severe epileptic episodes and subsequent developmental deterioration. Upon clinical evaluation she was found to have brain, eye, and liver abnormalities. Her serum aminotransferases and creatine kinase were abnormally high. Subjects 2 and 3 are siblings from a family unrelated to subject 1. Both siblings displayed hypotonia, muscle weakness, low muscle bulk, and elevated creatine kinase levels. Subject 3 also developed a seizure disorder. Muscle biopsies from subjects 1 and 3 were severely dystrophic with abnormal immunofluorescence and western blotting indicative of α-dystroglycan hypoglycosylation. Compound heterozygous mutations in TRAPPC11 were identified in subject 1: c.851A>C and c.965+5G>T. Cellular biological analyses on fibroblasts confirmed abnormal membrane trafficking. Subject 3 was found to have compound heterozygous mutations in GOSR2: c.430G>T and c.2T>G. Cellular biological analyses on fibroblasts from subject 3 using two different model cargo proteins did not reveal defects in protein transport. No mutations were found in any of the genes currently known to cause dystroglycanopathy in either individual. CONCLUSION: Recessive mutations in TRAPPC11 and GOSR2 are associated with congenital muscular dystrophy and hypoglycosylation of α-dystroglycan. This is the first report linking membrane trafficking proteins to dystroglycanopathy and suggests that these genes should be considered in the diagnostic evaluation of patients with congenital muscular dystrophy and dystroglycanopathy.


Assuntos
Distroglicanas/metabolismo , Distrofias Musculares/genética , Mutação , Proteínas Qb-SNARE/genética , Proteínas de Transporte Vesicular/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Encéfalo/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética/métodos , Feminino , Glicosilação , Humanos , Lactente , Músculo Esquelético/metabolismo , Distrofias Musculares/congênito , Distrofias Musculares/diagnóstico por imagem , Distrofias Musculares/metabolismo
7.
J Drugs Dermatol ; 17(3): 285-288, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29537446

RESUMO

Keratosis pilaris (KP) is a common skin finding that presents as follicular hyperkeratotic papules on the proximal extremities in patients with a propensity for atopy. Although often asymptomatic, the stippled appearance is cosmetically disturbing to patients and difficult to treat as current therapies are limited in availability and efficacy. Nitric oxide (NO) has been found to be essential in basic systemic and cutaneous physiologic function, specifically in terms of its anti-microbial and anti-inflammatory properties, which evolutionarily was maintained by ammonia-oxidizing bacteria (AOB). As modern hygiene practices have improved, there has been a gradual loss of cutaneous AOB and, therefore, the availability of an important source of human physiologic NO. We propose that restoring this dermal microflora with a purified strain of AOB, Nitrosomonas eutropha (D23), may reduce the overall cutaneous inflammatory state and, thus, be a potential therapeutic option for improving the cosmetic appearance of a skin condition such as KP which is often found in association with xerosis and atopic dermatitis. Clinical trial registry number: NCT03243617

J Drugs Dermatol. 2018;17(3):285-288.

.


Assuntos
Anormalidades Múltiplas/tratamento farmacológico , Anormalidades Múltiplas/metabolismo , Amônia/metabolismo , Doença de Darier/tratamento farmacológico , Doença de Darier/metabolismo , Sobrancelhas/anormalidades , Microbiota/efeitos dos fármacos , Nitrosomonas/efeitos dos fármacos , Nitrosomonas/metabolismo , Anormalidades Múltiplas/diagnóstico , Administração Tópica , Doença de Darier/diagnóstico , Método Duplo-Cego , Sobrancelhas/metabolismo , Feminino , Humanos , Masculino , Microbiota/fisiologia , Oxirredução/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/microbiologia , Resultado do Tratamento
8.
J Biochem Mol Toxicol ; 32(3): e22036, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29360218

RESUMO

Methylparabens (MP) are widely used as preservatives in cosmetics, pharmacy, and food industry. Although acute toxicity studies in animals indicated that parabens are not significantly toxic, the effects of chronic exposure under sublethal doses are still unknown and the number of related studies is limited. Our aim was to evaluate the effects of MP on the development of zebrafish embryos focusing on development, locomotor activity, oxidant-antioxidant status, apoptosis, and ccnd1 and myca expressions. The expressions of ccnd1 and myca were determined by RT-PCR. Lipid peroxidation (LPO), nitric oxide (NO), and glutathione-S-transferase (GST) activities were determined spectrophotometrically. Apoptosis was determined using acridine orange staining. Locomotor activity was measured using touch-evoked movement test. MP exposure increased malformations, LPO, apoptosis, ccnd1 and myca expressions, and decreased GST activities and NO levels compared with the control group. Our findings will lead to further understanding of the mechanism of MP toxicity, and merit further research.


Assuntos
Anormalidades Múltiplas/induzido quimicamente , Apoptose/efeitos dos fármacos , Ciclina D1/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Parabenos/toxicidade , Proteínas Proto-Oncogênicas c-myc/biossíntese , Proteínas de Peixe-Zebra/biossíntese , Peixe-Zebra/metabolismo , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Animais , Proteínas Proto-Oncogênicas c-myc/sangue
9.
Genome Med ; 10(1): 3, 2018 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-29310717

RESUMO

BACKGROUND: Glycosylphosphatidylinositol biosynthesis defects (GPIBDs) cause a group of phenotypically overlapping recessive syndromes with intellectual disability, for which pathogenic mutations have been described in 16 genes of the corresponding molecular pathway. An elevated serum activity of alkaline phosphatase (AP), a GPI-linked enzyme, has been used to assign GPIBDs to the phenotypic series of hyperphosphatasia with mental retardation syndrome (HPMRS) and to distinguish them from another subset of GPIBDs, termed multiple congenital anomalies hypotonia seizures syndrome (MCAHS). However, the increasing number of individuals with a GPIBD shows that hyperphosphatasia is a variable feature that is not ideal for a clinical classification. METHODS: We studied the discriminatory power of multiple GPI-linked substrates that were assessed by flow cytometry in blood cells and fibroblasts of 39 and 14 individuals with a GPIBD, respectively. On the phenotypic level, we evaluated the frequency of occurrence of clinical symptoms and analyzed the performance of computer-assisted image analysis of the facial gestalt in 91 individuals. RESULTS: We found that certain malformations such as Morbus Hirschsprung and diaphragmatic defects are more likely to be associated with particular gene defects (PIGV, PGAP3, PIGN). However, especially at the severe end of the clinical spectrum of HPMRS, there is a high phenotypic overlap with MCAHS. Elevation of AP has also been documented in some of the individuals with MCAHS, namely those with PIGA mutations. Although the impairment of GPI-linked substrates is supposed to play the key role in the pathophysiology of GPIBDs, we could not observe gene-specific profiles for flow cytometric markers or a correlation between their cell surface levels and the severity of the phenotype. In contrast, it was facial recognition software that achieved the highest accuracy in predicting the disease-causing gene in a GPIBD. CONCLUSIONS: Due to the overlapping clinical spectrum of both HPMRS and MCAHS in the majority of affected individuals, the elevation of AP and the reduced surface levels of GPI-linked markers in both groups, a common classification as GPIBDs is recommended. The effectiveness of computer-assisted gestalt analysis for the correct gene inference in a GPIBD and probably beyond is remarkable and illustrates how the information contained in human faces is pivotal in the delineation of genetic entities.


Assuntos
Citometria de Fluxo/métodos , Glicosilfosfatidilinositóis/biossíntese , Processamento de Imagem Assistida por Computador , Anormalidades Múltiplas/metabolismo , Automação , Biomarcadores/metabolismo , Humanos , Deficiência Intelectual/metabolismo , Fenótipo , Distúrbios do Metabolismo do Fósforo/metabolismo , Síndrome
10.
Eur J Pediatr Surg ; 28(1): 109-114, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28701000

RESUMO

INTRODUCTION: Pulmonary hypoplasia (PH), characterized by smaller lung size and reduced airway branching, remains a major cause of neonatal mortality in newborns with congenital diaphragmatic hernia (CDH). Integrin-mediated cell-matrix interactions play an essential role in the fetal lung mesenchyme by stimulating branching morphogenesis. Mice lacking integrin subunits α3 (Itga3) and α6 (Itga6) exhibit severe PH. Furthermore, Itga8-knockout mice show defective airway branching, suggesting that Itga3, Itga6, and Itga8 are crucial for fetal lung development. We hypothesized that expression of Itga3, Itga6, and Itga8 is decreased in the branching airway mesenchyme of hypoplastic rat lungs in the nitrofen-induced CDH model. MATERIALS AND METHODS: Time-mated rats received nitrofen or vehicle on gestational day 9 (D9). Fetuses were sacrificed on D15, D18, and D21, and dissected lungs were divided into control and nitrofen-exposed specimens (n = 12 per time-point and group, respectively). Pulmonary gene expression of Itga3, Itga6, and Itga8 was analyzed by quantitative real-time polymerase chain reaction. Immunofluorescence double-staining for Itga3, Itga6, and Itga8 was combined with the mesenchymal marker Fgf10 to evaluate protein expression and localization in branching airway tissue. RESULTS: Relative mRNA expression of Itga3, Itga6, and Itga8 was significantly decreased in lungs of nitrofen-exposed fetuses on D15, D18, and D21 compared with controls. Confocal laser scanning microscopy showed markedly diminished immunofluorescence of Itga3, Itga6, and Itga8 mainly in mesenchymal cells surrounding branching airways of nitrofen-exposed fetuses on D15, D18, and D21 compared with controls. CONCLUSION: Decreased expression of Itga3, Itga6, and Itga8 in the pulmonary mesenchyme may lead to disruptions in airway branching morphogenesis, thus contributing to PH in the nitrofen-induced CDH model.


Assuntos
Anormalidades Múltiplas/metabolismo , Hérnias Diafragmáticas Congênitas/complicações , Cadeias alfa de Integrinas/metabolismo , Integrina alfa3/metabolismo , Integrina alfa6/metabolismo , Pneumopatias/metabolismo , Pulmão/anormalidades , Pulmão/metabolismo , Mesoderma/metabolismo , Anormalidades Múltiplas/induzido quimicamente , Anormalidades Múltiplas/embriologia , Animais , Biomarcadores/metabolismo , Imunofluorescência , Hérnias Diafragmáticas Congênitas/induzido quimicamente , Hérnias Diafragmáticas Congênitas/embriologia , Pulmão/embriologia , Pneumopatias/induzido quimicamente , Pneumopatias/embriologia , Mesoderma/embriologia , Microscopia Confocal , Éteres Fenílicos , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real
11.
Eur J Pediatr Surg ; 28(1): 120-124, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28683507

RESUMO

AIM: The high incidence of cardiac malformations in humans and animal models with congenital diaphragmatic hernia (CDH) is well known. The hypoplasia of left heart is common among fetuses with CDH and has been identified as a poor prognostic factor. However, the precise mechanisms underlying cardiac maldevelopment in CDH are not fully understood. Ras-related C3 botulinum toxin substrate 1 (Rac1) plays a key role in cardiomyocyte polarity and embryonic heart development. Deficiency of Rac1 is reported to impair elongation and cytoskeletal organization of cardiomyocytes, resulting in congenital cardiac defects. We designed this study to test the hypothesis that Rac1 expression is downregulated in the developing hearts of rats with nitrofen-induced CDH. MATERIALS AND METHODS: Following ethical approval (REC1103), time-pregnant Sprague Dawley rats received nitrofen or vehicle on gestational day 9 (D9). Fetuses were sacrificed on D18 and D21 and divided into CDH and control (CTRL) (n = 6 for each group and time point). Quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, and confocal-immunofluorescence microscopy were performed to detect cardiac gene and protein expression of Rac1. MAIN RESULTS: qRT-PCR and Western blot analysis revealed that Rac1 expression was significantly decreased in the CDH group compared with controls (p < 0.05). Confocal-immunofluorescence microscopy revealed that Rac1 cardiac expression was markedly decreased in the CDH group compared with controls. CONCLUSION: Decreased cardiac Rac1 expression in the nitrofen-induced CDH suggests that Rac1 deficiency during morphogenesis may impair structural cardiac remodeling, resulting in congenital cardiac defects.


Assuntos
Anormalidades Múltiplas/metabolismo , Regulação para Baixo , Regulação da Expressão Gênica no Desenvolvimento , Cardiopatias Congênitas/metabolismo , Hérnias Diafragmáticas Congênitas/metabolismo , Miocárdio/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/genética , Animais , Biomarcadores/metabolismo , Western Blotting , Imunofluorescência , Cardiopatias Congênitas/embriologia , Cardiopatias Congênitas/genética , Hérnias Diafragmáticas Congênitas/induzido quimicamente , Hérnias Diafragmáticas Congênitas/embriologia , Hérnias Diafragmáticas Congênitas/genética , Microscopia Confocal , Éteres Fenílicos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real
12.
Bone ; 106: 187-193, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29051055

RESUMO

INTRODUCTION: Pierson syndrome is caused by a mutation of LAMB2, encoding for laminin ß2. Clinical phenotype is variable but usually associates congenital nephrotic syndrome (CNS) and ocular abnormalities. Neuromuscular impairment has also been described. METHODS: We report on a 15-year old girl, suffering from Pierson Syndrome, who developed severe bone deformations during puberty. This patient initially displayed CNS and microcoria, leading to the clinical diagnosis of Pierson syndrome. Genetic analysis revealed a truncating mutation and a splice site mutation of LAMB2. The patient received a renal transplantation (R-Tx) at the age of 3. After R-Tx, renal evolution was simple, the patient receiving low-dose corticosteroids, tacrolimus and mycophenolate mofetil. At the age of 12, bone deformations progressively appeared. At the time of bone impairment, renal function was subnormal (glomerular filtration rate using iohexol clearance 50mL/min per 1.73m2), and parameters of calcium/phosphate metabolism were normal (calcium 2.45mmol/L, phosphorus 1.30mmol/L, PTH 81ng/L, ALP 334U/L, 25OH-D 73nmol/L). Radiographs showed major deformations such as scoliosis, genu varum and diffuse epiphyseal abnormalities. A high resolution scanner (HR-pQCT) was performed, demonstrating a bone of "normal low" quantity and quality; major radial and cubital deformations were observed. Stainings of laminin ß2 were performed on bone and renal samples from the patient and healthy controls: as expected, laminin ß2 was expressed in the control kidney but not in the patient's renal tissue, and a similar pattern was observed in bone. CONCLUSION: This is the first case of skeletal impairment ever described in Pierson syndrome. Integrin α3ß1, receptor for laminin ß2, are found in podocytes and osteoblasts, and the observation of both the presence of laminin ß2 staining in healthy bone and its absence in the patient's bone raises the question of a potential role of laminin ß2 in bone physiology.


Assuntos
Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/fisiopatologia , Anormalidades do Olho/metabolismo , Anormalidades do Olho/fisiopatologia , Laminina/metabolismo , Síndrome Nefrótica/metabolismo , Síndrome Nefrótica/fisiopatologia , Distúrbios Pupilares/metabolismo , Distúrbios Pupilares/fisiopatologia , Anormalidades Múltiplas/genética , Adolescente , Anormalidades do Olho/genética , Feminino , Humanos , Laminina/genética , Mutação , Síndrome Nefrótica/genética , Doenças Neuromusculares/genética , Doenças Neuromusculares/metabolismo , Doenças Neuromusculares/fisiopatologia , Distúrbios Pupilares/genética
13.
Int J Mol Sci ; 19(1)2017 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-29283410

RESUMO

Kabuki syndrome (KS) is a rare disorder characterized by multiple congenital anomalies and variable intellectual disability caused by mutations in KMT2D/MLL2 and KDM6A/UTX, two interacting chromatin modifier responsible respectively for 56-75% and 5-8% of the cases. To date, three KS patients with mosaic KMT2D deletions in blood lymphocytes have been described. We report on three additional subjects displaying KMT2D gene mosaics including one in which a single nucleotide change results in a new frameshift mutation (p.L1199HfsX7), and two with already-known nonsense mutations (p.R4484X and p.R5021X). Consistent with previously published cases, mosaic KMT2D mutations may result in mild KS facial dysmorphisms and clinical and neurobehavioral features, suggesting that these characteristics could represent the handles for genetic testing of individuals with slight KS-like traits.


Assuntos
Anormalidades Múltiplas/genética , Códon sem Sentido , Proteínas de Ligação a DNA/genética , Face/anormalidades , Mutação da Fase de Leitura , Doenças Hematológicas/genética , Mosaicismo , Proteínas de Neoplasias/genética , Doenças Vestibulares/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/fisiopatologia , Adolescente , Sequência de Bases , Criança , Proteínas de Ligação a DNA/metabolismo , Face/fisiopatologia , Feminino , Expressão Gênica , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/metabolismo , Doenças Hematológicas/fisiopatologia , Humanos , Proteínas de Neoplasias/metabolismo , Testes Neuropsicológicos , Doenças Vestibulares/diagnóstico , Doenças Vestibulares/metabolismo , Doenças Vestibulares/fisiopatologia
14.
Orphanet J Rare Dis ; 12(1): 183, 2017 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-29258554

RESUMO

CLINICAL DESCRIPTION: KBG syndrome is characterized by macrodontia of upper central incisors, distinctive craniofacial features such as triangular face, prominent nasal bridge, thin upper lip and synophrys; skeletal findings including short stature, delayed bone age, and costovertebral anomalies; and developmental delay/intellectual disability sometimes associated with seizures and EEG abnormalities. The condition was named KBG syndrome after the initials of the last names of three original families reported in 1975. EPIDEMIOLOGY: The prevalence of KBG syndrome is not established. There are over 100 patients reported in the literature. It is likely that KBG syndrome is underreported due to incomplete recognition and very mild presentations of the disorder in some individuals. KBG syndrome is typically milder in females. ETIOLOGY: Causative variants in ANKRD11 have been identified in affected individuals. The vast majority of identified variants are loss of function, which include nonsense and frameshift variants and larger deletions at 16q24.3. Haploinsufficiency appears to be the mechanism of pathogenicity. GENETIC COUNSELING: Familial and de novo cases have been reported. Causative de novo variants occur approximately one third of the time. Transmission follows an autosomal dominant pattern. The syndrome displays inter- and intra-familial variability.


Assuntos
Anormalidades Múltiplas/metabolismo , Doenças do Desenvolvimento Ósseo/metabolismo , Deficiência Intelectual/metabolismo , Anormalidades Dentárias/metabolismo , Anormalidades Múltiplas/genética , Animais , Doenças do Desenvolvimento Ósseo/genética , Deleção Cromossômica , Hibridização Genômica Comparativa , Facies , Feminino , Haploinsuficiência/genética , Haploinsuficiência/fisiologia , Humanos , Deficiência Intelectual/genética , Masculino , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Convulsões/genética , Convulsões/metabolismo , Anormalidades Dentárias/genética
15.
Transl Psychiatry ; 7(11): 1261, 2017 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-29187755

RESUMO

1q21.1 hemizygous microdeletion is a copy number variant leading to eightfold increased risk of schizophrenia. In order to investigate biological alterations induced by this microdeletion, we generated a novel mouse model (Df(h1q21)/+) and characterized it in a broad test battery focusing on schizophrenia-related assays. Df(h1q21)/+ mice displayed increased hyperactivity in response to amphetamine challenge and increased sensitivity to the disruptive effects of amphetamine and phencyclidine hydrochloride (PCP) on prepulse inhibition. Probing of the direct dopamine (DA) pathway using the DA D1 receptor agonist SKF-81297 revealed no differences in induced locomotor activity compared to wild-type mice, but Df(h1q21)/+ mice showed increased sensitivity to the DA D2 receptor agonist quinpirole and the D1/D2 agonist apomorphine. Electrophysiological characterization of DA neuron firing in the ventral tegmental area revealed more spontaneously active DA neurons and increased firing variability in Df(h1q21)/+ mice, and decreased feedback reduction of DA neuron firing in response to amphetamine. In a range of other assays, Df(h1q21)/+ mice showed no difference from wild-type mice: gross brain morphology and basic functions such as reflexes, ASR, thermal pain sensitivity, and motor performance were unaltered. Similarly, anxiety related measures, baseline prepulse inhibition, and seizure threshold were unaltered. In addition to the central nervous system-related phenotypes, Df(h1q21)/+ mice exhibited reduced head-to tail length, which is reminiscent of the short stature reported in humans with 1q21.1 deletion. With aspects of both construct and face validity, the Df(h1q21)/+ model may be used to gain insight into schizophrenia-relevant alterations in dopaminergic transmission.


Assuntos
Anormalidades Múltiplas , Comportamento Animal , Deleção Cromossômica , Agonistas de Dopamina/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Neurônios Dopaminérgicos/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Megalencefalia , Núcleo Accumbens/metabolismo , Inibição Pré-Pulso , Receptores Dopaminérgicos/metabolismo , Esquizofrenia , Área Tegmentar Ventral/metabolismo , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Anormalidades Múltiplas/fisiopatologia , Anfetamina/farmacologia , Animais , Apomorfina/farmacologia , Comportamento Animal/efeitos dos fármacos , Benzazepinas/farmacologia , Cromossomos Humanos Par 1/metabolismo , Modelos Animais de Doenças , Agonistas de Dopamina/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Neurônios Dopaminérgicos/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Megalencefalia/metabolismo , Megalencefalia/patologia , Megalencefalia/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Accumbens/efeitos dos fármacos , Fenciclidina/farmacologia , Fenótipo , Inibição Pré-Pulso/efeitos dos fármacos , Quimpirol/farmacologia , Receptores Dopaminérgicos/efeitos dos fármacos , Esquizofrenia/metabolismo , Esquizofrenia/patologia , Esquizofrenia/fisiopatologia , Área Tegmentar Ventral/efeitos dos fármacos
16.
Clin J Am Soc Nephrol ; 12(12): 1962-1973, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29146704

RESUMO

BACKGROUND AND OBJECTIVES: Joubert syndrome is a genetically heterogeneous ciliopathy associated with >30 genes. The characteristics of kidney disease and genotype-phenotype correlations have not been evaluated in a large cohort at a single center. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We evaluated 97 individuals with Joubert syndrome at the National Institutes of Health Clinical Center using abdominal ultrasonography, blood and urine chemistries, and DNA sequencing. RESULTS: Patients were ages 0.6-36 years old (mean of 9.0±7.6 years old); 41 were female. Mutations were identified in 19 genes in 92 patients; two thirds of the mutations resided in six genes: TMEM67, C5orf42, CC2D2A, CEP290, AHI1, and KIAA0586. Kidney disease was detected in 30%, most commonly in association with the following genes: CEP290 (six of six), TMEM67 (11 of 22), and AHI1 (three of six). No kidney disease was identified in patients with mutations in C5orf42 (zero of 15) or KIAA0586 (zero of six). Prenatal ultrasonography of kidneys was normal in 72% of patients with kidney disease. Specific types of kidney disease included nephronophthisis (31%), an overlap phenotype of autosomal recessive polycystic kidney disease/nephronophthisis (35%), unilateral multicystic dysplastic kidney (10%), and indeterminate-type cystic kidney disease (24%). Early-onset hypertension occurred in 24% of patients with kidney disease. Age at ESRD (n=13) ranged from 6 to 24 years old (mean of 11.3±4.8 years old). CONCLUSIONS: Kidney disease occurs in up to one third of patients with Joubert syndrome, most commonly in those with mutations in CEP290, TMEM67, and AHI1. Patients with mutations in C5orf42 or KIAA0586 are less likely to develop kidney disease. Prenatal ultrasonography is a poor predictor of kidney involvement in Joubert syndrome. Unilateral multicystic dysplastic kidney and autosomal recessive polycystic kidney disease-like enlarged kidneys with early-onset hypertension can be part of the Joubert syndrome kidney phenotype.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Cerebelo/anormalidades , Anormalidades do Olho/genética , Anormalidades do Olho/metabolismo , Doenças Renais Císticas/congênito , Falência Renal Crônica/genética , Retina/anormalidades , Anormalidades Múltiplas/diagnóstico por imagem , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Adulto , Idade de Início , Antígenos de Neoplasias/genética , Proteínas de Ciclo Celular/genética , Cerebelo/diagnóstico por imagem , Cerebelo/metabolismo , Criança , Pré-Escolar , Anormalidades do Olho/complicações , Anormalidades do Olho/diagnóstico por imagem , Feminino , Genótipo , Humanos , Lactente , Doenças Renais Císticas/complicações , Doenças Renais Císticas/diagnóstico por imagem , Doenças Renais Císticas/genética , Doenças Renais Císticas/metabolismo , Falência Renal Crônica/etiologia , Imagem por Ressonância Magnética , Masculino , Proteínas de Membrana/genética , Rim Displásico Multicístico/complicações , Rim Displásico Multicístico/diagnóstico por imagem , Rim Displásico Multicístico/genética , Mutação , Proteínas de Neoplasias/genética , Fenótipo , Rim Policístico Autossômico Recessivo/complicações , Rim Policístico Autossômico Recessivo/diagnóstico por imagem , Rim Policístico Autossômico Recessivo/genética , Estudos Prospectivos , Proteínas/genética , Retina/diagnóstico por imagem , Retina/metabolismo , Ultrassonografia Pré-Natal , Adulto Jovem
17.
Hum Mol Genet ; 26(23): 4657-4667, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28973549

RESUMO

Joubert syndrome (JBTS) is the archetypal ciliopathy caused by mutation of genes encoding ciliary proteins leading to multi-system phenotypes, including a cerebello-retinal-renal syndrome. JBTS is genetically heterogeneous, however mutations in CEP290 are a common underlying cause. The renal manifestation of JBTS is a juvenile-onset cystic kidney disease, known as nephronophthisis, typically progressing to end-stage renal failure within the first two decades of life, thus providing a potential window for therapeutic intervention. In order to increase understanding of JBTS and its associated kidney disease and to explore potential treatments, we conducted a comprehensive analysis of primary renal epithelial cells directly isolated from patient urine (human urine-derived renal epithelial cells, hURECs). We demonstrate that hURECs from a JBTS patient with renal disease have elongated and disorganized primary cilia and that this ciliary phenotype is specifically associated with an absence of CEP290 protein. Treatment with the Sonic hedgehog (Shh) pathway agonist purmorphamine or cyclin-dependent kinase inhibition (using roscovitine and siRNA directed towards cyclin-dependent kinase 5) ameliorated the cilia phenotype. In addition, purmorphamine treatment was shown to reduce cyclin-dependent kinase 5 in patient cells, suggesting a convergence of these signalling pathways. To our knowledge, this is the most extensive analysis of primary renal epithelial cells from JBTS patients to date. It demonstrates the feasibility and power of this approach to directly assess the consequences of patient-specific mutations in a physiologically relevant context and a previously unrecognized convergence of Shh agonism and cyclin-dependent kinase inhibition as potential therapeutic targets.


Assuntos
Anormalidades Múltiplas/tratamento farmacológico , Anormalidades Múltiplas/patologia , Cerebelo/anormalidades , Cílios/patologia , Anormalidades do Olho/tratamento farmacológico , Anormalidades do Olho/patologia , Doenças Renais Císticas/tratamento farmacológico , Doenças Renais Císticas/patologia , Morfolinas/uso terapêutico , Purinas/uso terapêutico , Retina/anormalidades , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Cerebelo/metabolismo , Cerebelo/patologia , Criança , Pré-Escolar , Cílios/efeitos dos fármacos , Cílios/genética , Cílios/metabolismo , Ciliopatias/tratamento farmacológico , Ciliopatias/genética , Ciliopatias/metabolismo , Quinase 5 Dependente de Ciclina/genética , Quinase 5 Dependente de Ciclina/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Anormalidades do Olho/genética , Anormalidades do Olho/metabolismo , Humanos , Doenças Renais Císticas/genética , Doenças Renais Císticas/metabolismo , Falência Renal Crônica/genética , Falência Renal Crônica/metabolismo , Falência Renal Crônica/patologia , Masculino , Mutação , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Linhagem , Doenças Renais Policísticas/genética , Cultura Primária de Células , Retina/metabolismo , Retina/patologia , Roscovitina , Transdução de Sinais
18.
PLoS One ; 12(9): e0184473, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28934221

RESUMO

BACKGROUND: Platelet-derived growth factor receptor alpha (PDGFRα) is a cell-surface receptor tyrosine kinase for platelet-derived growth factors. Correct timing and level of Pdgfra expression is crucial for embryo development, and deletion of Pdgfra caused developmental defects of multiple endoderm and mesoderm derived structures, resulting in a complex phenotypes including orofacial cleft, spina bifida, rib deformities, and omphalocele in mice. However, it is not clear if deletion of Pdgfra at different embryonic stages differentially affects these structures. PURPOSE: To address the temporal requirement of Pdgfra in embryonic development. METHODS: We have deleted the Pdgfra in Pdgfra-expressing tissues at different embryonic stages in mice, examined and quantified the developmental anomalies. RESULTS: Current study showed that (i) conditional deletion of Pdgfra at different embryonic days (between E7.5 and E10.5) resulted in orofacial cleft, spina bifida, rib cage deformities, and omphalocele, and (ii) the day of Pdgfra deletion influenced the combinations, incidence and severities of these anomalies. Deletion of Pdgfra caused apoptosis of Pdgfra-expressing tissues, and developmental defects of their derivatives. CONCLUSION: Orofacial cleft, spina bifida and omphalocele are among the commonest skeletal and abdominal wall defects of newborns, but their genetic etiologies are largely unknown. The remarkable resemblance of our conditional Pdgfra knockout embryos to theses human congenital anomalies, suggesting that dysregulated PDGFRA expression could cause these anomalies in human. Future work should aim at defining (a) the regulatory elements for the expression of the human PDGFRA during embryonic development, and (b) if mutations / sequence variations of these regulatory elements cause these anomalies.


Assuntos
Desenvolvimento Embrionário/fisiologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Parede Abdominal/anormalidades , Parede Abdominal/embriologia , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Animais , Apoptose/fisiologia , Fenda Labial/embriologia , Fenda Labial/genética , Fenda Labial/metabolismo , Fissura Palatina/embriologia , Fissura Palatina/genética , Fissura Palatina/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Inativação de Genes , Hérnia Umbilical/embriologia , Hérnia Umbilical/genética , Hérnia Umbilical/metabolismo , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Esqueleto/anormalidades , Esqueleto/embriologia , Esqueleto/metabolismo , Disrafismo Espinal/embriologia , Disrafismo Espinal/genética , Disrafismo Espinal/metabolismo , Tamoxifeno , Fatores de Tempo
19.
Nat Cell Biol ; 19(10): 1178-1188, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28846093

RESUMO

Ciliopathies, including nephronophthisis (NPHP), Meckel syndrome (MKS) and Joubert syndrome (JBTS), can be caused by mutations affecting components of the transition zone, a domain near the base of the cilium that controls the protein composition of its membrane. We defined the three-dimensional arrangement of key proteins in the transition zone using two-colour stochastic optical reconstruction microscopy (STORM). NPHP and MKS complex components form nested rings comprised of nine-fold doublets. JBTS-associated mutations in RPGRIP1L or TCTN2 displace certain transition-zone proteins. Diverse ciliary proteins accumulate at the transition zone in wild-type cells, suggesting that the transition zone is a waypoint for proteins entering and exiting the cilium. JBTS-associated mutations in RPGRIP1L disrupt SMO accumulation at the transition zone and the ciliary localization of SMO. We propose that the disruption of transition-zone architecture in JBTS leads to a failure of SMO to accumulate at the transition zone and cilium, disrupting developmental signalling in JBTS.


Assuntos
Anormalidades Múltiplas/patologia , Cerebelo/anormalidades , Cílios/patologia , Ciliopatias/patologia , Anormalidades do Olho/patologia , Doenças Renais Císticas/patologia , Microscopia de Fluorescência/métodos , Retina/anormalidades , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adolescente , Adulto , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular , Cerebelo/metabolismo , Cerebelo/patologia , Criança , Cílios/metabolismo , Ciliopatias/genética , Ciliopatias/metabolismo , Anormalidades do Olho/genética , Anormalidades do Olho/metabolismo , Feminino , Predisposição Genética para Doença , Humanos , Processamento de Imagem Assistida por Computador , Doenças Renais Císticas/genética , Doenças Renais Císticas/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Mutação , Receptor Patched-1/genética , Receptor Patched-1/metabolismo , Fenótipo , Retina/metabolismo , Retina/patologia , Transdução de Sinais , Receptor Smoothened/genética , Receptor Smoothened/metabolismo , Processos Estocásticos , Adulto Jovem
20.
PLoS Genet ; 13(7): e1006936, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28753627

RESUMO

Mutations in BBS6 cause two clinically distinct syndromes, Bardet-Biedl syndrome (BBS), a syndrome caused by defects in cilia transport and function, as well as McKusick-Kaufman syndrome, a genetic disorder characterized by congenital heart defects. Congenital heart defects are rare in BBS, and McKusick-Kaufman syndrome patients do not develop retinitis pigmentosa. Therefore, the McKusick-Kaufman syndrome allele may highlight cellular functions of BBS6 distinct from the presently understood functions in the cilia. In support, we find that the McKusick-Kaufman syndrome disease-associated allele, BBS6H84Y; A242S, maintains cilia function. We demonstrate that BBS6 is actively transported between the cytoplasm and nucleus, and that BBS6H84Y; A242S, is defective in this transport. We developed a transgenic zebrafish with inducible bbs6 to identify novel binding partners of BBS6, and we find interaction with the SWI/SNF chromatin remodeling protein Smarcc1a (SMARCC1 in humans). We demonstrate that through this interaction, BBS6 modulates the sub-cellular localization of SMARCC1 and find, by transcriptional profiling, similar transcriptional changes following smarcc1a and bbs6 manipulation. Our work identifies a new function for BBS6 in nuclear-cytoplasmic transport, and provides insight into the disease mechanism underlying the congenital heart defects in McKusick-Kaufman syndrome patients.


Assuntos
Anormalidades Múltiplas/genética , Síndrome de Bardet-Biedl/genética , Chaperoninas do Grupo II/genética , Cardiopatias Congênitas/genética , Hidrocolpos/genética , Polidactilia/genética , Fatores de Transcrição/genética , Doenças Uterinas/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Transporte Ativo do Núcleo Celular/genética , Animais , Animais Geneticamente Modificados/genética , Síndrome de Bardet-Biedl/metabolismo , Síndrome de Bardet-Biedl/patologia , Cromatina/genética , Montagem e Desmontagem da Cromatina/genética , Cílios/metabolismo , Cílios/patologia , Citoplasma/metabolismo , Modelos Animais de Doenças , Cardiopatias Congênitas/metabolismo , Cardiopatias Congênitas/patologia , Humanos , Hidrocolpos/metabolismo , Hidrocolpos/patologia , Camundongos , Mutação , Polidactilia/metabolismo , Polidactilia/patologia , Transporte Proteico/genética , Fatores de Transcrição/biossíntese , Doenças Uterinas/metabolismo , Doenças Uterinas/patologia , Peixe-Zebra/genética
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