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1.
J Clin Invest ; 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31513549

RESUMO

Myocardin (MYOCD) is the founding member of a class of transcriptional co-activators that bind serum response factor to activate gene expression programs critical in smooth muscle (SM) and cardiac muscle development. Insights into the molecular functions of MYOCD have been obtained from cell culture studies and, to date, knowledge about in vivo roles of MYOCD comes exclusively from experimental animals. Here, we defined an often lethal congenital human disease associated with inheritance of pathogenic MYOCD variants. This disease manifested as a massively dilated urinary bladder, or megabladder, with disrupted SM in its wall. We provided evidence that monoallelic loss-of-function variants in MYOCD caused congenital megabladder in males only, whereas biallelic variants were associated with disease in both sexes, with a phenotype additionally involving the cardiovascular system. These results were supported by co-segregation of MYOCD variants with the phenotype in four unrelated families, by in vitro transactivation studies where pathogenic variants resulted in abrogated SM gene expression, and finding megabladder in two distinct mouse models with reduced Myocd activity. In conclusion, we have demonstrated that variants in MYOCD result in human disease, and the collective findings highlight a vital role for MYOCD in mammalian organogenesis.

3.
Clin Genet ; 96(3): 246-253, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31090057

RESUMO

Two distinct genomic disorders have been linked to Xq28-gains, namely Xq28-duplications including MECP2 and Int22h1/Int22h2-mediated duplications involving RAB39B. Here, we describe six unrelated patients, five males and one female, with Xq28-gains distal to MECP2 and proximal to the Int22h1/Int22h2 low copy repeats. Comparison with patients carrying overlapping duplications in the literature defined the MidXq28-duplication syndrome featuring intellectual disability, language impairment, structural brain malformations, microcephaly, seizures and minor craniofacial features. The duplications overlapped for 108 kb including FLNA, RPL10 and GDI1 genes, highly expressed in brain and candidates for the neurologic phenotype.

4.
Hum Mol Genet ; 28(13): 2133-2142, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30806661

RESUMO

Hereditary multiple osteochondromas (HMO) is a rare autosomal dominant skeletal disorder, caused by heterozygous variants in either EXT1 or EXT2, which encode proteins involved in the biogenesis of heparan sulphate. Pathogenesis and genotype-phenotype correlations remain poorly understood. We studied 114 HMO families (158 affected individuals) with causative EXT1 or EXT2 variants identified by Sanger sequencing, or multiplex ligation-dependent probe amplification and qPCR. Eighty-seven disease-causative variants (55 novel and 32 known) were identified including frameshift (42%), nonsense (32%), missense (11%), splicing (10%) variants and genomic rearrangements (5%). Informative clinical features were available for 42 EXT1 and 27 EXT2 subjects. Osteochondromas were more frequent in EXT1 as compared to EXT2 patients. Anatomical distribution of lesions showed significant differences based on causative gene. Microscopy analysis for selected EXT1 and EXT2 variants verified that EXT1 and EXT2 mutants failed to co-localize each other and loss Golgi localization by surrounding the nucleus and/or assuming a diffuse intracellular distribution. In a cell viability study, cells expressing EXT1 and EXT2 mutants proliferated more slowly than cells expressing wild-type proteins. This confirms the physiological relevance of EXT1 and EXT2 Golgi co-localization and the key role of these proteins in the cell cycle. Taken together, our data expand genotype-phenotype correlations, offer further insights in the pathogenesis of HMO and open the path to future therapies.

5.
J Med Genet ; 56(4): 246-251, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30711920

RESUMO

BACKGROUND: Structural variants (SVs) affecting non-coding cis-regulatory elements are a common cause of congenital limb malformation. Yet, the functional interpretation of these non-coding variants remains challenging. The human Liebenberg syndrome is characterised by a partial transformation of the arms into legs and has been shown to be caused by SVs at the PITX1 locus leading to its misregulation in the forelimb by its native enhancer element Pen. This study aims to elucidate the genetic cause of an unsolved family with a mild form of Liebenberg syndrome and investigate the role of promoters in long-range gene regulation. METHODS: Here, we identify SVs by whole genome sequencing (WGS) and use CRISPR-Cas9 genome editing in transgenic mice to assign pathogenicity to the SVs. RESULTS: In this study, we used WGS in a family with three mildly affected individuals with Liebenberg syndrome and identified the smallest deletion described so far including the first non-coding exon of H2AFY. To functionally characterise the variant, we re-engineered the 8.5 kb deletion using CRISPR-Cas9 technology in the mouse and showed that the promoter of the housekeeping gene H2afy insulates the Pen enhancer from Pitx1 in forelimbs; its loss leads to misexpression of Pitx1 by the pan-limb activity of the Pen enhancer causing Liebenberg syndrome. CONCLUSION: Our data indicate that housekeeping promoters may titrate promiscuous enhancer activity to ensure normal morphogenesis. The deletion of the H2AFY promoter as a cause of Liebenberg syndrome highlights this new mutational mechanism and its role in congenital disease.

6.
Hum Mutat ; 2018 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-30371979

RESUMO

Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders, characterized by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. Several pathways have been implicated in the pathogenesis of neuronal degeneration in HSAN, while recent observations point to an emerging role of cytoskeleton organization and function. Here, we report novel biallelic mutations in the DST gene encoding dystonin, a large cytolinker protein of the plakin family, in an adult form of HSAN type VI. Affected individuals harbored the premature termination codon variant p.(Lys4330*) in trans with the p.(Ala203Glu) change affecting a highly conserved residue in an isoform-specific N-terminal region of dystonin. Functional studies showed defects in actin cytoskeleton organization and consequent delayed cell adhesion, spreading and migration, while recombinant p.Ala203Glu dystonin loses the ability to bind actin. Our data aid in the clinical and molecular delineation of HSAN-VI and suggest a central role for cell-motility and cytoskeletal defects in its pathogenesis possibly interfering with the neuronal outgrowth and guidance processes.

7.
Am J Med Genet A ; 176(9): 2028-2033, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30194892

RESUMO

Cadherins are cell-adhesion molecules that control morphogenesis, cell migration, and cell shape changes during multiple developmental processes. Until now four distinct cadherins have been implicated in human Mendelian disorders, mainly featuring skin, retinal and hearing manifestations. Branchio-skeleto-genital (or Elsahy-Waters) syndrome (BSGS) is an ultra-rare condition featuring a characteristic face, premature loss of teeth, vertebral and genital anomalies, and intellectual disability. We have studied two sibs with BSGS originally described by Castori et al. in 2010. Exome sequencing led to the identification of a novel homozygous nonsense variant in the first exon of the cadherin-11 gene (CDH11), which results in a prematurely truncated form of the protein. Recessive variants in CDH11 have been recently demonstrated in two other sporadic patients and a pair of sisters affected by BSGS. Although the function of this cadherin (also termed Osteoblast-Cadherin) is not completely understood, its prevalent expression in osteoblastic cell lines and up-regulation during differentiation suggest a specific function in bone formation and development. This study identifies a novel loss-of-function variant in CDH11 as a cause of BSGS and supports the role of cadherin-11 as a key player in axial and craniofacial malformations.

8.
Eur J Hum Genet ; 26(9): 1266-1271, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29891882

RESUMO

A rare syndrome was first described in 1997 in a 17-year-old male patient presenting with Retinitis pigmentosa, HYpopituitarism, Nephronophthisis and Skeletal dysplasia (RHYNS). In the single reported familial case, two brothers were affected, arguing for X-linked or recessive mode of inheritance. Up to now, the underlying genetic basis of RHYNS syndrome remains unknown. Here we applied whole-exome sequencing in the originally described family with RHYNS to identify compound heterozygous variants in the ciliary gene TMEM67. Sanger sequencing confirmed a paternally inherited nonsense c.622A > T, p.(Arg208*) and a maternally inherited missense variant c.1289A > G, p.(Asp430Gly), which perturbs the correct splicing of exon 13. Overall, TMEM67 showed one of the widest clinical continuum observed in ciliopathies ranging from early lethality to adults with liver fibrosis. Our findings extend the spectrum of phenotypes/syndromes resulting from biallelic TMEM67 variants to now eight distinguishable clinical conditions including RHYNS syndrome.

10.
Cytogenet Genome Res ; 153(1): 22-28, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29141250

RESUMO

A 17-year-old girl presented with a distinct phenotype mainly featuring craniofacial dysmorphism, including a disproportioned large, round, elongated face; hypertelorism; deep-set eyes with short palpebral fissures; obesity (BMI 37), and a neuropsychiatric disorder with high-functioning autism. Postnatal conventional cytogenetic analyses from peripheral blood revealed a mosaic small supernumerary marker chromosome (sSMC) with a mos 47,XX,+mar[7]/46,XX[43] karyotype. By cenM-FISH technique, the sSMC was identified as a ring derivative of chromosome 5. Metaphase FISH analysis with a set of dedicated probes defined its origin from the pericentromeric region of chromosome 5, including the NIPBL gene at 5p13.2. Such sSMCs, exceedingly rare in the literature, underlie proximal trisomy 5p. In order to delineate a core phenotype of proximal trisomy 5p, we compared our patient's features with those of 6 patients found in the literature with similar der(5) chromosomes. Furthermore, a dozen individuals with 5p13 (micro)duplication syndrome was compared and discussed. We identified highly distinctive craniofacial dysmorphism, obesity, and intellectual disability and/or autism spectrum disorder as typical features of proximal 5p trisomy. In the critical region (band 5p13), the NIPBL gene is likely to be a major determinant of the neurobehavioral phenotype, and its presence at the sSMC level may be relevant to predict clinical outcome.


Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos Par 5/genética , Trissomia/genética , Adolescente , Transtorno Autístico/genética , Anormalidades Craniofaciais/genética , Feminino , Humanos , Proteínas/genética
11.
Mol Syndromol ; 8(4): 172-178, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28690482

RESUMO

Barber-Say syndrome (BSS) and ablepharon-macrostomia syndrome (AMS) are infrequently reported congenital malformation disorders caused by mutations in the TWIST2 gene. Both are characterized by abnormalities in ectoderm-derived structures and cause a very unusual morphology of mainly the face in individuals with otherwise normal cognition and normal physical functioning. We studied the impact that the presence of BSS and AMS has on psychosocial functioning of affected individuals and their families, using their point of view to start with. We tabulated frequently asked questions from affected individuals and families, and a parent of an affected child and an affected adult woman offered personal testimonies. We focused on perception of illness, body satisfaction, and the consequences for an otherwise normal individual who has a disorder that interferes with body image. The importance of paying particular attention to the management of both the physical appearance and the consequences of these entities on the quality of life is stressed by the affected individuals themselves.

12.
Gynecol Endocrinol ; 33(12): 918-922, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28609197

RESUMO

17α-Hydroxylase deficiency is an uncommon type of congenital adrenal hyperplasia (CAH) caused by mutations in the CYP17A1 gene encoding both 17α-hydroxylase and 17,20-lyase, essential for sex steroids production. Main clinical features include lack of pubertal development, hypertension, and hypokalemia. We report the first case of a 46,XX female homozygote for the p.Glu331del mutation in the CYP17A1 gene showing an atypical clinical presentation. She was evaluated the first time for primary amenorrhea and delayed puberty in the presence of low levels of androgens, 17ß-estradiol, serum cortisol, and high levels of progesterone and gonadotropins. After puberty, the patient did not show hypocortisolism and/or hypertension. She started estrogen therapy for pubertal induction, followed by ethinylestradiol/gestodene with clinical and biochemical stability during the follow-up period. At the age of 40 years, she developed hypokalemia and clinical signs of hypocortisolism. Oral corticosteroid treatment was started showing a prompt clinical improvement. Modeling analysis predicted the main outcome of the E331 deletion to impair cytochrome b5 binding, according to a major effect on the enzyme's lyase activity. These data broaden the molecular and clinical spectrum of CAH caused by 17α-hydroxylase deficiency and adds to current genotype-phenotype correlations.


Assuntos
Hiperplasia Suprarrenal Congênita/genética , Esteroide 17-alfa-Hidroxilase/genética , Adolescente , Feminino , Humanos
13.
PLoS One ; 12(3): e0174560, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28358911

RESUMO

BACKGROUND: To assess posterior pole (PP) retinal structure in patients with genetically confirmed autosomal dominant optic atrophy (ADOA) using new spectral domain optical coherence tomography (SD-OCT) segmentation technology. To analyze retinal PP thickness in relation to retinal sensitivity data from microperimetry (MP) in ADOA patients. METHODS AND FINDINGS: This prospective cross-sectional study included 11 patients with ADOA and 11 age-matched healthy subjects. All participants underwent both a "Posterior Pole" and "peripapillary RNFL (pRNFL)" scanning protocol using SD-OCT. Functional mapping of the PP was also performed using MP. A customized program was implemented in order to achieve accurate superimposition of MP sensitivity map onto SD-OCT map. The thickness of the PP different retinal layers and pRNFL was obtained and measured for each eye. Mean retinal sensitivity values and fixation stability were obtained and compared between ADOA patients and healthy subjects. Correlation analysis was performed on a point-to-point basis to evaluate the association between mean thickness and retinal sensitivity of each retinal layer. Total retinal thickness (TRT), Retinal Nerve Fiber Layer (RNFL), Ganglion Cell Layer (GCL), Inner Plexiform Layer (IPL), Inner Nuclear Layer (INL) and Inner Retinal Layers (IRL) at the posterior pole as well as pRNFL were significantly thinner in ADOA patients (P < 0.0001). On the contrary, the Outer Plexiform Layer (OPL) and the Outer Nuclear Layer (ONL) were significantly thicker in the ADOA group (P < 0.001). No significant differences were found in Retinal Pigment Epithelium (RPE) and Outer Retinal Layers (ORL) thickness between ADOA and controls. The average PP retinal sensitivity was significantly reduced in ADOA patients compared with controls (P < 0.001), as measured by microperimeter Nidek MP-1 (MP1). Fixation stability was significantly worse in the ADOA group (P = 0.01). The most severe sensitivity defects in ADOA patients were found at the level of the papillo-macular bundle (PMB). CONCLUSIONS: Inner retinal layers showed pathological changes in ADOA patients. In addition, the whole retinal PP (not only the PMB) was significantly altered in ADOA, both in terms of retinal thickness and sensitivity.


Assuntos
Atrofia Óptica Autossômica Dominante/diagnóstico por imagem , Doenças do Nervo Óptico/diagnóstico por imagem , Retina/diagnóstico por imagem , Tomografia de Coerência Óptica , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fibras Nervosas/patologia , Fibras Nervosas/ultraestrutura , Atrofia Óptica Autossômica Dominante/fisiopatologia , Doenças do Nervo Óptico/fisiopatologia , Retina/patologia , Retina/ultraestrutura , Células Ganglionares da Retina/patologia , Células Ganglionares da Retina/ultraestrutura , Acuidade Visual
15.
Eur J Hum Genet ; 25(2): 257-261, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27876818

RESUMO

Myotonic dystrophy type 1 is a multisystemic autosomal dominant disorder caused by the expansion of (CTG) n triplets in the 3'UTR of the DMPK gene, on chromosome 19q13.3. In the last years, few DM1 patients with different patterns of CCG/CTC interruptions at the 3' end of the DMPK expanded tract have been described. However, the role of these interruptions in DM1 pathogenesis is still unclear. To study the frequency, stability and the structure of DMPK variant expanded alleles in the Italian population, we have re-evaluated 254 Italian DM1 patients using triplet-primed PCR (TP-PCR), at both the 3' and 5' ends of the CTG expansion. In addition, three DM1 families were also investigated in order to analyze the intergenerational stability of the interrupted DMPK alleles. Fourteen DM1 patients showed a TP-PCR electrophoretic profile indicating CCG/CTC interruptions within the CTG expansion. Interestingly, interruptions have been detected and, for the first time, sequenced at the 5' end of the CTG array. Analysis of five intergenerational transmissions revealed a substantial intrafamilial stability of the DM1 mutation among relatives. Our results support the hypothesis that CCG/CTC interruptions within the DMPK expanded alleles have a stabilizing effect on the mutational dynamics and can modulate the severity of symptoms in DM1 patients.


Assuntos
Alelos , Distrofia Miotônica/genética , Miotonina Proteína Quinase/genética , Linhagem , Expansão das Repetições de Trinucleotídeos , Região 5'-Flanqueadora , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distrofia Miotônica/diagnóstico
16.
Nature ; 538(7624): 265-269, 2016 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-27706140

RESUMO

Chromosome conformation capture methods have identified subchromosomal structures of higher-order chromatin interactions called topologically associated domains (TADs) that are separated from each other by boundary regions. By subdividing the genome into discrete regulatory units, TADs restrict the contacts that enhancers establish with their target genes. However, the mechanisms that underlie partitioning of the genome into TADs remain poorly understood. Here we show by chromosome conformation capture (capture Hi-C and 4C-seq methods) that genomic duplications in patient cells and genetically modified mice can result in the formation of new chromatin domains (neo-TADs) and that this process determines their molecular pathology. Duplications of non-coding DNA within the mouse Sox9 TAD (intra-TAD) that cause female to male sex reversal in humans, showed increased contact of the duplicated regions within the TAD, but no change in the overall TAD structure. In contrast, overlapping duplications that extended over the next boundary into the neighbouring TAD (inter-TAD), resulted in the formation of a new chromatin domain (neo-TAD) that was isolated from the rest of the genome. As a consequence of this insulation, inter-TAD duplications had no phenotypic effect. However, incorporation of the next flanking gene, Kcnj2, in the neo-TAD resulted in ectopic contacts of Kcnj2 with the duplicated part of the Sox9 regulatory region, consecutive misexpression of Kcnj2, and a limb malformation phenotype. Our findings provide evidence that TADs are genomic regulatory units with a high degree of internal stability that can be sculptured by structural genomic variations. This process is important for the interpretation of copy number variations, as these variations are routinely detected in diagnostic tests for genetic disease and cancer. This finding also has relevance in an evolutionary setting because copy-number differences are thought to have a crucial role in the evolution of genome complexity.


Assuntos
Montagem e Desmontagem da Cromatina/genética , Variações do Número de Cópias de DNA/genética , Doença/genética , Duplicação Gênica/genética , Animais , DNA/genética , Facies , Feminino , Fibroblastos , Dedos/anormalidades , Deformidades Congênitas do Pé/genética , Expressão Gênica , Genômica , Deformidades Congênitas da Mão/genética , Masculino , Camundongos , Fenótipo , Fatores de Transcrição SOX9/genética
17.
Clin Chim Acta ; 455: 39-45, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26790753

RESUMO

Niemann-Pick C disease (NPCD) is a rare autosomal recessive neurovisceral disorder with a heterogeneous clinical presentation. Cholestan-3ß,5α,6ß-triol and 7-ketocholesterol have been proposed as biomarkers for the screening of NPCD. In this work, we assessed oxysterols levels in a cohort of Italian patients affected by NPCD and analyzed the obtained results in the context of the clinical, biochemical and molecular data. In addition, a group of patients affected by Niemann-Pick B disease (NPBD) were also analyzed. NPC patients presented levels of both oxysterols way above the cut off value, except for 5 siblings presenting the variant biochemical phenotype who displayed levels of 3ß,5α,6ß-triol below or just above the cut-off value; 2 of them presented also normal levels of 7-KC. Both oxysterols were extremely high in a patient presenting the neonatal systemic lethal phenotype. All NPB patients showed increased oxysterols levels. In conclusion, the reported LC-MS/MS assay provides a robust non-invasive screening tool for NPCD. However, false negative results can be obtained in patients expressing the variant biochemical phenotype. These data strengthen the concept that the results should always be interpreted in the context of the patients' clinical picture and filipin staining and/or genetic studies might still be undertaken in patients with normal levels of oxysterols if symptoms are highly suggestive of NPCD. Both oxysterols are significantly elevated in NPB patients; thus a differential diagnosis should always be performed in patients presenting isolated hepatosplenomegaly, a common clinical sign of both NPCD and NPBD.


Assuntos
Proteínas de Transporte/genética , Colestanos/sangue , Cetocolesteróis/sangue , Glicoproteínas de Membrana/genética , Mutação , Doenças de Niemann-Pick/sangue , Esfingomielina Fosfodiesterase/genética , Calibragem , Estudos de Coortes , Humanos , Itália , Doenças de Niemann-Pick/genética , Reprodutibilidade dos Testes
18.
Am J Med Genet A ; 170A(2): 297-305, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26639658

RESUMO

One set of missense mutations in the neuron specific beta tubulin isotype 3 (TUBB3) has been reported to cause malformations of cortical development (MCD), while a second set has been reported to cause isolated or syndromic Congenital Fibrosis of the Extraocular Muscles type 3 (CFEOM3). Because TUBB3 mutations reported to cause CFEOM had not been associated with cortical malformations, while mutations reported to cause MCD had not been associated with CFEOM or other forms of paralytic strabismus, it was hypothesized that each set of mutations might alter microtubule function differently. Here, however, we report two novel de novo heterozygous TUBB3 amino acid substitutions, G71R and G98S, in four patients with both MCD and syndromic CFEOM3. These patients present with moderately severe CFEOM3, nystagmus, torticollis, and developmental delay, and have intellectual and social disabilities. Neuroimaging reveals defective cortical gyration, as well as hypoplasia or agenesis of the corpus callosum and anterior commissure, malformations of hippocampi, thalami, basal ganglia and cerebella, and brainstem and cranial nerve hypoplasia. These new TUBB3 substitutions meld the two previously distinct TUBB3-associated phenotypes, and implicate similar microtubule dysfunction underlying both.


Assuntos
Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/patologia , Malformações do Desenvolvimento Cortical/genética , Malformações do Desenvolvimento Cortical/patologia , Mutação/genética , Tubulina (Proteína)/genética , Adulto , Sequência de Aminoácidos , Substituição de Aminoácidos , Criança , Pré-Escolar , Feminino , Fibrose , Humanos , Masculino , Dados de Sequência Molecular , Oftalmoplegia , Linhagem , Fenótipo , Homologia de Sequência de Aminoácidos , Adulto Jovem
19.
Cell Reprogram ; 17(4): 275-87, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26474030

RESUMO

The generation of human induced pluripotent stem cells (hiPSCs) derived from an autologous extraembryonic fetal source is an innovative personalized regenerative technology that can transform own-self cells into embryonic stem-like ones. These cells are regarded as a promising candidate for cell-based therapy, as well as an ideal target for disease modeling and drug discovery. Thus, hiPSCs enable researchers to undertake studies for treating diseases or for future applications of in utero therapy. We used a polycistronic lentiviral vector (hSTEMCCA-loxP) encoding OCT4, SOX2, KLF4, and cMYC genes and containing loxP sites, excisible by Cre recombinase, to reprogram patient-specific fetal cells derived from prenatal diagnosis for several genetic disorders, such as myotonic dystrophy type 1 (DM1), ß-thalassemia (ß-Thal), lymphedema-distichiasis syndrome (LDS), spinal muscular atrophy (SMA), cystic fibrosis (CF), as well as from wild-type (WT) fetal cells. Because cell types tested to create hiPSCs influence both the reprogramming process efficiency and the kinetics, we used chorionic villus (CV) and amniotic fluid (AF) cells, demonstrating how they represent an ideal cell resource for a more efficient generation of hiPSCs. The successful reprogramming of both CV and AF cells into hiPSCs was confirmed by specific morphological, molecular, and immunocytochemical markers and also by their teratogenic potential when inoculated in vivo. We further demonstrated the stability of reprogrammed cells over 10 and more passages and their capability to differentiate into the three embryonic germ layers, as well as into neural cells. These data suggest that hiPSCs-CV/AF can be considered a valid cellular model to accomplish pathogenesis studies and therapeutic applications.


Assuntos
Feto/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Animais , Células Cultivadas , Reprogramação Celular , Amostra da Vilosidade Coriônica , Fibrose Cística/embriologia , Pestanas/anormalidades , Pestanas/embriologia , Feminino , Feto/fisiologia , Vetores Genéticos , Humanos , Fatores de Transcrição Kruppel-Like/genética , Lentivirus/genética , Linfedema/embriologia , Camundongos , Atrofia Muscular Espinal/embriologia , Distrofia Miotônica/embriologia , Fator 3 de Transcrição de Octâmero/genética , Gravidez , Proteínas Proto-Oncogênicas c-myc/genética , Fatores de Transcrição SOXB1/genética , Transgenes , Talassemia beta/embriologia
20.
Case Rep Surg ; 2015: 916039, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26346436

RESUMO

Simultaneous bilateral spontaneous pneumothorax is a very rare clinical event, comprising approximately 1% of all spontaneous pneumothoraces. Clinical signs and symptoms may vary from mild chest pain and dyspnea to severe respiratory failure; nevertheless immediate treatment is mandatory as this condition can deteriorate and progress to tension pneumothorax. An underlying lung disease has been commonly described; in most istances primary or secondary tumors, interstitial diseases, and infectious diseases. Birt-Hogg-Dubè syndrome is a rare inherited disorder clinically characterized by multiple fibrofolliculomas, renal tumors, lung cysts, and, in ~24% of the patients, occurrence of spontaneous pneumothorax. In this case, we firstly report the concurrence of these rare conditions, as a patient presenting a simultaneous bilateral spontaneous pneumothorax was diagnosed with Birt-Hogg-Dubè syndrome based on the typical radiological findings and genetic testing of the folliculin gene located on chromosome 17.

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