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1.
Am J Hum Genet ; 107(5): 977-988, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33058759

RESUMO

PRKACA and PRKACB code for two catalytic subunits (Cα and Cß) of cAMP-dependent protein kinase (PKA), a pleiotropic holoenzyme that regulates numerous fundamental biological processes such as metabolism, development, memory, and immune response. We report seven unrelated individuals presenting with a multiple congenital malformation syndrome in whom we identified heterozygous germline or mosaic missense variants in PRKACA or PRKACB. Three affected individuals were found with the same PRKACA variant, and the other four had different PRKACB mutations. In most cases, the mutations arose de novo, and two individuals had offspring with the same condition. Nearly all affected individuals and their affected offspring shared an atrioventricular septal defect or a common atrium along with postaxial polydactyly. Additional features included skeletal abnormalities and ectodermal defects of variable severity in five individuals, cognitive deficit in two individuals, and various unusual tumors in one individual. We investigated the structural and functional consequences of the variants identified in PRKACA and PRKACB through the use of several computational and experimental approaches, and we found that they lead to PKA holoenzymes which are more sensitive to activation by cAMP than are the wild-type proteins. Furthermore, expression of PRKACA or PRKACB variants detected in the affected individuals inhibited hedgehog signaling in NIH 3T3 fibroblasts, thereby providing an underlying mechanism for the developmental defects observed in these cases. Our findings highlight the importance of both Cα and Cß subunits of PKA during human development.


Assuntos
Anormalidades Múltiplas/genética , Disfunção Cognitiva/genética , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/genética , Dedos/anormalidades , Mutação em Linhagem Germinativa , Defeitos dos Septos Cardíacos/genética , Polidactilia/genética , Dedos do Pé/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Animais , Sequência de Bases , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/patologia , AMP Cíclico/metabolismo , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/química , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/deficiência , Feminino , Dedos/patologia , Regulação da Expressão Gênica no Desenvolvimento , Defeitos dos Septos Cardíacos/diagnóstico , Defeitos dos Septos Cardíacos/patologia , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Holoenzimas/química , Holoenzimas/deficiência , Holoenzimas/genética , Humanos , Recém-Nascido , Masculino , Camundongos , Modelos Moleculares , Mosaicismo , Células NIH 3T3 , Linhagem , Polidactilia/diagnóstico , Polidactilia/patologia , Estrutura Secundária de Proteína , Dedos do Pé/patologia
2.
Am J Med Genet A ; 191(4): 1101-1106, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36598152

RESUMO

Mosaic genome-wide paternal uniparental disomy (GWpUPD) is a rare condition in which two euploid cell lines coexist in the same individual, one with biparental content and one with genome-wide paternal isodisomy. We report a complex prenatal diagnosis with discordant results from cultured and uncultured samples. A pregnant woman was referred for placental mesenchymal dysplasia and fetal omphalocele. Karyotype, array-CGH and Beckwith-Wiedemann Syndrome (BWS) testing (methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) of 11p15) performed on amniocytes were negative. After intrauterine fetal demise, the clinical suspicion persisted and BWS MS-MLPA was repeated on cultured cells from umbilical cord and amniotic fluid, revealing a mosaicism for KvH19 hypermethylation/KCNQ1OT1:TSS:DMR hypomethylation. These results, along with microsatellite analysis of the BWS region, were consistent with mosaic paternal 11p15 isodisomy. A concurrent maternal contamination exclusion test, analyzing polymorphic microsatellite markers on multiple chromosomes, showed an imbalance in favor of paternal alleles at all examined loci on cultured amniocytes and umbilical cord samples. This led to suspicion of mosaic GWpUPD, later confirmed by SNP-array, identifying a mosaic genome-wide paternal isodisomy affecting 60% of fetal cells. The assessment of mosaic GWpUPD requires multiple approaches beyond the current established diagnostic processes, also entertaining possible low-rate mosaicism. Clinical acumen and an integrated testing approach are the key to a successful diagnosis.


Assuntos
Síndrome de Beckwith-Wiedemann , Dissomia Uniparental , Humanos , Feminino , Gravidez , Placenta , Mosaicismo , Metilação de DNA , Síndrome de Beckwith-Wiedemann/genética , Células Cultivadas
3.
Hum Mutat ; 41(12): 2087-2093, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32906221

RESUMO

Clinical expression of Ellis-van Creveld syndrome (EvC) is variable and mild phenotypes have been described, including patients with mostly cardiac and limb involvement. Whether these cases are part of the EvC phenotypic spectrum or separate conditions is disputed. Herein, we describe a family with vertical transmission of atrioventricular canal defect (AVCD), common atrium, and postaxial polydactyly. Targeted sequencing of EVC, EVC2, WDR35, DYNC2LI1, and DYNC2H1 identified different compound heterozygosity in EVC genotypes in the two affected members, consisting of a nonsense (p.Arg622Ter) and a missense (p.Arg663Pro) variant in the father, and the same nonsense variant and a noncanonical splice-site in-frame change (c.1316-7A>G) in the daughter. Complementary DNA sequencing, immunoblot, and immunofluorescence experiments using patient-derived fibroblasts and Evc-/- mouse embryonic fibroblasts showed that p.Arg622Ter is a loss-of-function mutation, whereas p.Arg663Pro and the splice-site change c.1316-7A>G are hypomorphic variants resulting in proteins that retain, in part, the ability to complex with EVC2. Our molecular and functional data demonstrate that at least in some cases the condition characterized as "common atrium/AVCD with postaxial polydactyly" is a mild form of EvC due to hypomorphic EVC mutations, further supporting the occurrence of genotype-phenotype correlations in this syndrome.


Assuntos
Síndrome de Ellis-Van Creveld/genética , Dedos/anormalidades , Predisposição Genética para Doença , Defeitos dos Septos Cardíacos/genética , Proteínas de Membrana/genética , Mutação/genética , Polidactilia/genética , Dedos do Pé/anormalidades , Adulto , Animais , Criança , Pré-Escolar , Síndrome de Ellis-Van Creveld/diagnóstico por imagem , Família , Feminino , Dedos/diagnóstico por imagem , Defeitos dos Septos Cardíacos/diagnóstico por imagem , Humanos , Masculino , Camundongos , Linhagem , Polidactilia/diagnóstico por imagem , Dedos do Pé/diagnóstico por imagem
4.
Am J Med Genet A ; 170(10): 2531-9, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27513709

RESUMO

Previous reports summarized the seizure types occurring in patients with idic(15) syndrome. To better define this issue, we retrospectively analyzed the evolution of electroencephalogram findings and seizures in 35 patients with confirmed idic(15). Epilepsy occurred in 28 patients (80%), with a median age of onset of 3 years 3 months. The initial seizures were infantile spasms associated with a hypsarrhythmic electroencephalogram (nine patients), focal/generalized tonic (seven patients), or atypical absences (eight patients). High doses of oral steroids were given in all nine children with infantile spasms, with remission of seizures and resolution of electroencephalogram abnormalities. Among them, three were seizure free at the time of evaluation, but six later developed Lennox-Gastaut syndrome or Lennox-Gastaut-like syndrome. The eight patients with atypical absences developed Lennox-Gastaut syndrome or Lennox-Gastaut-like syndrome. Epilepsy was well controlled in 32% of the patients; satisfactorily controlled (seizures reduced >75%) in 21.4%; partially controlled (seizures reduced <50%) in 10.7%; and uncontrolled in 32%. One patient was not taking any anti-epileptic drugs by his parents' choice. Fourteen percent were on monotherapy; whereas the other 82% were on polytherapy. Seizures stopped at a median age of 5 years 5 months. The interictal electroencephalogram showed slow/sharp waves, and/or biphasic spikes-polyspikes, spike/wave complexes, and an excess of fast activity mainly over the fronto-temporal areas. Epilepsy is a major clinical challenge in patients with idic(15), associated with a poor prognosis in 55%. Frontal lobe seizures are a novel finding. © 2016 Wiley Periodicals, Inc.


Assuntos
Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/fisiopatologia , Eletroencefalografia , Convulsões/diagnóstico , Adolescente , Adulto , Idade de Início , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Aberrações Cromossômicas , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/terapia , Cromossomos Humanos Par 15/genética , Terapia Combinada , Hibridização Genômica Comparativa , Metilação de DNA , Eletroencefalografia/métodos , Feminino , Seguimentos , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Masculino , Fenótipo , Estudos Retrospectivos , Convulsões/genética , Convulsões/terapia , Adulto Jovem , Receptor Nicotínico de Acetilcolina alfa7/genética , Proteínas Centrais de snRNP/genética
5.
Nat Genet ; 39(8): 1007-12, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17603483

RESUMO

Noonan and LEOPARD syndromes are developmental disorders with overlapping features, including cardiac abnormalities, short stature and facial dysmorphia. Increased RAS signaling owing to PTPN11, SOS1 and KRAS mutations causes approximately 60% of Noonan syndrome cases, and PTPN11 mutations cause 90% of LEOPARD syndrome cases. Here, we report that 18 of 231 individuals with Noonan syndrome without known mutations (corresponding to 3% of all affected individuals) and two of six individuals with LEOPARD syndrome without PTPN11 mutations have missense mutations in RAF1, which encodes a serine-threonine kinase that activates MEK1 and MEK2. Most mutations altered a motif flanking Ser259, a residue critical for autoinhibition of RAF1 through 14-3-3 binding. Of 19 subjects with a RAF1 mutation in two hotspots, 18 (or 95%) showed hypertrophic cardiomyopathy (HCM), compared with the 18% prevalence of HCM among individuals with Noonan syndrome in general. Ectopically expressed RAF1 mutants from the two HCM hotspots had increased kinase activity and enhanced ERK activation, whereas non-HCM-associated mutants were kinase impaired. Our findings further implicate increased RAS signaling in pathological cardiomyocyte hypertrophy.


Assuntos
Cardiomiopatia Hipertrófica/genética , Síndrome LEOPARD/genética , Mutação de Sentido Incorreto , Síndrome de Noonan/genética , Proteínas Proto-Oncogênicas c-raf/genética , Animais , Células COS , Cardiomiopatia Hipertrófica/metabolismo , Chlorocebus aethiops , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Síndrome LEOPARD/metabolismo , Síndrome de Noonan/metabolismo , Estrutura Terciária de Proteína , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Proteínas Tirosina Fosfatases/genética , Proteínas Proto-Oncogênicas c-raf/química , Proteínas Proto-Oncogênicas c-raf/metabolismo , Transdução de Sinais , Transfecção , Proteínas ras/metabolismo
6.
Stem Cell Res ; 78: 103468, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38852424

RESUMO

Hypomyelinating leukodystrophies (HLD) are a group of heterogeneous genetic disorders characterized by a deficit in myelin deposition during brain development. Specifically, 4H-Leukodystrophy is a recessive disease due to biallelic mutations in the POLR3A gene, which encodes one of the subunits forming the catalytic core of RNA polymerase III (PolIII). The disease also presents non-neurological signs such as hypodontia and hypogonadotropic hypogonadism. Here, we report the generation of a human induced pluripotent stem cell (hiPSC) line from fibroblasts of the first identified carrier of the biallelic POLR3A variants c.1802 T > A and c.4072G > A.


Assuntos
Células-Tronco Pluripotentes Induzidas , RNA Polimerase III , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , RNA Polimerase III/genética , RNA Polimerase III/metabolismo , Linhagem Celular , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Masculino , Alelos
7.
Mov Disord ; 28(6): 787-94, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23677909

RESUMO

Mutations or exon deletions of the epsilon-sarcoglycan (SGCE) gene cause myoclonus-dystonia (M-D), but a subset of M-D patients are mutation-negative and the sensitivity and specificity of current genetic testing criteria are unknown. We screened 46 newly enrolled M-D patients for SGCE mutations and deletions; moreover, 24 subjects previously testing negative for SGCE mutations underwent gene dosage analysis. In our combined cohorts, we calculated sensitivity, specificity, positive and negative predictive values, and area under the curve of 2 published sets of M-D diagnostic criteria. A stepwise logistic regression was used to assess which patients' characteristics best discriminated mutation carriers and to calculate a new mutation predictive score ("new score"), which we validated in previously published cohorts. Nine of 46 (19.5%) patients of the new cohort carried SCGE mutations, including 5 novel point mutations and 1 whole-gene deletion; in the old cohort, 1 patient with a complex phenotype carried a 5.9-Mb deletion encompassing SGCE. Current diagnostic criteria had a poor ability to discriminate SGCE-positive from SGCE-negative patients in our cohort; conversely, age of onset, especially if associated with psychiatric features (as included in the new score), showed the best discriminatory power to individuate SGCE mutation carriers, both in our cohort and in the validation cohort. Our results suggest that young age at onset of motor symptoms, especially in association with psychiatric disturbance, are strongly predictive for SGCE positivity. We suggest performing gene dosage analysis by multiple ligation-dependent probe amplification (MLPA) to individuate large SGCE deletions that can be responsible for complex phenotypes.


Assuntos
Distúrbios Distônicos/genética , Predisposição Genética para Doença/genética , Mutação/genética , Sarcoglicanas/genética , Adulto , Distúrbios Distônicos/diagnóstico , Distúrbios Distônicos/fisiopatologia , Éxons/genética , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Curva ROC , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
8.
Stem Cell Res ; 67: 103023, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36638628

RESUMO

Familial Hypocalciuric Hypercalcemia (FHH1) is a rare autosomal dominant disease with low penetrance, caused by inactivating mutations of the calcium-sensing receptor (CaSR) gene, characterized by significant hypercalcemia, inappropriately normal serum PTH levels and a low urinary calcium level. Human induced pluripotent stem cells (hiPSCs) from a patient carrying a previously identified heterozygous mutation, a p.T972M amino acid substitution in cytoplasmic tail of CasR, were produced using a virus, xeno-free and non-integrative protocol.


Assuntos
Hipercalcemia , Células-Tronco Pluripotentes Induzidas , Humanos , Mutação Puntual , Receptores de Detecção de Cálcio/genética , Receptores de Detecção de Cálcio/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Hipercalcemia/genética , Mutação , Cálcio
9.
Eur J Hum Genet ; 31(4): 479-484, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36599940

RESUMO

Deleterious variants of DYNC2H1 gene are associated with a wide spectrum of skeletal ciliopathies (SC). We used targeted parallel sequencing to analyze 25 molecularly unsolved families with different SCs. Deleterious DYNC2H1 variants were found in six sporadic patients and two monozygotic (MZ) twins. Clinical diagnoses included short rib-polydactyly type 3 in two cases, and asphyxiating thoracic dystrophy (ATD) in one case. Remarkably, clinical diagnosis fitted with EvC, mixed ATD/EvC and short rib-polydactyly/EvC phenotypes in three sporadic patients and the MZ twins. EvC/EvC-like features always occurred in compound heterozygotes sharing a previously unreported splice site change (c.6140-5A>G) or compound heterozygotes for two missense variants. These results expand the DYNC2H1 mutational repertoire and its clinical spectrum, suggesting that EvC may be occasionally caused by DYNC2H1 variants presumably acting as hypomorphic alleles.


Assuntos
Ciliopatias , Dineínas do Citoplasma , Síndrome de Ellis-Van Creveld , Polidactilia , Humanos , Ciliopatias/diagnóstico , Ciliopatias/genética , Dineínas do Citoplasma/genética , Síndrome de Ellis-Van Creveld/diagnóstico , Síndrome de Ellis-Van Creveld/genética , Mutação , Polidactilia/genética
10.
Haematologica ; 97(1): 47-55, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21993670

RESUMO

BACKGROUND: The genetic characterization of chronic lymphocytic leukemia cells correlates with the behavior, progression and response to treatment of the disease. DESIGN AND METHODS: Our aim was to investigate the role of ATM gene alterations, their biological consequences and their value in predicting disease progression. The ATM gene was analyzed by denaturing high performance liquid chromatography and multiplex ligation probe amplification in a series of patients at diagnosis. The results were correlated with immunoglobulin gene mutations, cytogenetic abnormalities, ZAP-70 and CD38 expression, TP53 mutations, gene expression profile and treatment-free interval. RESULTS: Mutational screening of the ATM gene identified point mutations in 8/57 cases (14%). Multiplex ligation probe amplification analysis identified six patients with 11q deletion: all of them had at least 20% of deleted cells, analyzed by fluorescent in situ hybridization. Overall, ATM point mutations and deletions were detected in 14/57 (24.6%) cases at presentation, representing the most common unfavorable genetic anomalies in chronic lymphocytic leukemia, also in stage A patients. Patients with deleted or mutated ATM had a significantly shorter treatment-free interval compared to patients without ATM alterations. ATM-mutated cases had a peculiar gene expression profile characterized by the deregulation of genes involved in apoptosis and DNA repair. Finally, definition of the structure of the ATM-mutated protein led to a hypothesis that functional abnormalities are responsible for the unfavorable clinical course of patients carrying these point mutations. CONCLUSIONS: ATM alterations are present at diagnosis in about 25% of individuals with chronic lymphocytic leukemia; these alterations are associated with a peculiar gene expression pattern and a shorter treatment-free interval.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Progressão da Doença , Perfilação da Expressão Gênica , Leucemia Linfocítica Crônica de Células B/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genética , Adulto , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/metabolismo , Análise por Conglomerados , Proteínas de Ligação a DNA/metabolismo , Feminino , Duplicação Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Proteínas Serina-Treonina Quinases/metabolismo , Reprodutibilidade dos Testes , Análise de Sobrevida , Proteínas Supressoras de Tumor/metabolismo
11.
Genes Chromosomes Cancer ; 50(4): 263-74, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21319261

RESUMO

Given that TP53 alterations predict prognosis and response to therapy in chronic lymphocytic leukemia (CLL), screening for TP53 mutations has an increasing role in patient management. TP53 direct sequencing is a time-consuming method, while the AmpliChip p53 Research Test is a novel non time-consuming microarray-based resequencing assay and queries Exons 2-11. We evaluated the impact of TP53 mutations on clinical outcome by analyzing 98 untreated CLL using the AmpliChip p53 Research Test and direct sequencing and performed microarrays analysis on TP53 mutated and/or deleted cases. The AmpliChip p53 Research Test detected 17 mutations in 14 patients (17.3%); a significant association between TP53 mutations and del(17p) was recorded. From a clinical standpoint, a higher percentage of mutation was found in CLL with unfavorable outcome (17.2% vs. 7.1% in progressive vs. stable cases). Detection of TP53 mutations by the AmpliChip p53 Research Test was associated with a significantly worse survival (P = 0.0002). Comparison of the array and direct sequencing tests showed that the p53 Research Test detected more mutations, although it failed to identify two microdeletions. Finally, microarrays analysis showed a more distinctive signature associated with del(17p) than with TP53 mutations, likely due to a concomitant gene dosage effect. The AmpliChip p53 Research Test is a straightforward method that bears prognostic value. This study confirms a high percentage of TP53 mutations in CLL with unfavorable outcome and a significant association between TP53 aberrations and del(17p). Finally, specific gene expression profiles are recognized for TP53 alterations.


Assuntos
Genes p53/genética , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular , Deleção Cromossômica , Cromossomos Humanos Par 17/genética , Progressão da Doença , Feminino , Perfilação da Expressão Gênica/métodos , Instabilidade Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Mutação Puntual , Prognóstico , Deleção de Sequência/genética
12.
Stem Cell Res ; 63: 102846, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35759972

RESUMO

Mucopolysaccharidosis type II (Hunter Syndrome) is a rare X-linked inherited lysosomal storage disorder presenting a wide genetic heterogeneity. It is due to pathogenic variants in the IDS gene, causing the deficit of the lysosomal hydrolase iduronate 2-sulfatase, degrading the glycosaminoglycans (GAGs) heparan- and dermatan-sulfate. Based on the presence/absence of neurocognitive signs, commonly two forms are recognized, the severe and the attenuate ones. Here we describe a line of induced pluripotent stem cells, generated from dermal fibroblasts, carrying the mutation c.479C>T, and obtained from a patient showing an attenuated phenotype. The line will be useful to study the disease neuropathogenesis.


Assuntos
Iduronato Sulfatase , Células-Tronco Pluripotentes Induzidas , Mucopolissacaridose II , Glicosaminoglicanos , Humanos , Iduronato Sulfatase/genética , Ácido Idurônico , Células-Tronco Pluripotentes Induzidas/patologia , Mucopolissacaridose II/genética , Mucopolissacaridose II/patologia , Fenótipo
13.
Stem Cell Res ; 63: 102835, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35714448

RESUMO

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease affecting both upper and lower motoneurons. The transactive response DNA binding protein (TARDBP) gene, encoding for TDP-43, is one of the most commonly mutated gene associated with familial cases of ALS (10%). We generated a human induced pluripotent stem cell (hiPSC) line from the fibroblasts of an asymptomatic subject carrying the TARDBP p.G376D mutation. This mutation is very rare and was described in a large Apulian family, in which all ALS affected members are carriers of the mutation. The subject here described is the first identified asymptomatic carrier of the mutation.


Assuntos
Esclerose Lateral Amiotrófica , Células-Tronco Pluripotentes Induzidas , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Heterozigoto , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Mutação/genética
14.
Stem Cell Res ; 65: 102946, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36272304

RESUMO

Charcot-Marie-Tooth type 4B3 (CMT4B3) is a rare subtype of hereditary neuropathy associated with variants in the MTMR5/SBF1 gene. Herein, we report the generation and characterization of a hiPSC line from a 12-year-old Italian girl with early onset severe polyneuropathy with motor and axonal involvement, harboring biallelic variants in the MTMR5/SBF1 gene. Fibroblasts were reprogrammed using non-integrating episomal plasmids, and iPSCs successfully passed the stemness and pluripotency tests. Patient-specific hiPSCs were produced to obtain a disease model for the study of this rare condition.


Assuntos
Doença de Charcot-Marie-Tooth , Peptídeos e Proteínas de Sinalização Intracelular , Células-Tronco Pluripotentes , Criança , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Feminino , Doença de Charcot-Marie-Tooth/genética , Linhagem Celular
15.
Neurogenetics ; 12(3): 233-40, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21365283

RESUMO

We report the detailed clinical presentation and molecular features of a spinal neurofibromatosis familial case where a 40-year-old woman, presenting with multiple bilateral spinal neurofibromas and no other clinical feature of neurofibromatosis type 1 (NF1), inherited a paternal large multiexonic deletion (c.5944-?_7126+?del) which resulted in NF1 gene haploinsufficiency at the RNA level. In the clinically unaffected 73-year-old father, spinal cord MRI disclosed bilateral and symmetrical hypertrophy of spinal lumbosacral roots. Our study widens the phenotypic and mutational spectrum of NF1 and illustrates the difficulties of counseling patients with border-line or atypical presentation of this disorder.


Assuntos
Deleção de Genes , Genes da Neurofibromatose 1 , Neurofibromatoses/genética , Nervos Espinhais/patologia , Adulto , Idoso , Análise Mutacional de DNA , Éxons , Família , Feminino , Humanos , Masculino , Neurofibromatoses/diagnóstico , Neurofibromatoses/diagnóstico por imagem , Neurofibromatoses/patologia , Linhagem , Radiografia , Nervos Espinhais/diagnóstico por imagem
16.
Am J Med Genet A ; 155A(3): 582-5, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21344624

RESUMO

Anecdotal cases of polymicrogyria (PMG; a malformation of cortical development consisting of an excessive number of small gyri with abnormal lamination) in patients with neurofibromatosis type 1 (NF1) have been described; however, the cases were unilateral and had negative NF1 genetic testing. We describe an 11-year-old girl with NF1 manifesting as a complex epileptic syndrome, including partial seizures secondarily generalized and status epilepticus, who had in association, bilateral, asymmetrical (opercular and paracentral lobular) PMG. She had a 1-bp deletion (c.1862delC) in exon 12b of the NF1 gene. It is notable that, given the key role played by the NF1 gene product, neurofibromin, in normal brain development, and the relatively high frequency of other brain findings in NF1, there are not more NF1 cases with brain malformations manifesting as PMG.


Assuntos
Encéfalo/patologia , Malformações do Desenvolvimento Cortical/complicações , Neurofibromatose 1/complicações , Criança , Feminino , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Gravidez
17.
Am J Med Genet A ; 152A(6): 1467-73, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20503322

RESUMO

We report on the clinical and molecular features of a family in which neurofibromatosis type 1 (NF1) occurred in two of three siblings born to unaffected parents and in one granddaughter. Linkage analysis showed that the two affected siblings and the daughter of one of them shared the same paternal allele, whereas they had inherited different maternal alleles. We detected a disease-causing deletion (c.4773-3622-?_5749+?del) encompassing three NF1 gene exons in affected individuals. This mutation occurred on the paternally derived allele, arguing for a germline mosaicism in the probands' father. Real-time PCR showed that the mutation was present in about 10-17% of the paternal sperms. Current results confirm that germline mosaicism can explain the recurrence of NF1 in offspring of unaffected parents.


Assuntos
Mutação em Linhagem Germinativa , Mosaicismo , Neurofibromatose 1/genética , Neurofibromina 1/genética , Alelos , Éxons/genética , Pai , Feminino , Humanos , Masculino , Linhagem , Recidiva , Deleção de Sequência
18.
Genes (Basel) ; 11(4)2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32224912

RESUMO

DNA methylation in the human genome is largely programmed and shaped by transcription factor binding and interaction between DNA methyltransferases and histone marks during gamete and embryo development. Normal methylation profiles can be modified at single or multiple loci, more frequently as consequences of genetic variants acting in cis or in trans, or in some cases stochastically or through interaction with environmental factors. For many developmental disorders, specific methylation patterns or signatures can be detected in blood DNA. The recent use of high-throughput assays investigating the whole genome has largely increased the number of diseases for which DNA methylation analysis provides information for their diagnosis. Here, we review the methylation abnormalities that have been associated with mono/oligogenic diseases, their relationship with genotype and phenotype and relevance for diagnosis, as well as the limitations in their use and interpretation of results.


Assuntos
Metilação de DNA , Epigenômica , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Genoma Humano , Humanos , Fenótipo
19.
Ann Hum Genet ; 73(Pt 5): 532-9, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19691550

RESUMO

We screened ATM gene mutations in 104 Italian Ataxia-Telangiectasia patients from 91 unrelated families (detection rate 90%) and found 21 recurrent mutations in 63 families. The majority (67%) of patients were compound heterozygotes, while 33% were homozygotes. To determine the existence of common haplotypes and potential founder effects, we analyzed five microsatellite markers within and flanking the ATM gene. Haplotype analysis was carried out in 48/63 families harbouring 16 of the 21 recurrent mutations. Forty different haplotypes were detected in the 48 A-T families studied. We found that the majority of patients with the same recurrent mutation originated from the same geographical area. All but one recurrent mutation analyzed displayed a common haplotype suggesting a single origin that then spread to different geographical areas. The high number of different haplotypes does not allow the screening of ATM mutations by haplotype analysis alone in the Italian population. The finding of recurrent public mutations without founder effect suggests the existence of 'mild' hot spots of mutation located along the sequence of the ATM gene.


Assuntos
Ataxia Telangiectasia/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Efeito Fundador , Mutação , Proteínas Serina-Treonina Quinases/genética , Proteínas Supressoras de Tumor/genética , Proteínas Mutadas de Ataxia Telangiectasia , Células Cultivadas , Feminino , Haplótipos , Humanos , Itália , Masculino , Linhagem
20.
J Clin Endocrinol Metab ; 93(3): 910-3, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18073314

RESUMO

CONTEXT: Type 2 deiodinase (D2) converts T4 in T3 in several human tissues, including hypothalamus and pituitary, and, therefore, plays a pivotal role in the negative feedback regulation of TSH secretion. A common variant of the gene, threonine (Thr) 92 alanine (Ala), has been identified and associated with decreased D2 enzymatic activity. OBJECTIVE: Our objective was to investigate whether this polymorphism predicts the T4 dosage needed to obtain target TSH levels in thyroidectomized patients. SETTING: Ambulatory patients were included in the study. PATIENTS: A total of 191 consecutive thyroid cancer patients, previously treated by near total thyroidectomy and radioiodine ablation, were studied. They were on stable T4 dose treatment aimed at obtaining either suppressed (supp) (n=117, <0.1 mU/liter) or near-supp (n=74, >or=0.1<0.5 mU/liter) serum TSH levels. MAIN OUTCOME MEASURES: DNA genotyping for D2 Thr92Ala variant and evaluation of T4 dose (microg/kg) needed to obtain target TSH levels were determined. RESULTS: Ala/Ala homozygous patients needed a higher T4 dose as compared with patients carrying the Thr92 variant (X/Thr patients) according to a recessive genetic model (2.08+/-0.43 vs. 1.90+/-0.35 microg/kg; P<0.05). This difference was observable in the near-supp group (P=0.002), but not in the supp group (P=0.4). CONCLUSIONS: D2 Thr92Ala polymorphism seems to predict the need for higher T4 intake in thyroidectomized patients. If this finding is confirmed in additional studies, it may predict the T4 requirement to suppress TSH on the basis of the individual genetic background.


Assuntos
Iodeto Peroxidase/genética , Polimorfismo Genético , Tireoidectomia , Tireotropina/sangue , Tiroxina/uso terapêutico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Iodotironina Desiodinase Tipo II
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