RESUMO
Polycystic ovary syndrome (PCOS) is a condition resulting from the interaction between environmental factors and hereditary components, profoundly affecting offspring development. Although the etiology of this disease remains unclear, aberrant in utero androgen exposure is considered one of the pivotal pathogenic factors. Herein, we demonstrate the intergenerational inheritance of PCOS-like phenotypes in F2 female offspring through F1 males caused by maternal testosterone exposure in F0 mice. We found impaired serum hormone expression and reproductive system development in prenatal testosterone-treated F1 male and F2 female mice (PTF1 and PTF2). In addition, downregulated N6-methyladenosine (m6A) methyltransferase and binding proteins induced mRNA hypomethylation in the PTF1 testis, including frizzled-6 (Fzd6). In the PTF2 ovary, decreased FZD6 protein expression inhibited the mammalian target of rapamycin (mTOR) signaling pathway and activated Forkhead box O3 (FoxO3) phosphorylation, which led to impaired follicular development. These data indicate that epigenetic modification of the mTOR signaling pathway could be involved in the intergenerational inheritance of maternal testosterone exposure-induced impairments in the PTF2 ovary through male PTF1 mice.
Assuntos
Herança Paterna , Efeitos Tardios da Exposição Pré-Natal , Testosterona , Animais , Feminino , Masculino , Camundongos , Efeitos Tardios da Exposição Pré-Natal/genética , Gravidez , Testosterona/sangue , Herança Paterna/genética , Exposição Materna/efeitos adversos , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/metabolismo , Síndrome do Ovário Policístico/induzido quimicamente , Epigênese Genética , Androgênios/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Ovário/metabolismo , Ovário/efeitos dos fármacos , Testículo/metabolismo , Testículo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Metilação de DNA/efeitos dos fármacos , Proteína Forkhead Box O3/metabolismo , Proteína Forkhead Box O3/genéticaRESUMO
OBJECTIVE: This study aimed to delineate the age-dependent clinical penetrance and expression of heterozygous rearranged during transfection (RET) missense mutations associated with multiple endocrine neoplasia 2A (MEN2A) according to parental inheritance. DESIGN: This was an observational study of RET carriers operated for MEN2A-associated tumors between 1985 and 2021. METHODS: Kaplan-Meier time-to-event and multivariable Cox proportional hazards regression analyses were performed on node metastases from medullary thyroid cancer, pheochromocytoma, bilateral pheochromocytoma, and primary hyperparathyroidism. RESULTS: Some 405 (70.1%) of 578 patients carrying heterozygous MEN2A RET missense mutations had information about the parental inheritance of the trait. On Kaplan-Meier analysis, offspring who inherited the trait from the father developed node metastases (Plog-rank= 0.007), pheochromocytoma (Plog-rank= 0.029), bilateral pheochromocytoma (Plog-rank= 0.002), and primary hyperparathyroidism (Plog-rank= 0.018) at a significantly younger age than offspring who inherited the trait from the mother. On multivariable Cox regression, controlling for index status, offspring sex, and (where feasible) mutational risk, parental inheritance was consistently associated with each MEN2A-associated tumor (hazard ratios (HR) = 1.7-1.8 for the earlier manifestations node metastases and pheochromocytoma vs HR of 2.9-3.4 for the late manifestations bilateral pheochromocytoma and primary hyperparathyroidism). Herein, node metastases were 3.1- and 1.7-fold more closely associated with mutational risk (HR of 5.3 for high and 2.9 for moderate-high risk mutations vs low-moderate risk mutations) than parental inheritance (HR = 1.7). CONCLUSION: These findings illustrate the importance of considering not just mutational risk but also parental inheritance when it comes to personalization of screening for and early detection of the various components of MEN2A-associated tumors.
Assuntos
Herança Materna/genética , Neoplasia Endócrina Múltipla Tipo 2a/genética , Mutação de Sentido Incorreto/genética , Herança Paterna/genética , Penetrância , Caracteres Sexuais , Neoplasias das Glândulas Suprarrenais/genética , Adulto , Carcinoma Neuroendócrino/genética , Feminino , Heterozigoto , Humanos , Hiperparatireoidismo/genética , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Feocromocitoma/genética , Modelos de Riscos Proporcionais , Neoplasias da Glândula Tireoide/genéticaRESUMO
OBJECTIVE: We present partial monosomy 8p (8p23.2âpter) and partial trisomy 15q (15q21.2âqter) and incidental detection of a familial chromosome translocation of paternal origin in a pregnancy associated with increased nuchal translucency (NT) and an abnormal maternal serum screening result. CASE REPORT: A 29-year-old primigravid woman underwent chorionic villus sampling (CVS) at 13 weeks of gestation because of an increased NT thickness of 3.2 mm at 12 weeks of gestation and an abnormal maternal serum screening for Down syndrome result with a calculated risk of 1/29. Her husband was 33 years old, and there was no family history of congenital malformations. CVS revealed a derived chromosome 8 or der(8). Cytogenetic analysis of the parents revealed a karyotype of 46,XY,t(8;15)(p21.3;q13) in the father and a karyotype of 46,XX in the mother. The CVS result was 46,XY,der(8)t(8;15)(p21.3;q13)pat. The woman requested for amniocentesis at 16 weeks of gestation. Array comparative genomic hybridization (aCGH) analysis on the DNA extracted from uncultured amniocytes revealed a result of arr 8p23.3p23.2 (191,530-2,625,470) × 1.0, arr 15q21.2q26.3 (50,903,432-102,338,129) × 3.0 with a 2.434-Mb deletion of 8p23.3-p23.2 including DLGAP2, CLN8 and ARHGEF10, and a 51.435-Mb duplication of 15q21.2-q26.3 including CYP19A1 and IGF1R. Conventional cytogenetic analysis of cultured amniocytes revealed the result of 46,XY,der(8) t(8;15)(p23.2;q21.2)pat in the fetus. The pregnancy was subsequently terminated, and a malformed fetus was delivered with characteristic craniofacial dysmorphism. CONCLUSION: Maternal serum screening and NT screening may incidentally detect familial unbalanced reciprocal translocations, and aCGH analysis is useful for a precise determination of the breakpoints of the translocation and the involvement of the related genes under such a circumstance.
Assuntos
Anormalidades Múltiplas/diagnóstico , Translocação Genética/genética , Trissomia/diagnóstico , Anormalidades Múltiplas/embriologia , Anormalidades Múltiplas/genética , Aborto Eugênico , Adulto , Amostra da Vilosidade Coriônica , Deleção Cromossômica , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 8/genética , Hibridização Genômica Comparativa , Análise Citogenética , Feminino , Humanos , Achados Incidentais , Masculino , Testes para Triagem do Soro Materno , Medição da Translucência Nucal , Herança Paterna/genética , Gravidez , Trissomia/genéticaRESUMO
OBJECTIVE: The aim is to develop a novel noninvasive prenatal testing (NIPT) method that simultaneously performs fetal aneuploidy screening and the detection of de novo and paternally derived mutations. METHODS: A total of 68 pregnancies, including 26 normal pregnancies, 7 cases with fetal aneuploidies, 7 cases with fetal achondroplasia or thanatophoric dysplasia, 18 cases with fetal skeletal abnormalities, and 10 cases with ß-thalassemia high risk were recruited. Plasma cell-free DNA was amplified by Targeted And Genome-wide simultaneous sequencing (TAGs-seq) to generate around 99% of total reads covering the whole-genome region and around 1% covering the target genes. The reads on the whole-genome region were analyzed for fetal aneuploidy using a binary hypothesis T-score and the reads on target genes were analyzed for point mutations by calculating the minor allelic frequency of loci on FGFR3 and HBB. TAGs-seq results were compared with conventional NIPT and diagnostic results. RESULTS: In each sample, TAGs-seq generated 44.7-54 million sequencing reads covering the whole-genome region of 0.1-3× and the target genes of >1000×depth. All cases of fetal aneuploidy and de novo mutations of achondroplasia/thanatophoric dysplasia were identified with high sensitivities and specificities except for one false-negative paternal mutation of ß-thalassemia. CONCLUSIONS: TAGs-seq is a novel NIPT method that combines the fetal aneuploidy screening and the detection of de novo FGFR3 mutations and paternal HBB mutations.
Assuntos
Aneuploidia , Feto/anormalidades , Teste Pré-Natal não Invasivo/métodos , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/análise , Talassemia beta/complicações , Adulto , Feminino , Feto/metabolismo , Humanos , Teste Pré-Natal não Invasivo/estatística & dados numéricos , Herança Paterna/genética , Gravidez , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/sangue , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Talassemia beta/diagnóstico , Talassemia beta/epidemiologiaRESUMO
A growing body of evidence has shown that gestational exposure to environmental factors such as imbalanced diet, environmental chemicals, and stress can lead to late-onset health effects in offspring and that some of these effects are heritable by the next generation and subsequent generations. Furthermore, altered epigenetic modifications in DNA methylation, histone modifications and small RNAs in a single sperm genome have been shown to transmit disease phenotypes acquired from the environment to later generations. Recently, our group found that gestational exposure of F0 pregnant dams to an inorganic arsenic, sodium arsenite, increases the incidence of hepatic tumors in male F2 mice, and the effects are paternally transmitted to the F2. Here, we first overview the epigenetic changes involved in paternal intergenerational and transgenerational inheritance caused by exposure to environmental factors. Then, we discuss our recent studies regarding paternal inheritance of the tumor-augmenting effects in F2 mice by gestational arsenite exposure, in which we investigated alterations of DNA methylation status in F2 tumors and causative F1 sperm. We also discuss the possible targets of the F2 effects. Finally, we discuss future perspectives on the studies that are needed to fully understand the health effects of arsenic exposure.
Assuntos
Arsênio/efeitos adversos , Epigênese Genética/efeitos dos fármacos , Herança Paterna/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Animais , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Epigênese Genética/genética , Feminino , Genoma/efeitos dos fármacos , Genoma/genética , Humanos , Herança Paterna/genética , Fenótipo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genéticaRESUMO
Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by a mutation or deletion of the maternally inherited UBE3A allele. In neurons, the paternally inherited UBE3A allele is silenced in cis by a long non-coding RNA called UBE3A-ATS. Here, as part of a systematic screen, we found that Cas9 can be used to activate ('unsilence') paternal Ube3a in cultured mouse and human neurons when targeted to Snord115 genes, which are small nucleolar RNAs that are clustered in the 3' region of Ube3a-ATS. A short Cas9 variant and guide RNA that target about 75 Snord115 genes were packaged into an adeno-associated virus and administered to a mouse model of AS during the embryonic and early postnatal stages, when the therapeutic benefit of restoring Ube3a is predicted to be greatest1,2. This early treatment unsilenced paternal Ube3a throughout the brain for at least 17 months and rescued anatomical and behavioural phenotypes in AS mice. Genomic integration of the adeno-associated virus vector into Cas9 target sites caused premature termination of Ube3a-ATS at the vector-derived polyA cassette, or when integrated in the reverse orientation, by transcriptional collision with the vector-derived Cas9 transcript. Our study shows that targeted genomic integration of a gene therapy vector can restore the function of paternally inherited UBE3A throughout life, providing a path towards a disease-modifying treatment for a syndromic neurodevelopmental disorder.
Assuntos
Síndrome de Angelman/genética , Síndrome de Angelman/terapia , Proteína 9 Associada à CRISPR/metabolismo , Sistemas CRISPR-Cas/genética , Edição de Genes , Terapia Genética/métodos , RNA Longo não Codificante/genética , Ubiquitina-Proteína Ligases/genética , Animais , Proteína 9 Associada à CRISPR/genética , Dependovirus/genética , Modelos Animais de Doenças , Feminino , Inativação Gênica , Vetores Genéticos/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sistema Nervoso/metabolismo , Herança Paterna/genética , Fenótipo , RNA Guia de Cinetoplastídeos/genéticaRESUMO
OBJECTIVE: We present detection of paternal origin of fetal trisomy 18 in a pregnancy conceived by assisted reproductive technology (ART) and in vitro fertilization (IVF). CASE REPORT: A 39-year-old woman underwent ART and IVF because of primary infertility. The woman was infertile because of myoma and endometriosis. Her husband was 39 years old, and the sperm analysis was normal. The couple was phenotypically normal. This pregnancy was conceived successfully by IVF. She received non-invasive prenatal testing at 11 weeks of gestation, the result showed a high risk for trisomy 18. She underwent chorionic villus sampling at 12 weeks of gestation, and the result was 47,XY,+18 in 24/24 cultured chorionic villi cells. Prenatal ultrasound findings were unremarkable. She underwent amniocentesis at 17 weeks of gestation, and the result was 47,XY,+18 in 20/20 colonies of cultured amniocytes. The pregnancy was subsequently terminated. Postnatal cytogeneic analysis confirmed the prenatal diagnosis. Polymorphic DNA marker analysis on the DNAs extracted from the umbilical cord and parental bloods showed a paternal origin of the extra chromosome 18, indicating a paternal origin of fetal trisomy 18. Cytogenetic analysis of paternal blood revealed a karyotype of 46,XY. CONCLUSION: Fetal trisomy 18 in pregnancies conceived by ART may be of paternal origin, and determination of paternal origin by polymorphic DNA marker analysis is useful for genetic counseling under such a circumstance.
Assuntos
Fertilização in vitro , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Adulto , Amniocentese , Amostra da Vilosidade Coriônica , Feminino , Marcadores Genéticos , Humanos , Masculino , Herança Paterna/genética , Gravidez , Ultrassonografia Pré-NatalRESUMO
XLαs, the extra-large isoform of alpha-subunit of the stimulatory guanine nucleotide-binding protein (Gsα), is paternally expressed. The significance of XLαs in humans remains largely unknown. Here, we report a patient who presented with increased bone mass, hypophosphatemia, and elevated parathyroid hormone (PTH) levels. His serum calcium was in the lower limit of the normal range. Whole exome sequencing of this subject found a novel non-sense variant c.424G>T (p. G142*) in the first exon of XLαs, which was inherited from his father and transmitted to his daughter. This variant was predicted to exclusively influence the expression of XLαs, while possibly having no significant effects on other gene products of this locus. Ellsworth-Howard test revealed normal renal response to PTH in proband. Human SaOS2 cells transfected with mutant XLαs failed to generate cyclic adenosine monophosphate under PTH stimulation, indicating skeletal resistance to this hormone. This subject showed higher circulating sclerostin, dickkopf1, and osteoprotegerin (OPG) levels, while lower receptor activator of nuclear factor kappa-B ligand/OPG ratio, leading to reduced bone resorption. Our findings indicate that XLαs plays a critical role in bone metabolism and GNAS locus should be considered as a candidate gene for high bone mass.
Assuntos
Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Predisposição Genética para Doença , Hipofosfatemia Familiar/genética , Osteopetrose/genética , Adulto , Linhagem Celular , Códon sem Sentido/genética , Éxons/genética , Humanos , Hipofosfatemia Familiar/patologia , Masculino , Osteopetrose/patologia , Hormônio Paratireóideo/farmacologia , Herança Paterna/genética , Pseudo-Hipoparatireoidismo/genética , Pseudo-Hipoparatireoidismo/patologiaRESUMO
Allopolyploidy is acknowledged as an important force in plant evolution. Frequent allopolyploidy in Nicotiana across different timescales permits the evaluation of genome restructuring and repeat dynamics through time. Here we use a clustering approach on high-throughput sequence reads to identify the main classes of repetitive elements following three allotetraploid events, and how these are inherited from the closest extant relatives of the maternal and paternal subgenome donors. In all three cases, there was a lack of clear maternal, cytoplasmic bias in repeat evolution, i.e., lack of a predicted bias towards maternal subgenome-derived repeats, with roughly equal contributions from both parental subgenomes. Different overall repeat dynamics were found across timescales of <0.5 (N. rustica L.), 4 (N. repanda Willd.) and 6 (N. benthamiana Domin) Ma, with nearly additive, genome upsizing, and genome downsizing, respectively. Lower copy repeats were inherited in similar abundance to the parental subgenomes, whereas higher copy repeats contributed the most to genome size change in N. repanda and N. benthamiana. Genome downsizing post-polyploidisation may be a general long-term trend across angiosperms, but at more recent timescales there is species-specific variance as found in Nicotiana.
Assuntos
Nicotiana/genética , Poliploidia , Sequências Repetitivas de Ácido Nucleico/genética , Citoplasma/metabolismo , DNA de Plantas/genética , Evolução Molecular , Tamanho do Genoma/genética , Genoma de Planta/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Herança Materna/genética , Herança Paterna/genética , Duplicações Segmentares Genômicas/genética , Especificidade da Espécie , Nicotiana/metabolismoAssuntos
Mosaicismo/embriologia , Herança Paterna/genética , Esclerose Tuberosa/diagnóstico , Esclerose Tuberosa/genética , Adulto , Feminino , Variação Genética , Humanos , Masculino , Ilustração Médica , Gravidez , Espermatozoides/metabolismo , Esclerose Tuberosa/embriologia , Proteína 2 do Complexo Esclerose Tuberosa/genética , Ultrassonografia Pré-NatalRESUMO
Pancreatoblastoma is a rare type of pancreatic cancer in children. Here, we describe a case in which Beckwith-Wiedemann syndrome (BWS) was first suspected because of placental mesenchymal dysplasia. Although the baby did not show the stigmata characteristic of BWS or abnormal peripheral blood methylation, she developed a massive pancreatoblastoma 2 months later. She survived after partial excision of the tumor and chemotherapy. The methylation pattern of the pancreatoblastoma tissue was typical of BWS. Single nucleotide polymorphism (SNP) array analyzes revealed that the pancreatoblastoma tissue had genome-wide loss of maternal alleles. Peripheral blood and nontumor pancreatic tissue showed normal biparental genomic contribution. Interphase fluorescence in situ hybridization analysis with centromeric probes for chromosomes 2 and 11 revealed haploid pancreatoblastoma cells, whereas the placental mesenchymal dysplasia tissue and nontumor pancreas tissue showed diploidy. SNP genotype analysis suggested the presence of mosaicism with the pancreatoblastoma tissue having a different paternal haplotype than that of the peripheral blood and nontumor pancreatic tissue. We report for the first time mosaic paternal haploidy associated with pancreatoblastoma. Babies with placental mesenchymal dysplasia, even those without a definitive diagnosis of BWS, need to be closely followed for the occurrence of embryonic tumors.
Assuntos
Síndrome de Beckwith-Wiedemann/genética , Mosaicismo , Neoplasias Pancreáticas/genética , Dissomia Uniparental/genética , Síndrome de Beckwith-Wiedemann/fisiopatologia , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 2/genética , Metilação de DNA/genética , Feminino , Genótipo , Haploidia , Humanos , Hibridização in Situ Fluorescente , Lactente , Recém-Nascido , Mesoderma/patologia , Neoplasias Pancreáticas/fisiopatologia , Herança Paterna/genética , Placenta/patologia , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Dissomia Uniparental/fisiopatologiaRESUMO
The primary function of the UBE2T ubiquitin conjugase is in the monoubiquitination of the FANCI-FANCD2 heterodimer, a central step in the Fanconi anemia (FA) pathway. Genetic inactivation of UBE2T is responsible for the phenotypes of FANCT patients; however, a FANCT patient carrying a maternal duplication and a paternal deletion in the UBE2T loci displayed normal peripheral blood counts and UBE2T protein levels in B-lymphoblast cell lines. To test whether reversion by recombination between UBE2T AluYa5 elements could have occurred in the patient's hematopoietic stem cells despite the defects in homologous recombination (HR) in FA cells, we constructed HeLa cell lines containing the UBE2T AluYa5 elements and neighboring intervening sequences flanked by fluorescent reporter genes. Introduction of a DNA double strand break in the model UBE2T locus in vivo promoted single strand annealing (SSA) between proximal Alu elements and deletion of the intervening color marker gene, recapitulating the reversion of the UBE2T duplication in the FA patient. To test whether UBE2T null cells retain HR activity, the UBE2T genes were knocked out in HeLa cells and U2OS cells. CRISPR/Cas9-mediated genetic knockout of UBE2T only partially reduced HR, demonstrating that UBE2T-independent pathways can compensate for the recombination defect in UBE2T/FANCT null cells.
Assuntos
Elementos Alu/genética , Anemia de Fanconi/genética , Recombinação Homóloga/genética , Enzimas de Conjugação de Ubiquitina/genética , Sistemas CRISPR-Cas/genética , Quebras de DNA de Cadeia Dupla , Dano ao DNA/genética , Anemia de Fanconi/patologia , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Deleção de Genes , Duplicação Gênica/genética , Células HeLa , Células-Tronco Hematopoéticas/metabolismo , Humanos , Herança Materna/genética , Herança Paterna/genéticaRESUMO
Atelosteogenesis type I (AOI) is an autosomal dominant skeletal dysplasia caused by mutations in the filaminB (FLNB) gene with classic and well-recognizable clinical findings. However, parents affected with a mild phenotype, probably with somatic mosaicism, can generate offspring with a much more severe phenotype of AOI. In the present report, we describe a female newborn with classic AOI leading to early neonatal death, whose diagnostic was based on prenatal radiological findings and on the physical examination of the father. Since her father had limb deformities and corporal asymmetry, suggesting somatic mosaicism, his biological samples were analyzed through a gene panel for skeletal dysplasias. A missense mutation not previously described in the literature was detected in the FLNB gene, affecting â¼ 20% of the evaluated cells and, therefore, confirming the diagnosis of mosaic AOI in the father. The molecular analysis of the father was crucial to suggest the diagnosis of AOI in the newborn, since she died early and there were no biological samples available.
A atelosteogênese tipo I (AOI) é uma displasia esquelética autossômica dominante causada por mutações no gene filamina B (FLNB) com achados clínicos clássicos e bem reconhecíveis. No entanto, pais afetados com um fenótipo mais leve, provavelmente com mosaicismo somático, podem gerar uma prole com um fenótipo muito mais grave de AOI. No presente relato, descrevemos um recém-nascido do sexo feminino com AOI clássica, que levou à morte neonatal precoce, e cujo diagnóstico foi baseado em achados radiológicos pré-natais e no exame físico de seu genitor. Como o genitor apresentava deformidades em membros e assimetria corporal, que sugeriam mosaicismo somático, suas amostras biológicas foram analisadas por meio de um painel de genes para displasias esqueléticas. Uma mutação missense, não descrita anteriormente na literatura, foi detectada no gene FLNB, afetando â¼ 20% das células avaliadas, e, portanto, confirmando o diagnóstico de AOI em mosaico no genitor. A análise molecular realizada no genitor foi fundamental para sugerir o diagnóstico de AOI na recém-nascida, uma vez que esta morreu precocemente, e não havia amostras biológicas disponíveis.
Assuntos
Mosaicismo , Osteocondrodisplasias/diagnóstico por imagem , Osteocondrodisplasias/genética , Herança Paterna/genética , Fenótipo , Ultrassonografia Pré-Natal , Adolescente , Feminino , Humanos , Masculino , GravidezRESUMO
Abstract Atelosteogenesis type I (AOI) is an autosomal dominant skeletal dysplasia caused by mutations in the filamin B (FLNB) gene with classic and well-recognizable clinical findings. However, parents affected with a mild phenotype, probably with somatic mosaicism, can generate offspring with a much more severe phenotype of AOI. In the present report, we describe a female newborn with classic AOI leading to early neonatal death, whose diagnostic was based on prenatal radiological findings and on the physical examination of the father. Since her father had limb deformities and corporal asymmetry, suggesting somatic mosaicism, his biological samples were analyzed through a gene panel for skeletal dysplasias. A missense mutation not previously described in the literature was detected in the FLNB gene, affecting ~ 20% of the evaluated cells and, therefore, confirming the diagnosis ofmosaic AOI in the father. The molecular analysis of the father was crucial to suggest the diagnosis of AOI in the newborn, since she died early and there were no biological samples available.
Resumo A atelosteogênese tipo I (AOI) é uma displasia esquelética autossômica dominante causada por mutações no gene filamina B (FLNB) comachados clínicos clássicos e bem reconhecíveis. No entanto, pais afetados com um fenótipo mais leve, provavelmente commosaicismo somático, podem gerar uma prole comumfenótipomuito mais grave de AOI. No presente relato, descrevemos um recém-nascido do sexo feminino comAOI clássica, que levou à morte neonatal precoce, e cujo diagnóstico foi baseado em achados radiológicos pré-natais e no exame físico de seu genitor. Como o genitor apresentava deformidades em membros e assimetria corporal, que sugeriam mosaicismo somático, suas amostras biológicas foram analisadas por meio de um painel de genes para displasias esqueléticas. Umamutação missense, não descrita anteriormente na literatura, foi detectada no gene FLNB, afetando ~ 20% das células avaliadas, e, portanto, confirmando o diagnóstico de AOI em mosaico no genitor. A análise molecular realizada no genitor foi fundamental para sugerir o diagnóstico de AOI na recém-nascida, uma vez que esta morreu precocemente, e não havia amostras biológicas disponíveis.
Assuntos
Humanos , Masculino , Feminino , Gravidez , Adolescente , Osteocondrodisplasias/genética , Osteocondrodisplasias/diagnóstico por imagem , Fenótipo , Ultrassonografia Pré-Natal , Herança Paterna/genética , MosaicismoRESUMO
Given prior evidence that an affected woman conveys a higher risk of ovarian cancer to her sister than to her mother, we hypothesized that there exists an X-linked variant evidenced by transmission to a woman from her paternal grandmother via her father. We ascertained 3,499 grandmother/granddaughter pairs from the Familial Ovarian Cancer Registry at the Roswell Park Cancer Institute observing 892 informative pairs with 157 affected granddaughters. We performed germline X-chromosome exome sequencing on 186 women with ovarian cancer from the registry. The rate of cancers was 28.4% in paternal grandmother/granddaughter pairs and 13.9% in maternal pairs consistent with an X-linked dominant model (Chi-square test X2 = 0.02, p = 0.89) and inconsistent with an autosomal dominant model (X2 = 20.4, p<0.001). Paternal grandmother cases had an earlier age-of-onset versus maternal cases (hazard ratio HR = 1.59, 95%CI: 1.12-2.25) independent of BRCA1/2 status. Reinforcing the X-linked hypothesis, we observed an association between prostate cancer in men and ovarian cancer in his mother and daughters (odds ratio, OR = 2.34, p = 0.034). Unaffected mothers with affected daughters produced significantly more daughters than sons (ratio = 1.96, p<0.005). We performed exome sequencing in reported BRCA negative cases from the registry. Considering age-of-onset, one missense variant (rs176026 in MAGEC3) reached chromosome-wide significance (Hazard ratio HR = 2.85, 95%CI: 1.75-4.65) advancing the age of onset by 6.7 years. In addition to the well-known contribution of BRCA, we demonstrate that a genetic locus on the X-chromosome contributes to ovarian cancer risk. An X-linked pattern of inheritance has implications for genetic risk stratification. Women with an affected paternal grandmother and sisters of affected women are at increased risk for ovarian cancer. Further work is required to validate this variant and to characterize carrier families.
Assuntos
Genes Ligados ao Cromossomo X , Hereditariedade , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Herança Paterna/genética , Adulto , Idade de Início , Neoplasias da Mama/complicações , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Família , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Neoplasias Ovarianas/complicações , Linhagem , Sistema de RegistrosRESUMO
Dietary intake of methyl donors, such as folic acid and methionine, shows considerable intra-individual variation in human populations. While it is recognized that maternal departures from the optimum of dietary methyl donor intake can increase the risk for mental health issues and neurological disorders in offspring, it has not been explored whether paternal dietary methyl donor intake influences behavioral and cognitive functions in the next generation. Here, we report that elevated paternal dietary methyl donor intake in a mouse model, transiently applied prior to mating, resulted in offspring animals (methyl donor-rich diet (MD) F1 mice) with deficits in hippocampus-dependent learning and memory, impaired hippocampal synaptic plasticity and reduced hippocampal theta oscillations. Gene expression analyses revealed altered expression of the methionine adenosyltransferase Mat2a and BK channel subunit Kcnmb2, which was associated with changes in Kcnmb2 promoter methylation in MD F1 mice. Hippocampal overexpression of Kcnmb2 in MD F1 mice ameliorated altered spatial learning and memory, supporting a role of this BK channel subunit in the MD F1 behavioral phenotype. Behavioral and gene expression changes did not extend into the F2 offspring generation. Together, our data indicate that paternal dietary factors influence cognitive and neural functions in the offspring generation.
Assuntos
Cognição/fisiologia , Suplementos Nutricionais/efeitos adversos , Herança Paterna/fisiologia , Animais , Metilação de DNA , Dieta , Epigênese Genética , Pai , Ácido Fólico/metabolismo , Hipocampo/metabolismo , Subunidades beta do Canal de Potássio Ativado por Cálcio de Condutância Alta , Aprendizagem/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Metionina/metabolismo , Metionina Adenosiltransferase , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Herança Paterna/genética , Regiões Promotoras GenéticasRESUMO
Acipenser dabryanus is listed as a Critical Endangered species in the IUCN Red List and the first class protected animals in China. Fortunately, A. dabryanus specimens are being successfully bred in captivity for conservation. However, for effective ex situ conservation, we should be aware of the genetic diversity and the degree of relatedness of the individuals selected for breeding. In this study, we aimed at the development of novel and reliable microsatellites used for the genetic study of A. dabryanus. A total of 14,321 simple sequence repeats (SSRs) were detected by transcriptome sequencing and screening. We selected 20 novel and polymorphic microsatellites (non-dinucleotide) with good repeatability from the 100 tested loci for a subsequent genetic and paternity study. A set of captive broodstock (F1 stock, n = 43) and their offspring (F2 stock, n = 96) were used to examine the efficiency of the 20 SSRs for assigning parentage to offspring, with an allocation success of 91.7%. We also found that only a few families predominantly contributed to the progeny produced by the 43 breeders. In addition, mitochondrial DNA data showed that the captive broodstock (F1 individuals) had an excellent probability of the same lineage, implying that a high level of inbreeding may have occurred in these individuals. Our research provides useful information on genetic diversity and reproductive pattern of A. dabryanus, and the 20 SSRs developed in this study can be applied to the future breeding program to avoid inbreeding for this stock or other related species of Acipenseriformes.
Assuntos
Peixes/genética , Repetições de Microssatélites/genética , Herança Paterna/genética , Poliploidia , Animais , Sequência de Bases , DNA Mitocondrial/genética , Feminino , Variação Genética , Masculino , Motivos de Nucleotídeos/genética , Reprodução/genética , Transcriptoma/genéticaRESUMO
Long non-coding RNAs (lncRNAs) play an important role in epigenetic regulation, and abnormalities may lead to male infertility. To investigate whether lncRNAs are involved in intergenerational inheritance of obesity and obesity-induced decline in fertility, we divided mice into obesity (F0 mice fed a high-fat diet, F0-HFD) and non-obese (F0 mice fed normal chow, F0-NC) model groups and their male offspring (F1-HFD and F1-NC, respectively). We examined the differences in the expression levels of lncRNAs and mRNAs in the F0-HFD/F0-NC and F1-HFD/F1-NC groups. The results revealed similar expression patterns in the F1-HFD/F0-HFD groups at both the lncRNA and mRNA levels. The maximum difference in the lncRNA expression was observed between the F0-HFD and F0-NC groups. The differentially expressed lncRNA targets and mRNAs identified in our study are mainly involved in GnRH signalling pathway, metabolic process, and Hippo signalling pathway; similarly expressed lncRNAs and mRNAs in F1-HFD/F0-HFD are closely linked with G-protein coupled receptor signalling pathway, pancreatic polypeptide receptor activity, and lysine biosynthesis, which may play an important role in the molecular mechanism of intergenerational inheritance of obesity. Furthermore, potential genes that might play important roles in the pathogenesis of obesity-related low fertility were revealed by lncRNA-and mRNA-interaction studies based on the microarray expression profiles. In conclusion, we found that lncRNA could be involved in obesity-induced infertility by expressing abnormalities, which could act as genetic vectors of paternal inheritance of obesity.
Assuntos
Dieta Hiperlipídica , Vetores Genéticos/genética , Obesidade/etiologia , Herança Paterna/genética , RNA Longo não Codificante/genética , Animais , Biologia Computacional/métodos , Dieta Hiperlipídica/efeitos adversos , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Masculino , Camundongos , Reprodutibilidade dos Testes , Espermatozoides/metabolismo , TranscriptomaRESUMO
X-linked recessive myotubular myopathy (XLMTM) is a disorder associated with mutations in the myotubularin gene (MTM1) that usually affects boys, with transmission of the mutated allele from the mother. Here we describe a family with unexpected grand paternal transmission of a novel mutation in MTM1 (c.646_648dupGTT; p.Val216dup) identified in a severely affected infant boy with a centronuclear myopathy. We confirmed the carrier status of the mother, but surprisingly we found that her father was a carrier of the mutated MTM1 gene together with wild-type MTM1. A muscle biopsy from the grandfather revealed occasional typical necklace fibers with internalized nucleus, which is typically found in MTM1-associated myopathies. Further analysis of the grandfather revealed equal amounts of DNA with the wild-type sequence and DNA with the c.646_648dupGTT variant in five different tissues examined. In the presence of a normal karyotype (46,XY) in the grandfather and no evidence of intragenic duplication of MTM1, the result was interpreted as postzygotic mosaicism and the mutation had probably occurred at the first mitosis of the zygote. This study demonstrates the importance of considering the possibility of paternal transmission in families with severe X-linked disorders. The muscle biopsy with the finding of typical necklace fibers was important to further establish the pathogenicity of the novel MTM1 mutation.