Identification and Functional Characterization of Two Intronic NIPBL Mutations in Two Patients with Cornelia de Lange Syndrome

Cornelia de Lange syndrome (CdLS) is a rare genetically heterogeneous disorder with a high phenotypic variability including mental retardation, developmental delay, and limb malformations. The genetic causes in about 30% of patients with CdLS are still unknown. We report on the functional characterization of two intronic NIPBL mutations in two patients with CdLS that do not affect a conserved splice-donor or acceptor site. Interestingly, mRNA analyses showed aberrantly spliced transcripts missing exon 28 or 37, suggesting the loss of the branch site by the c.5329-15A>G transition and a disruption of the polypyrimidine by the c.6344del(-13)-(-8) deletion. While the loss of exon 28 retains the reading frame of the NIBPL transcript resulting in a shortened protein, the loss of exon 37 shifts the reading frame with the consequence of a premature stop of translation. Subsequent quantitative PCR analysis demonstrated a 30% decrease of the total NIPBL mRNA levels associated with the frameshift transcript. Consistent with our results, this patient shows a more severe phenotype compared to the patient with the aberrant transcript that retains its reading frame. Thus, intronic variants identified by sequencing analysis in CdLS diagnostics should carefully be examined before excluding them as nonrelevant to disease

Taxonomic review of the genus Stenotus Jakovlev (Hemiptera: Heteroptera: Miridae) from the Korean Peninsula

AbstractA genus Stenotus Jakovlev (Hemiptera: Heteroptera: Miridae) is reviewed taxonomically from the Korean Peninsula with a new record Stenotus binotatus (Fabricius 1794). Morphological information, such as descriptions of male and female genitalia, of the Korean species with photographs and illustrations, and a key to the Korean species are provided

Spinocerebellar ataxia type 17: Report of a family with reduced penetrance of an unstable Gln(49 )TBP allele, haplotype analysis supporting a founder effect for unstable alleles and comparative analysis of SCA17 genotypes

BACKGROUND: Spinocerebellar ataxia type 17 (SCA17), a neurodegenerative disorder in man, is caused by an expanded polymorphic polyglutamine-encoding trinucleotide repeat in the gene for TATA-box binding protein (TBP), a main transcription factor. Observed pathogenic expansions ranged from 43 – 63 glutamine (Gln) codons (Gln(43–63)). Reduced penetrance is known for Gln(43–48 )alleles. In the vast majority of families with SCA17 an expanded CAG repeat interrupted by a CAA CAG CAA element is inherited stably. RESULTS: Here, we report the first pedigree with a Gln(49 )allele that is a) not interrupted, b) unstable upon transmission, and c) associated with reduced penetrance or very late age of onset. The 76-year-old father of two SCA17 patients carries the Gln(49 )TBP allele but presents without obvious neurological symptoms. His children with Gln(53 )and Gln(52 )developed ataxia at the age of 41 and 50. Haplotype analysis of this and a second family both with uninterrupted expanded and unstable pathological SCA17 alleles revealed a common core genotype not present in the interrupted expansion of an unrelated SCA17 patient. Review of the literature did not present instability in SCA17 families with expanded alleles interrupted by the CAA CAG CAA element. CONCLUSION: The presence of a Gln(49 )SCA17 allele in an asymptomatic 76-year-old male reams the discussion of reduced penetrance and genotypes producing very late disease onset. In SCA17, uninterrupted expanded alleles of TBP are associated with repeat instability and a common founder haplotype. This suggests for uninterrupted expanded alleles a mutation mechanism and some clinical genetic features distinct from those alleles interrupted by a CAA CAG CAA element

Evidence for a General Neural Signature of Face Familiarity

We explored the neural signatures of face familiarity using cross-participant and cross-experiment decoding of event-related potentials, evoked by unknown and experimentally familiarized faces from a set of experiments with different participants, stimuli, and familiarization-types. Human participants of both sexes were either familiarized perceptually, via media exposure, or by personal interaction. We observed significant cross-experiment familiarity decoding involving all three experiments, predominantly over posterior and central regions of the right hemisphere in the 270–630 ms time window. This shared face familiarity effect was most prominent across the Media and the Personal, as well as between the Perceptual and Personal experiments. Cross-experiment decodability makes this signal a strong candidate for a general neural indicator of face familiarity, independent of familiarization methods, participants, and stimuli. Furthermore, the sustained pattern of temporal generalization suggests that it reflects a single automatic processing cascade that is maintained over time

Elevated activity of transcription factor nuclear factor of activated T-cells 5 (NFAT5) and diabetic nephropathy

The expression of aldose reductase is tightly regulated by the transcription factor tonicity response element binding protein (TonEBP/NFAT5) binding to three osmotic response elements (OREs; OREA, OREB, and OREC) in the gene. The aim was to investigate the contribution of NFAT5 to the pathogenesis of diabetic nephropathy. Peripheral blood mononuclear cells (PBMCs) were isolated from the following subjects: 44 Caucasoid patients with type 1 diabetes, of whom 26 had nephropathy and 18 had no nephropathy after a diabetes duration of 20 years, and 13 normal healthy control subjects. In addition, human mesangial cells (HMCs) were isolated from the normal lobe of 10 kidneys following radical nephrectomy for renal cell carcinoma. Nuclear and cytoplasmic proteins were extracted from PBMCs and HMCs and cultured in either normal or high-glucose (31 mmol/l D-glucose) conditions for 5 days. NFAT5 binding activity was quantitated using electrophoretic mobility shift assays for each of the OREs. Western blotting was used to measure aldose reductase and sorbitol dehydrogenase protein levels. There were significant fold increases in DNA binding activities of NFAT5 to OREB (2.06 ?? 0.03 vs. 1.33 ?? 0.18, P = 0.033) and OREC (1.94 ?? 0.21 vs. 1.39 ?? 0.11, P = 0.024) in PBMCs from patients with diabetic nephropathy compared with diabetic control subjects cultured under high glucose. Aldose reductase and sorbitol dehydrogenase protein levels in the patients with diabetic nephropathy were significantly increased in PBMCs cultured in high-glucose conditions. In HMCs cultured under high glucose, there were significant increases in NFAT5 binding activities to OREA, OREB, and OREC by 1.38 ?? 0.22-, 1.84 ?? 0.44-, and 2.38 ?? 1.15-fold, respectively. Similar results were found in HMCs exposed to high glucose (aldose reductase 1.30 ?? 0.06-fold and sorbitol dehydrogenease 1.54 ?? 0.24-fold increases). Finally, the silencing of the NFAT5 gene in vitro reduced the expression of the aldose reductase gene. In conclusion, these results show that aldose reductase is upregulated by the transcriptional factor NFAT5 under high-glucose conditions in both PBMCs and HMCsclose121

Consumo y cultura masiva: reflexiones a propósito de la literatura de autoayuda y sus lectores

Teniendo en cuenta que la cultura es comprensible a partir del estudio de sus componentes simbólicos, en nuestra tesis de doctorado indagamos en una práctica cultural cuyo interés se renueva incesantemente resistiendo a los avatares del tiempo: la lectura. Acotamos el estudio a un género de la cultura de masas que ostenta una imponente presencia en el mercado editorial actual: la literatura de autoayuda. Asimismo, con la intención de dar una realidad sociocultural a la figura del lector, abordamos un caso en particular: San Salvador de Jujuy (Argentina). A partir de ello, en este artículo, reflexionamos específicamente a propósito de las expectativas de lectura y nos preguntamos: ¿qué se busca en la literatura? Sobre la base de nuestra investigación, concluimos en que el consumo de los libros de autoayuda puede vincularse, por un lado, a la necesidad de dar orden y sentido a la historia personal y, por otro, a la búsqueda de sentimientos etéreos, la libertad y la felicidadDado que a cultura é entendida através do estudo de seus componentes simbólicos, em nossa tese de doutorado, investigamos uma prática cultural que renova incessantemente interesse y resiste às vicissitudes do tempo: a leitura. Limitamos o estudo a um gênero da cultura de massa que detém uma presença dominante no mercado editorial atual: a literatura de auto-ajuda. Além disso, com a intenção de dar uma realidade sociocultural à figura do leitor, nós abordamos um caso particular: San Salvador de Jujuy (Argentina). A partir disso, neste artigo, refletimos especificamente sobre as expectativas de leitura e questionamos: o que se busca na literatura? Com base em nossa pesquisa, concluímos que o consumo de livros de autoajuda pode ser ligado, por um lado, com a necessidade de dar forma e sentido à história pessoal e, por outro, com a busca de sentimentos etéreos, a liberdade e felicidade.Given that culture is understandable from the study of symbolic components, in our doctoral thesis (Canavire, 2013) we investigate a cultural practice whose interest is renewed constantly resisting the vicissitudes of time: reading. We delimit the study to a genre of massive culture that boasts an imposing presence in the current publishing market: self-help literature. Also, with the intention of giving a sociocultural reality to the figure of the reader, we tackle a particular case: San Salvador de Jujuy (Argentina). From this, in this article, specifically we reflect with regard to expectations about reading and we ask what is searched in the literature? Based on our research, we conclude that the consumption of self-help books can be linked, on the one hand, with the need to give order and meaning to the personal history and, on the other, to looking ethereal feelings, freedom and happiness.Fil: Canavire, Vanina Belén. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Jujuy; Argentin

Genes and biological processes commonly disrupted in rare and heterogeneous developmental delay syndromes

Rare copy number variations (CNVs) are a recognized cause of common human disease. Predicting the genetic element(s) within a small CNV whose copy number loss or gain underlies a specific phenotype might be achieved reasonably rapidly for single patients. Identifying the biological processes that are commonly disrupted within a large patient cohort which possess larger CNVs, however, requires a more objective approach that exploits genomic resources. In this study, we first identified 98 large, rare CNVs within patients exhibiting multiple congenital anomalies. All patients presented with global developmental delay (DD), while other secondary symptoms such as cardiac defects, craniofacial features and seizures were varyingly presented. By applying a robust statistical procedure that matches patients’ clinical phenotypes to laboratory mouse gene knockouts, we were able to strongly implicate anomalies in brain morphology and, separately, in long-term potentiation as manifestations of these DD patients’ disorders. These and other significantly enriched model phenotypes provide insights into the pathoetiology of human DD and behavioral and anatomical secondary symptoms that are specific to DD patients. These enrichments set apart 103 genes, from among thousands overlapped by these CNVs, as strong candidates whose copy number change causally underlies approximately 46% of the cohort's DD syndromes and between 59 and 80% of the cohort's secondary symptoms. We also identified significantly enriched model phenotypes among genes overlapped by CNVs in both DD and learning disability cohorts, indicating a congruent etiology. These results demonstrate the high predictive potential of model organism phenotypes when implicating candidate genes for rare genomic disorders