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

A novel missense mutation in <em>CACNA1A</em> evaluated by <em>in silico</em> protein modeling is associated with non-episodic spinocerebellar ataxia with slow progression.

Spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2) and familial hemiplegic migraine type 1 (FHM1) are allelic disorders of the gene CACNA1A encoding the P/Q subunit of a voltage gated calcium channel. While SCA6 is related to repeat expansions affecting the C-terminal part of the protein, EA2 and FHM phenotypes are usually associated with nonsense and missense mutations leading to impaired channel properties. In three unrelated families with dominant cerebellar ataxia, symptoms cosegregated with CACNA1A missense mutations of evolutionary highly conserved amino acids (exchanges p.E668K, p.R583Q and p.D302N). To evaluate pathogenic effects, in silico, protein modeling analyses were performed which indicate structural alterations of the novel mutation p.E668K within the homologous domain 2 affecting CACNA1A protein function.The phenotype is characterised by a very slowly progressive ataxia, while ataxic episodes or migraine are uncommon. These findings enlarge the phenotypic spectrum of CACNA1A mutations

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

Exome sequencing unravels unexpected differential diagnoses in individuals with the tentative diagnosis of Coffin&ndash;Siris and Nicolaides&ndash;Baraitser syndromes.

Coffin&ndash;Siris syndrome (CSS) and Nicolaides&ndash;Baraitser syndrome (NCBRS) are rare intellectual disability/congenital malformation syndromes that represent distinct entities but show considerable clinical overlap. They are caused by mutations in genes encoding members of the BRG1- and BRM-associated factor (BAF) complex. However, there are a number of patients with the clinical diagnosis of CSS or NCBRS in whom the causative mutation has not been identified. In this study, we performed trio-based whole-exome sequencing (WES) in ten previously described but unsolved individuals with the tentative diagnosis of CSS or NCBRS and found causative mutations in nine out of ten individuals. Interestingly, our WES analysis disclosed overlapping differential diagnoses including Wiedemann&ndash;Steiner, Kabuki, and Adams&ndash;Oliver syndromes. In addition, most likely causative de novo mutations were identified in GRIN2A and SHANK3. Moreover, trio-based WES detected SMARCA2 and SMARCA4 deletions, which had not been annotated in a previous Haloplex target enrichment and next-generation sequencing of known CSS/NCBRS genes emphasizing the advantages of WES as a diagnostic tool. In summary, we discuss the phenotypic and diagnostic challenges in clinical genetics, establish important differential diagnoses, and emphasize the cardinal features and the broad clinical spectrum of BAF complex disorders and other disorders caused by mutations in epigenetic landscapers

Mutations in chromatin regulators functionally link Cornelia de Lange syndrome and clinically overlapping phenotypes

The coordinated tissue-specific regulation of gene expression is essential for the proper development of all organisms. Mutations in multiple transcriptional regulators cause a group of neurodevelopmental disorders termed \u201ctranscriptomopathies\u201d that share core phenotypical features including growth retardation, developmental delay, intellectual disability and facial dysmorphism. Cornelia de Lange syndrome (CdLS) belongs to this class of disorders and is caused by mutations in different subunits or regulators of the cohesin complex. Herein, we report on the clinical and molecular characterization of seven patients with features overlapping with CdLS who were found to carry mutations in chromatin regulators previously associated to other neurodevelopmental disorders that are frequently considered in the differential diagnosis of CdLS. The identified mutations affect the methyltransferase-encoding genes KMT2A and SETD5 and different subunits of the SWI/SNF chromatin-remodeling complex. Complementary to this, a patient with Coffin\u2013Siris syndrome was found to carry a missense substitution in NIPBL. Our findings indicate that mutations in a variety of chromatin-associated factors result in overlapping clinical phenotypes, underscoring the genetic heterogeneity that should be considered when assessing the clinical and molecular diagnosis of neurodevelopmental syndromes. It is clear that emerging molecular mechanisms of chromatin dysregulation are central to understanding the pathogenesis of these clinically overlapping genetic disorders