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Neural tube defects (NTDs) are congenital malformations resulting from the improper or incomplete closure of the neural tube during embryonic development. A number of similar malformations of the protective coverings surrounding the central nervous system are also often included under this umbrella term, which may not strictly fit this definition. A range of NTD phenotypes exist and have been reported in humans and a wide range of domestic and livestock species. In the veterinary literature, these include cases of anencephaly, encephalocele, dermoid sinus, spina bifida, and craniorachischisis. While environmental factors have a role, genetic predisposition may account for a significant part of the risk of NTDs in these animal cases. Studies of laboratory model species (fish, birds, amphibians, and rodents) have been instrumental in improving our understanding of the neurulation process. In mice, over 200 genes that may be involved in this process have been identified and variant phenotypes investigated. Like laboratory mouse models, domestic animals and livestock species display a wide range of NTD phenotypes. They remain, however, a largely underutilized population and could complement already established laboratory models. Here we review reports of NTDs in companion animals and livestock, and compare these to other animal species and human cases. We aim to highlight the potential of nonlaboratory animal models for mutation discovery as well as general insights into the mechanisms of neurulation and the development of NTDs. [ABSTRACT FROM AUTHOR]

Background & Aims Very early onset inflammatory bowel disease (VEO-IBD), IBD diagnosed at 5 years of age or younger, frequently presents with a different and more severe phenotype than older-onset IBD. We investigated whether patients with VEO-IBD carry rare or novel variants in genes associated with immunodeficiencies that might contribute to disease development. Methods Patients with VEO-IBD and parents (when available) were recruited from the Children’s Hospital of Philadelphia from March 2013 through July 2014. We analyzed DNA from 125 patients with VEO-IBD (age, 3 wk to 4 y) and 19 parents, 4 of whom also had IBD. Exome capture was performed by Agilent SureSelect V4, and sequencing was performed using the Illumina HiSeq platform. Alignment to human genome GRCh37 was achieved followed by postprocessing and variant calling. After functional annotation, candidate variants were analyzed for change in protein function, minor allele frequency less than 0.1%, and scaled combined annotation-dependent depletion scores of 10 or less. We focused on genes associated with primary immunodeficiencies and related pathways. An additional 210 exome samples from patients with pediatric IBD (n = 45) or adult-onset Crohn’s disease (n = 20) and healthy individuals (controls, n = 145) were obtained from the University of Kiel, Germany, and used as control groups. Results Four hundred genes and regions associated with primary immunodeficiency, covering approximately 6500 coding exons totaling more than 1 Mbp of coding sequence, were selected from the whole-exome data. Our analysis showed novel and rare variants within these genes that could contribute to the development of VEO-IBD, including rare heterozygous missense variants in IL10RA and previously unidentified variants in MSH5 and CD19 . Conclusions In an exome sequence analysis of patients with VEO-IBD and their parents, we identified variants in genes that regulate B- and T-cell functions and could contribute to pathogenesis. Our analysis could lead to the identification of previously unidentified IBD-associated variants. [ABSTRACT FROM AUTHOR]

Two inherited deficiencies have been described in purine de novo synthesis pathway. Both the defects are diagnosed by detecting ribosides—dephosphorylated substrates of the enzymes—in patient's urine. We describe here a synthesis and mass spectrometric fragmentation of ribosides potentially of diagnostic importance for defects in the second part of the pathway. All the species, except 5-amino-4-imidazolesuccinocarboxamideriboside can be synthesized from the commercially available 5-amino-4-imidazolecarboxamideriboside by chemical methods. Fragmentation spectra of the compounds were obtained by the ion trap mass spectrometry. During fragmentation an opening of the imidazole ring was not observed for any of the compounds but loss of its substituents in the form of small molecules (NH3, CO2, CO) is the major route of fragmentation. The ribose moiety cleaves off molecule(s) of water, undergoes a cross-ring cleavage or breaks away as a whole. [ABSTRACT FROM AUTHOR]

Much interest surrounds the receptors α2β1 and glycoprotein VI (GPVI) whose synchronized action mediates the attachment and activation of platelets on collagen, essential for preventing blood loss but also the most thrombogenic component of the vessel wall. Subject to density variations on platelets through natural polymorphisms, the absence of α2β1 or GPVI uniquely leads to a substantial block of hemostasis without causing major bleeding. Specific to the megakaryocyte lineage, GPVI and its signaling pathways are most promising targets for anti-thrombotic therapy. This review looks at the clinical consequences of the loss of collagen receptor function with emphasis on both the inherited and acquired loss of GPVI with brief mention of mouse models when necessary. A detailed survey of rare case reports of patients with inherited disease-causing variants of the GP6 gene is followed by an assessment of the causes and clinical consequences of acquired GPVI deficiency, a more frequent finding most often due to antibody-induced platelet GPVI shedding. Release of soluble GPVI is brought about by platelet metalloproteinases; a process induced by ligand or antibody binding to GPVI or even high shear forces. Also included is an assessment of the clinical importance of GPVI-mediated platelet interactions with fibrin and of the promise shown by the pharmacological inhibition of GPVI in a cardiovascular context. The role for GPVI in platelet function in inflammation and in the evolution and treatment of major illnesses such as rheumatoid arthritis, cancer and sepsis is also discussed. [ABSTRACT FROM AUTHOR]