The mouse Mid1 gene: implications for the pathogenesis of Opitz syndrome and the evolution of the mammalian pseudoautosomal region

We have recently reported isolation of the gene responsible for X- linked Opitz G/BBB syndrome, a defect of midline development. MID1 is located on the distal short arm of the human X chromosome (Xp22. 3) and encodes a novel member of the B box family of zinc finger proteins. We have now cloned the murine homolog of MID1 and performed preliminary expression studies during development. Mid1 expression in undifferentiated cells in the central nervous, gastrointestinal and urogenital systems suggests that abnormal cell proliferation may underlie the defect in midline development characteristic of Opitz syndrome. We have also found that Mid1 is located within the mouse pseudoautosomal region (PAR) in Mus musculus , while it seems to be X- specific in Mus spretus. Therefore, Mid1 is likely to be a recent acquisition of the M. musculus PAR. Genetic and FISH analyses also demonstrated a high frequency of unequal crossovers in the murine PAR, creating spontaneous deletion/duplication events involving Mid1. These data provide evidence for the first time that genetic instability of the PAR may affect functionally important genes. In addition, we show that MID1 is the first example of a gene subject to X-inactivation in man while escaping it in mouse. These data contribute to a better understanding of the molecular content and evolution of the rodent PAR.      

A new heparin fragment decreases liver ischemia-reperfusion injury

<正>To the Editor:Ischemia-reperfusion injury following surgery and transplantation can lead to irreversible multiorgan failure.Intracellular calcium overload is associated to cellular death during ischemiareperfusion.A recently discovered heparin fragment (HF),trisulfated disaccharide (TD),that acts on sodium-calcium exchanger(NCX) decreasing intracellular Ca²⁺,showed effectiveness on protecting hepatocytes from ischemia-reperfusion injury [1],     

Expanding the spectrum of PTH1R mutations in patients with primary failure of tooth eruption

Objectives

Primary failure of tooth eruption (PFE) is a rare autosomal-dominant disease characterized by severe lateral open bite as a consequence of incomplete eruption of posterior teeth. Heterozygous mutations in the parathyroid hormone 1 receptor (PTH1R) gene have been shown to cause PFE likely due to protein haploinsufficiency. To further expand on the mutational spectrum of PFE-associated mutations, we report here on the sequencing results of the PTH1R gene in 70 index PFE cases.

Materials and methods

Sanger sequencing of the PTH1R coding exons and their immediate flanking intronic sequences was performed with DNA samples from 70 index PFE cases.

Results

We identified a total of 30 unique variants, of which 12 were classified as pathogenic based on their deleterious consequences on PTH1R protein while 16 changes were characterized as unclassified variants with as yet unknown effects on disease pathology. The remaining two variants represent common polymorphisms.

Conclusions

Our data significantly increase the number of presently known unique PFE-causing PTH1R mutations and provide a series of variants with unclear pathogenicity which will require further in vitro assaying to determine their effects on protein structure and function.

Clinical relevance

Management of PTH1R-associated PFE is problematic, in particular when teeth are exposed to orthodontic force. Therefore, upon clinical suspicion of PFE, molecular DNA testing is indicated to support decision making for further treatment options.     

Strategies to address participant misrepresentation for eligibility in Web‐based research

Emerging methodological research suggests that the World Wide Web (“Web”) is an appropriate venue for survey data collection, and a promising area for delivering behavioral intervention. However, the use of the Web for research raises concerns regarding sample validity, particularly when the Web is used for recruitment and enrollment. The purpose of this paper is to describe the challenges experienced in two different Web‐based studies in which participant misrepresentation threatened sample validity: a survey study and an online intervention study. The lessons learned from these experiences generated three types of strategies researchers can use to reduce the likelihood of participant misrepresentation for eligibility in Web‐based research. Examples of procedural/design strategies, technical/software strategies and data analytic strategies are provided along with the methodological strengths and limitations of specific strategies. The discussion includes a series of considerations to guide researchers in the selection of strategies that may be most appropriate given the aims, resources and target population of their studies. Copyright © 2014 John Wiley & Sons, Ltd.     

Skin tests, T cell responses and self-reported symptoms in children with allergic rhinitis and asthma due to house dust mite allergy

Background In allergic responses, a distinction is made between an early-phase response, several minutes after allergen exposure, and a late-phase response after several hours. During the late phase, eosinophils and T cells infiltrate the mucosa and play an important role in inflammation. Objective The aim of this study was to examine the relationship between allergen-induced late-phase skin responses and in vitro T cell reactivity. In addition, the relationship between allergen-induced skin or T cell responses and the severity of self-reported symptoms was studied in children with house dust mite allergy. Methods A total of 59 house dust mite-allergic children (6–18 years) were recruited in general practice. These children or their parents rated their nasal and asthma symptoms on diary cards during 1 month. Allergen skin tests were performed and read after 15 min (early phase) and 6 h (late phase). Allergen-specific T cell proliferation was determined, and Th2 cytokine (IL-5 and IL-13) secretion was analysed. Results The size of the late-phase skin response correlated with in vitro T cell proliferation (r_s=0.38, P=0.003) but not with Th2 cytokine secretion (r_s=0.16, P=0.2 for both IL-5 and IL-13). Moreover, the late-phase skin response and T cell proliferation correlated with asthma symptoms (r_s=0.30, P=0.02 for skin response and r_s=0.28, P=0.03 for T cell proliferation) but not with nasal symptoms (r_s=0.19, P=0.15 for skin response and r_s=0.09, P=0.52 for T cell proliferation). The early-phase skin response correlated with the nasal symptom score (r_s=0.34, P=0.01) but not with asthma symptom scores (r_s<0.005, P=0.97). Conclusion In this study, the late-phase skin test response correlated with in vitro T cell proliferation but not with Th2 cytokine secretion. We found weak or no correlations between late-phase skin responses and symptoms of asthma or rhinitis in children with house dust mite allergy. This suggests that late-phase skin responses reflect certain T cell properties but are of limited value for the evaluation of airway symptoms in atopic children.