Antiviral and regulatory T cell immunity in a patient with stromal interaction molecule 1 deficiency

Stromal interaction molecule 1 (STIM1) deficiency is a rare genetic disorder of store-operated calcium entry, associated with a complex syndrome including immunodeficiency and immune dysregulation. The link from the molecular defect to these clinical manifestations is incompletely understood. We report two patients with a homozygous R429C point mutation in STIM1 completely abolishing store-operated calcium entry in T cells. Immunological analysis of one patient revealed that despite the expected defect of T cell proliferation and cytokine production in vitro, significant antiviral T cell populations were generated in vivo. These T cells proliferated in response to viral Ags and showed normal antiviral cytotoxicity. However, antiviral immunity was insufficient to prevent chronic CMV and EBV infections with a possible contribution of impaired NK cell function and a lack of NKT cells. Furthermore, autoimmune cytopenia, eczema, and intermittent diarrhea suggested impaired immune regulation. FOXP3-positive regulatory T (Treg) cells were present but showed an abnormal phenotype. The suppressive function of STIM1-deficient Treg cells in vitro, however, was normal. Given these partial defects in cytotoxic and Treg cell function, impairment of other immune cell populations probably contributes more to the pathogenesis of immunodeficiency and autoimmunity in STIM1 deficiency than previously appreciated.     

Haploinsufficiency of a spliceosomal GTPase encoded by EFTUD2 causes mandibulofacial dysostosis with microcephaly

Mandibulofacial dysostosis with microcephaly (MFDM) is a rare sporadic syndrome comprising craniofacial malformations, microcephaly, developmental delay, and a recognizable dysmorphic appearance. Major sequelae, including choanal atresia, sensorineural hearing loss, and cleft palate, each occur in a significant proportion of affected individuals. We present detailed clinical findings in 12 unrelated individuals with MFDM; these 12 individuals compose the largest reported cohort to date. To define the etiology of MFDM, we employed whole-exome sequencing of four unrelated affected individuals and identified heterozygous mutations or deletions of EFTUD2 in all four. Validation studies of eight additional individuals with MFDM demonstrated causative EFTUD2 mutations in all affected individuals tested. A range of EFTUD2-mutation types, including null alleles and frameshifts, is seen in MFDM, consistent with haploinsufficiency; segregation is de novo in all cases assessed to date. U5-116kD, the protein encoded by EFTUD2, is a highly conserved spliceosomal GTPase with a central regulatory role in catalytic splicing and post-splicing-complex disassembly. MFDM is the first multiple-malformation syndrome attributed to a defect of the major spliceosome. Our findings significantly extend the range of reported spliceosomal phenotypes in humans and pave the way for further investigation in related conditions such as Treacher Collins syndrome.     

Empirical evaluation reveals best fit of a logistic mutation model for human Y-chromosomal microsatellites

The rate of microsatellite mutation is dependent upon both the allele length and the repeat motif, but the exact nature of this relationship is still unknown. We analyzed data on the inheritance of human Y-chromosomal microsatellites in father-son duos, taken from 24 published reports and comprising 15,285 directly observable meioses. At the six microsatellites analyzed (DYS19, DYS389I, DYS390, DYS391, DYS392, and DYS393), a total of 162 mutations were observed. For each locus, we employed a maximum-likelihood approach to evaluate one of several single-step mutation models on the basis of the data. For five of the six loci considered, a novel logistic mutation model was found to provide the best fit according to Akaike's information criterion. This implies that the mutation probability at the loci increases (nonlinearly) with allele length at a rate that differs between upward and downward mutations. For DYS392, the best fit was provided by a linear model in which upward and downward mutation probabilities increase equally with allele length. This is the first study to empirically compare different microsatellite mutation models in a locus-specific fashion.     

Current allele distribution of the human longevity gene APOE in Europe can mainly be explained by ancient admixture

Variation in apolipoprotein E (APOE) has been shown to have the strongest genetic effect on human longevity. The aim of this study was to unravel the evolutionary history of the three major APOE alleles in Europe by analysing ancient samples up to 12,000 years old. We detected significant allele frequency shifts between populations and over time. Our analyses indicated that selection led to large frequency differences between the earliest European populations (i.e., hunter-gatherers vs. first farmers), possibly due to changes in diet/lifestyle. In contrast, the allele distributions in populations from ~4000 BCE onward can mainly be explained by admixture, suggesting that it also played an important role in shaping current APOE variation. In any case, the resulting allele frequencies strongly influence the predisposition for longevity today, likely as a consequence of past adaptations and demographic processes.     

Prenatal stress programs lipid metabolism enhancing cardiovascular risk in the female F1, F2, and F3 generation in the primate model common marmoset (Callithrix jacchus)

Background Many human diseases are modulated by intrauterine environment, which is called prenatal programming. This study investigated effects of prenatal glucocorticoids on the lipid metabolism of three filial generations of common marmosets. Methods Pregnant primates were treated with dexamethasone during pregnancy. Body weight and blood lipid parameters of adult female offspring (F1: n = 5, F2: n = 6, F3: n = 3) were compared with age‐related female controls (n = 12). Results F1, F2, and F3 offspring showed significantly lower percentage of plasma n3 fatty acids than controls. F2 and F3 presented higher cholesterol levels, with significantly more LDL cholesterol, significantly less HDL triglycerides and an enhanced cholesterol/HDL cholesterol ratio. Body weight was not significantly affected. Conclusions Prenatal dexamethasone led to higher amounts of cardiovascular risk factors and less protective parameters in female F1–F3 offspring. The intergenerational consequences suggest prenatal programming through epigenetic effects.     

Synthese der amadori-verbindung: 2-desoxy-2-[(1-desoxy-D-fructofuranuronsäure)-1-yl]amino-α-D-glucopyranose

Condensation of 2-amino-2-deoxy-D-glucose hydrochloride with D-glucuronic acid in methanol containing a trace of pyridine gave crystalline 2-deoxy-2-[(1-deoxy-D-fructofuranuronic acid)-1-yl]amino-α-D-glucopyranose (2) in a yield of 34%. The compound was characterized by analytical and spectroscopic data and by its hepta-O-acetyl derivative. At pH 6.5, 2 was split quantitatively into 2-amino-2-deoxy-D-glucose and D-glucuronic acid.     

Immunochip analysis identifies association of the RAD50/IL13 region with human longevity

Human longevity is characterized by a remarkable lack of confirmed genetic associations. Here, we report on the identification of a novel locus for longevity in the RAD50/IL13 region on chromosome 5q31.1 using a combined European sample of 3208 long‐lived individuals (LLI) and 8919 younger controls. First, we performed a large‐scale association study on 1458 German LLI (mean age 99.0 years) and 6368 controls (mean age 57.2 years) by targeting known immune‐associated loci covered by the Immunochip. The analysis of 142 136 autosomal single nucleotide polymorphisms (SNPs) revealed an Immunochip‐wide significant signal (P_Immunochip = 7.01 × 10^–9) for the SNP rs2075650 in the TOMM40/APOE region, which has been previously described in the context of human longevity. To identify novel susceptibility loci, we selected 15 markers with P_Immunochip < 5 × 10^–4 for replication in two samples from France (1257 LLI, mean age 102.4 years; 1811 controls, mean age 49.1 years) and Denmark (493 LLI, mean age 96.2 years; 740 controls, mean age 63.1 years). The association at SNP rs2706372 replicated in the French study collection and showed a similar trend in the Danish participants and was also significant in a meta‐analysis of the combined French and Danish data after adjusting for multiple testing. In a meta‐analysis of all three samples, rs2706372 reached a P‐value of P_{Immunochip+Repl} = 5.42 × 10^?7 (OR = 1.20; 95% CI = 1.12–1.28). SNP rs2706372 is located in the extended RAD50/IL13 region. RAD50 seems a plausible longevity candidate due to its involvement in DNA repair and inflammation. Further studies are needed to identify the functional variant(s) that predispose(s) to a long and healthy life.     

Inducibility of chemical defenses in Norway spruce bark is correlated with unsuccessful mass attacks by the spruce bark beetle

Secondary attraction to aggregation pheromones plays a central role in the host colonization behavior of the European spruce bark beetle Ips typographus. However, it is largely unknown how the beetles pioneering an attack locate suitable host trees, and eventually accept or reject them. To find possible biomarkers for host choice by I. typographus, we analyzed the chemistry of 58 Norway spruce (Picea abies) trees that were subsequently either (1) successfully attacked and killed, (2) unsuccessfully attacked, or (3) left unattacked. The trees were sampled before the main beetle flight in a natural Norway spruce-dominated forest. No pheromones were used to attract beetles to the experimental trees. To test the trees' defense potential, each tree was treated in a local area with the defense hormone methyl jasmonate (MeJ), and treated and untreated bark were analyzed for 66 different compounds, including terpenes, phenolics and alkaloids. The chemistry of MeJ-treated bark correlated strongly with the success of I. typographus attack, revealing major chemical differences between killed trees and unsuccessfully attacked trees. Surviving trees produced significantly higher amounts of most of the 39 analyzed mono-, sesqui-, and diterpenes and of 4 of 20 phenolics. Alkaloids showed no clear pattern. Differences in untreated bark were less pronounced, where only 1,8-cineole and (-)-limonene were significantly higher in unsuccessfully attacked trees. Our results show that the potential of individual P. abies trees for inducing defense compounds upon I. typographus attack may partly determine tree resistance to this bark beetle by inhibiting its mass attack.