Trisomy 7 mosaicism, maternal uniparental heterodisomy 7 and Hirschsprung's disease in a child with Silver-Russell syndrome

Prenatal trisomy 7 is usually a cell culture artifact in amniocytes with normal diploid karyotype at birth and normal fetal outcome. In the same way, true prenatal trisomy 7 mosaicism usually results in a normal child except when trisomic cells persist after birth or when trisomy rescue leads to maternal uniparental disomy, which is responsible for 5.5-7% of patients with Silver-Russell syndrome (SRS). We report here on the unusual association of SRS and Hirschsprung's disease (HSCR) in a patient with maternal uniparental heterodisomy 7 and trisomy 7 mosaicism in intestine and skin fibroblasts. HSCR may be fortuitous given its frequency, multifactorial inheritance and genetic heterogeneity. However, the presence of the trisomy 7 mosaicism in intestine as well as in skin fibroblasts suggests that SRS and HSCR might possibly be related. Such an association might result from either an increased dosage of a nonimprinted gene due to trisomy 7 mosaicism in skin fibroblasts (leading to SRS) and in intestine (leading to HSCR), or from an overexpression, through genomic imprinting, of maternally expressed imprinted allele(s) in skin fibroblasts and intestine or from a combination of trisomy 7 mosaicism and genomic imprinting. This report suggests that the SRS phenotype observed in maternal uniparental disomy 7 (mUPD(7)) patients might also result from an undetected low level of trisomy 7 mosaicism. In order to validate this hypothesis, we propose to perform a conventional and molecular cytogenetic analysis in different tissues every time mUPD7 is displayed.     

Characterization of cystic fibrosis conductance transmembrane regulator gene mutations and IVS8 poly(T) variants in Portuguese patients with congenital absence of the vas deferens

BACKGROUND: Cystic fibrosis conductance transmembrane regulator (CFTR) gene mutations and IVS8 poly(T) variants in Portuguese patients with bilateral (CBAVD) and unilateral (CUAVD) congenital absence of the vas deferens remain to be evaluated. METHODS: Patient screening was carried out by PCR, denaturing gradient gel electrophoresis and DNA sequencing. RESULTS: CFTR mutations were found in 18 out of 31 (58.1%) CBAVD and in three of four (75%) CUAVD patients. The most frequent mutations were F508del and R334W in CBAVD and G542X in CUAVD, with the allelic frequencies of R334W (6.5%) and G542X (25%) being particular to the Portuguese population. The 5T allelic frequency was 3.5% in the fertile male population, 25% in CUAVD and 27.4% in CBAVD patients. The combined frequency of mutations (CFTR+5T) was increased in CBAVD to 22 out of 31 (71%). The frequency of CFTR mutations was compared with that of patients with secondary obstructive azoospermia (OAZ; one out of 16, 6.3%) and non-obstructive azoospermia (NOAZ; two out of 22, 9.1%) with conserved spermatogenesis, which were similar to the general population. However, whereas the 5T allelic frequency in OAZ was similar to that of the general population (3.1%), it was increased in NOAZ cases (14.3%). CONCLUSIONS: Data confirm that CFTR+5T mutations represent the most common genetic abnormality in CAVD, and suggest that cases of NOAZ may be associated with the 5T allele.     

Clustering patterns of LOD scores for asthma-related phenotypes revealed by a genome-wide screen in 295 French EGEA families

A genome-wide scan for asthma phenotypes was conducted in the whole sample of 295 EGEA families selected through at least one asthmatic subject. In addition to asthma, seven phenotypes involved in the main asthma physiopathological pathways were considered: SPT (positive skin prick test response to at least one of 11 allergens), SPTQ score being the number of positive skin test responses to 11 allergens, Phadiatop (positive specific IgE response to a mixture of allergens), total IgE levels, eosinophils, bronchial responsiveness (BR) to methacholine challenge and %predicted FEV(1). Four regions showed evidence for linkage (P相似文献   

Evidence for gene x smoking exposure interactions in a genome-wide linkage screen of asthma and bronchial hyper-responsiveness in EGEA families

Asthma and bronchial hyper-responsiveness (BHR), an asthma-related phenotype, result from many genetic (G) and environmental (E) factors. Passive exposure to tobacco smoke (ETS) in early life is one of these risk factors. Following a genome scan for asthma and associated phenotypes conducted in 295 French Epidemiological study on the Genetics and Environment of Asthma, our present aim was to investigate interactions between genetic susceptibility to asthma and to BHR with passive ETS using two different methods: the predivided sample test (PST) and the mean interaction test (MIT). PST and MIT consider the identical by descent (identity by descent) distribution at all markers in affected sib-pairs with 2, 1 or 0 sib(s) exposed to ETS. While the PST allows detection of both linkage and G x E interaction, the MIT tests for linkage by taking into account a possible interaction. Among the six regions detected at P相似文献   

Inhibition of progesterone production in human luteinized granulosa cells treated with LXR agonists

Progesterone production by luteal cells is dependent on the supply of cholesterol by lipoproteins. The aim of this study was to determine whether the liver X receptors (LXRs) contribute to cholesterol homeostasis and progesterone secretion in human luteinized granulosa cells. Cells were isolated from follicular aspirates of patients undergoing in vitro fertilization. Luteinization was induced by a 7-day treatment with human chorionic gonadotrophin. LXR beta was expressed at higher levels than LXR alpha in granulosa cells and its expression was increased during luteinization. Treatment of luteinized granulosa cells by LXR agonists induced a significant time- and dose-dependent reduction in progesterone secretion (50% reductions after a 7-day treatment with 1-microM of either GW3965 or T0901317). mRNA levels of steroidogenic genes including steroidogenic acute regulatory protein and P450 side-chain cleavage were only moderately affected by LXR activation, with a significant reduction that was observed at 10 microM agonist concentration. Cellular cholesterol was markedly reduced after treatment with LXR agonists as a result of an increased cholesterol efflux that was related to the induction of LXR target genes (ABCA1, ABCG1, apo E, PLTP). Our study identifies LXRs as new, key actors contributing to regulation of cholesterol metabolism and steroidogenesis in luteinized granulosa cells.     

Multilocus sequence typing reveals that the population structure of Candida dubliniensis is significantly less divergent than that of Candida albicans

The pathogenic yeast Candida dubliniensis is phylogenetically very closely related to Candida albicans, and both species share many phenotypic and genetic characteristics. DNA fingerprinting using the species-specific probe Cd25 and sequence analysis of the internal transcribed spacer (ITS) region of the ribosomal gene cluster previously showed that C. dubliniensis is comprised of three major clades comprising four distinct ITS genotypes. Multilocus sequence typing (MLST) has been shown to be very useful for investigating the epidemiology and population biology of C. albicans and has identified many distinct major and minor clades. In the present study, we used MLST to investigate the population structure of C. dubliniensis for the first time. Combinations of 10 loci previously tested for MLST analysis of C. albicans were assessed for their discriminatory ability with 50 epidemiologically unrelated C. dubliniensis isolates from diverse geographic locations, including representative isolates from the previously identified three Cd25-defined major clades and the four ITS genotypes. Dendrograms created by using the unweighted pair group method with arithmetic averages that were generated using the data from all 10 loci revealed a population structure which supports that previously suggested by DNA fingerprinting and ITS genotyping. The MLST data revealed significantly less divergence within the C. dubliniensis population examined than within the C. albicans population. These findings show that MLST can be used as an informative alternative strategy for investigating the population structure of C. dubliniensis. On the basis of the highest number of genotypes per variable base, we recommend the following eight loci for MLST analysis of C. dubliniensis: CdAAT1b, CdACC1, CdADP1, CdMPIb, CdRPN2, CdSYA1, exCdVPS13, and exCdZWF1b, where “Cd” indicates C. dubliniensis and “ex” indicates extended sequence.     

DiC14-amidine cationic liposomes stimulate myeloid dendritic cells through Toll-like receptor 4

DiC14-amidine cationic liposomes were recently shown to promote Th1 responses when mixed with allergen. To further define the mode of action of diC14-amidine as potential vaccine adjuvant, we characterized its effects on mouse and human myeloid dendritic cells (DC). First, we observed that, as compared with two other cationic liposomes, only diC14-amidine liposomes induced the production of IL-12p40 and TNF-alpha by mouse bone marrow-derived DC. DiC14-amidine liposomes also activated human DC, as shown by synthesis of IL-12p40 and TNF-alpha, accumulation of IL-6, IFN-beta and CXCL10 mRNA, and up-regulation of membrane expression of CD80 and CD86. DC stimulation by diC14-amidine liposomes was associated with activation of NF-kappaB, ERK1/2, JNK and p38 MAP kinases. Finally, we demonstrated in mouse and human cells that diC14-amidine liposomes use Toll-like receptor 4 to elicit both MyD88-dependent and Toll/IL-1R-containing adaptor inducing interferon IFN-beta (TRIF)-dependent responses.     

The fate of the large striatal interneurons expressing calretinin in Huntington's disease

Huntington's disease (HD) is characterized by the atrophy of the striatum due to losses of projection neurons, while interneurons are relatively spared. However, little is known about the fate of the large interneurons that express calretinin (Cr) in HD. We addressed this issue by applying a double immunofluorescent labeling technique to postmortem striatum from HD patients and controls. We compared the distribution and density of Cr-positive (+) interneurons and their degree of choline acetyltransferase (ChAT) coexpression in normal and HD cases. Large interneurons containing only Cr, ChAT, or both occurred in the normal human striatum and a twofold decrease in the density of Cr+/ChAT+ and Cr-/ChAT+ neurons was recorded in HD striatum compared to controls. However, studies undertaken with neurokinin-1 receptor as a marker of large Cr+ and ChAT+ neurons revealed that these neurons are selectively spared in HD. Hence, the apparent decrease in the number of Cr+/ChAT+ and Cr-/ChAT+ neurons in HD is better explained by a diminution in the expression of Cr and ChAT than by the degeneration of these cells. Altogether, our data suggest that neurodegenerative processes at play in HD affect the expression of Cr and ChAT in the large striatal interneurons without causing their death.     

EDNRB mutations cause Waardenburg syndrome type II in the heterozygous state

Waardenburg syndrome (WS) is a genetic disorder characterized by sensorineural hearing loss and pigmentation anomalies. The clinical definition of four WS types is based on additional features due to defects in structures mostly arising from the neural crest, with type I and type II being the most frequent. While type I is tightly associated to PAX3 mutations, WS type II (WS2) remains partly enigmatic with mutations in known genes (MITF, SOX10) accounting for only 30% of the cases. We performed exome sequencing in a WS2 index case and identified a heterozygous missense variation in EDNRB. Interestingly, homozygous (and very rare heterozygous) EDNRB mutations are already described in type IV WS (i.e., in association with Hirschsprung disease [HD]) and heterozygous mutations in isolated HD. Screening of a WS2 cohort led to the identification of an overall of six heterozygous EDNRB variations. Clinical phenotypes, pedigrees and molecular segregation investigations unraveled a dominant mode of inheritance with incomplete penetrance. In parallel, cellular and functional studies showed that each of the mutations impairs the subcellular localization of the receptor or induces a defective downstream signaling pathway. Based on our results, we now estimate EDNRB mutations to be responsible for 5%–6% of WS2.