FATP4 missense and nonsense mutations cause similar features in Ichthyosis Prematurity Syndrome

<p>Abstract</p> <p>Background</p> <p>Ichthyosis Prematurity Syndrome (IPS) is an autosomal recessive disorder characterized by premature birth, non-scaly ichthyosis and atopic manifestations. The disease was recently shown to be caused by mutations in the gene encoding the fatty acid transport protein 4 (FATP4) and a specific reduction in the incorporation of very long chain fatty acids (VLCFA) into cellular lipids.</p> <p>Findings</p> <p>We screened probands from five families segregating IPS for mutations in the <it>FATP4 </it>gene. Four probands were compound heterozygous for four different mutations of which three are novel. Four patients were heterozygous and one patient homozygous for the previously reported non-sense mutation p.C168X (c.504c > a). All patients had clinical characteristics of IPS and a similar clinical course.</p> <p>Conclusions</p> <p>Missense mutations and non-sense mutations in <it>FATP4 </it>are associated with similar clinical features suggesting that missense mutations have a severe impact on FATP4 function. The results broaden the mutational spectrum in <it>FATP4 </it>associated with IPS for molecular diagnosis of and further functional analysis of FATP4.</p

Modulation of Transcriptional and Inflammatory Responses in Murine Macrophages by the Mycobacterium tuberculosis Mammalian Cell Entry (Mce) 1 Complex

The outcome of many infections depends on the initial interactions between agent and host. Aiming at elucidating the effect of the M. tuberculosis Mce1 protein complex on host transcriptional and immunological responses to infection with M. tuberculosis, RNA from murine macrophages at 15, 30, 60 min, 4 and 10 hrs post-infection with M. tuberculosis H37Rv or Δ-mce1 H37Rv was analyzed by whole-genome microarrays and RT-QPCR. Immunological responses were measured using a 23-plex cytokine assay. Compared to uninfected controls, 524 versus 64 genes were up-regulated by 15 min post H37Rv- and Δ-mce1 H37Rv-infection, respectively. By 15 min post-H37Rv infection, a decline of 17 cytokines combined with up-regulation of Ccl24 (26.5-fold), Clec4a2 (23.2-fold) and Pparγ (10.5-fold) indicated an anti-inflammatory response initiated by IL-13. Down-regulation of Il13ra1 combined with up-regulation of Il12b (30.2-fold), suggested switch to a pro-inflammatory response by 4 hrs post H37Rv-infection. Whereas no significant change in cytokine concentration or transcription was observed during the first hour post Δ-mce1 H37Rv-infection, a significant decline of IL-1b, IL-9, IL-13, Eotaxin and GM-CSF combined with increased transcription of Il12b (25.1-fold) and Inb1 (17.9-fold) by 4 hrs, indicated a pro-inflammatory response. The balance between pro-and anti-inflammatory responses during the early stages of infection may have significant bearing on outcome

Insulin Concentration Modulates Hepatic Lipid Accumulation in Mice in Part via Transcriptional Regulation of Fatty Acid Transport Proteins

Fatty liver disease (FLD) is commonly associated with insulin resistance and obesity, but interestingly it is also observed at low insulin states, such as prolonged fasting. Thus, we asked whether insulin is an independent modulator of hepatic lipid accumulation.In mice we induced, hypo- and hyperinsulinemia associated FLD by diet induced obesity and streptozotocin treatment, respectively. The mechanism of free fatty acid induced steatosis was studied in cell culture with mouse liver cells under different insulin concentrations, pharmacological phosphoinositol-3-kinase (PI3K) inhibition and siRNA targeted gene knock-down. We found with in vivo and in vitro models that lipid storage is increased, as expected, in both hypo- and hyperinsulinemic states, and that it is mediated by signaling through either insulin receptor substrate (IRS) 1 or 2. As previously reported, IRS-1 was up-regulated at high insulin concentrations, while IRS-2 was increased at low levels of insulin concentration. Relative increase in either of these insulin substrates, was associated with an increase in liver-specific fatty acid transport proteins (FATP) 2&5, and increased lipid storage. Furthermore, utilizing pharmacological PI3K inhibition we found that the IRS-PI3K pathway was necessary for lipogenesis, while FATP responses were mediated via IRS signaling. Data from additional siRNA experiments showed that knock-down of IRSs impacted FATP levels.States of perturbed insulin signaling (low-insulin or high-insulin) both lead to increased hepatic lipid storage via FATP and IRS signaling. These novel findings offer a common mechanism of FLD pathogenesis in states of both inadequate (prolonged fasting) and ineffective (obesity) insulin signaling

RESTRICTION ENZYMES INDUCED BANDS IN THE CAVE CRICKET DOLICHOPODA-SCHIAVAZZII (ORTHOPTERA, RHAPHIDOPHORIDAE) - IMPLICATIONS FOR HETEROCHROMATIN CHARACTERIZATION AND SATELLITE DNA DISTRIBUTION

In this study the activity of some class II restriction endonucleases, RE, on fixed metaphase chromosomes has been tested on two sample populations of the cave cricket Dolichopoda schiavazzii, a species endemic in Tuscany. In particular, the 6-base cutter PstI was chosen to detect the occurrence and localization on chromosomes of a satellite DNA family (named pDoP102) whose repetition units, analyzed in a previous study, contain the cleavage site of this enzyme. A comparison of the PstI digestion pattern and the C-banding one, suggests that this satDNA family is mainly localized in certain heterochromatic regions of chromosomes 1, 3, 8, 10 and in the Y chromosome. As a negative control in situ digestion was performed with RE AluI whose cleavage site is not contained in the pDoP102 satDNA sequence. The partial overlap between the PstI and AluI digested regions suggests the occurrence of at least another satDNA family detected by PstI and containing the AluI target. AluI restriction banding also showed variation between the two population samples, suggesting a role of these cytological markers in microevolutionary studies

RESTRICTION ENZYMES INDUCED BANDS IN THE CAVE CRICKET DOLICHOPODA-SCHIAVAZZII (ORTHOPTERA, RHAPHIDOPHORIDAE) - IMPLICATIONS FOR HETEROCHROMATIN CHARACTERIZATION AND SATELLITE DNA DISTRIBUTION

In this study the activity of some class II restriction endonucleases, RE, on fixed metaphase chromosomes has been tested on two sample populations of the cave cricket Dolichopoda schiavazzii, a species endemic in Tuscany. In particular, the 6-base cutter PstI was chosen to detect the occurrence and localization on chromosomes of a satellite DNA family (named pDoP102) whose repetition units, analyzed in a previous study, contain the cleavage site of this enzyme. A comparison of the PstI digestion pattern and the C-banding one, suggests that this satDNA family is mainly localized in certain heterochromatic regions of chromosomes 1, 3, 8, 10 and in the Y chromosome. As a negative control in situ digestion was performed with RE AluI whose cleavage site is not contained in the pDoP102 satDNA sequence. The partial overlap between the PstI and AluI digested regions suggests the occurrence of at least another satDNA family detected by PstI and containing the AluI target. AluI restriction banding also showed variation between the two population samples, suggesting a role of these cytological markers in microevolutionary studies