Primrose syndrome and 3q13.31 microdeletion syndrome are clinically related disorders characterized by tall stature, macrocephaly, intellectual disability, disturbed behavior and unusual facial features, with diabetes, deafness, progressive muscle wasting and ectopic calcifications specifically occurring in the former. We report that missense mutations in ZBTB20, residing within the 3q13.31 microdeletion syndrome critical region, underlie Primrose syndrome. This finding establishes a genetic link between these disorders and delineates the impact of ZBTB20 dysregulation on development, growth and metabolism.

FSGS is characterized by the presence of partial sclerosis of some but not all glomeruli. Studies of familial FSGS have been instrumental in identifying podocytes as critical elements in maintaining glomerular function, but underlying mutations have not been identified for all forms of this genetically heterogeneous condition. Here, exome sequencing in members of an index family with dominant FSGS revealed a nonconservative, disease-segregating variant in the PAX2 transcription factor gene. Sequencing in probands of a familial FSGS cohort revealed seven rare and private heterozygous single nucleotide substitutions (4% of individuals). Further sequencing revealed seven private missense variants (8%) in a cohort of individuals with congenital abnormalities of the kidney and urinary tract. As predicted by in silico structural modeling analyses, in vitro functional studies documented that several of the FSGS-associated PAX2 mutations perturb protein function by affecting proper binding to DNA and transactivation activity or by altering the interaction of PAX2 with repressor proteins, resulting in enhanced repressor activity. Thus, mutations in PAX2 may contribute to adult-onset FSGS in the absence of overt extrarenal manifestations. These results expand the phenotypic spectrum associated with PAX2 mutations, which have been shown to lead to congenital abnormalities of the kidney and urinary tract as part of papillorenal syndrome. Moreover, these results indicate PAX2 mutations can cause disease through haploinsufficiency and dominant negative effects, which could have implications for tailoring individualized drug therapy in the future.

Mutations in CREBBP cause Rubinstein–Taybi syndrome. By using exome sequencing, and by using Sanger in one patient, CREBBP mutations were detected in 11 patients who did not, or only in a very limited manner, resemble Rubinstein–Taybi syndrome. The combined facial signs typical for Rubinstein–Taybi syndrome were absent, none had broad thumbs, and three had only somewhat broad halluces. All had apparent developmental delay (being the reason for molecular analysis); five had short stature and seven had microcephaly. The facial characteristics were variable; main characteristics were short palpebral fissures, telecanthi, depressed nasal ridge, short nose, anteverted nares, short columella, and long philtrum. Six patients had autistic behavior, and two had self‐injurious behavior. Other symptoms were recurrent upper airway infections (n = 5), feeding problems (n = 7) and impaired hearing (n = 7). Major malformations occurred infrequently. All patients had a de novo missense mutation in the last part of exon 30 or beginning of exon 31 of CREBBP, between base pairs 5,128 and 5,614 (codons 1,710 and 1,872). No missense or truncating mutations in this region have been described to be associated with the classical Rubinstein–Taybi syndrome phenotype. No functional studies have (yet) been performed, but we hypothesize that the mutations disturb protein–protein interactions by altering zinc finger function. We conclude that patients with missense mutations in this specific CREBBP region show a phenotype that differs substantially from that in patients with Rubinstein–Taybi syndrome, and may prove to constitute one (or more) separate entities. © 2016 Wiley Periodicals, Inc.

Hepatitis C virus (HCV) proteins are known to interfere at several levels with both innate and adaptive responses of the host. A key target in these effects is the interferon (IFN) signaling pathway. While the effects of nonstructural proteins are well established, the role of structural proteins remains controversial. We investigated the effect of HCV structural proteins on the expression of interferon regulatory factor 1 (IRF-1), a secondary transcription factor of the IFN system responsible for inducing several key antiviral and immunomodulatory genes. We found substantial inhibition of IRF-1 expression in cells expressing the entire HCV replicon. Suppression of IRF-1 synthesis was mainly mediated by the core structural protein and occurred at the transcriptional level. The core protein in turn exerted a transcriptional repression of several interferonstimulated genes, targets of IRF-1, including interleukin-15 (IL-15), IL-12, and low-molecular-mass polypeptide 2. These data recapitulate in a unifying mechanism, i.e., repression of IRF-1 expression, many previously described pathogenetic effects of HCV core protein and suggest that HCV core-induced IRF-1 repression may play a pivotal role in establishing persistent infection by dampening an effective immune response.Infection with hepatitis C virus (HCV) represents the major cause of liver disease, affecting more than 170 million individuals worldwide (26). After a subclinical phase, more than 80% of patients progress to persistent HCV infection, which is the leading cause of chronic liver disease associated with cirrhosis and hepatocellular carcinoma (13). The persistence of the virus in the majority of infected individuals is linked to the ability of HCV to evade and/or antagonize the host immune response at both the local and systemic levels. Accordingly, although hepatocytes are a major target of HCV infection, the virus can also replicate in immune cells, including effector cells (1,11). In this respect, resistance to interferon (IFN) therapy is a hallmark of evolution in persistence, indicating that knocking down the antiviral and immunomodulating effects of IFN is a successful strategy for evading the host immune surveillance (21). The production and secretion of IFN type I is pivotal in inducing a global antiviral state through paracrine IFN production and the subsequent activation of interferon-stimulated genes (ISGs) within the infected cells and in the surrounding tissues (70). The role of IFN in HCV infection is thus crucial (21). Functional genomic analyses from cohorts of human subjects with chronic infection have shown that infection is associated with a gene expression profile marked by ISGs whose level of expression is related to different degrees of liver fibrosis and cirrhosis (67). Similarly, gene expression profiling has demonstrated that acute resolving infections in chimpanzees are associated with high levels of hepatic ISG expression (4).The single-stranded RNA genome of HCV is translated into a polypeptide precursor of 3,010 amino aci...

Veillonella parvula is an anaerobic gram-negative coccus that is part of the normal flora of the animal and human mouth and gastrointestinal and genitourinary tracts. Oral V. parvula is involved in the development of early periodontal disease as well as different types of serious infections. Present data on molecular mechanisms responsible for innate immune response against Veillonella are very scanty. The aim of this study was to investigate the Toll-like receptor (TLR) pathways responsible for V. parvula lipopolysaccharide (LPS) and to identify the intracellular pathways induced by this recognition. V. parvula LPS stimulated tumor necrosis factor alpha (TNF-␣) and interleukin-6 (IL-6) release in human peripheral blood mononuclear cells (PBMC) in a dose-dependent manner. Pretreatment of cells with a TLR4 antagonist significantly reduced TNF-␣ and IL-6 production in PBMC stimulated with either Veillonella or Escherichia coli LPS. However, V. parvula LPS was 10-to 100-fold less active than E. coli LPS for cytokine induction. TNF-␣, IL-1␤, IL-6, and IL-10 were released in wild-type and TLR2 ؊/؊ , but not TLR4 ؊/؊ , mouse macrophage cultures. V. parvula LPS was able to activate the human PBMC p38 mitogen-activated protein kinase (MAPK). A specific p38 MAPK inhibitor strongly inhibited V. parvula LPS-induced TNF-␣, IL-1␤, IL-6, and IL-10. In conclusion, V. parvula LPS is able to induce cytokine production in both human and murine in vitro models, although it is less effective than Enterobacteriaceae LPS. V. parvula LPS-stimulated cytokine induction, as well as p38 MAPK activation, are TLR4-dependent features.Veillonella organisms are small, nonfermentative, strictly anaerobic, gram-negative cocci which form part of the normal flora of the oral, genitourinary, respiratory, and intestinal tracts of humans and animals (10). The genus Veillonella was first isolated by Veillon and Zuber in 1898 and currently consists of eight species (28).Veillonella species have been reported as causes of serious infections, including meningitis (6), osteomyelitis and discitis (7, 28), prosthetic joint infection (26), and acute and chronic pleuropulmonary infection (33).Risk factors for Veillonella infection include periodontal disease, immunodeficiency, intravenous drug use, and premature birth (28). V. parvula is an important pathogen implicated in periodontitis and other dental infections (3, 18), and it is one of the most common anaerobic pathogens in chronic maxillary sinusitis and deep neck infections (9, 37). V. parvula has also been reported as a pathogen for osteomyelitis (34) and abscessed orchiepididymitis with sepsis (4). Endovascular infections reportedly may range from bacteremia to severe endocarditis and fatal cases of sepsis (8,14,25).Lipopolysaccharides (LPS) are major pathogenic factors of gram-negative bacteria. LPS from aerobic and facultative bacteria have been extensively studied (5). On the contrary, very little is known regarding the biological activity of LPS from anaerobic microorganisms such as Veillonella (1...