Mutations in Myosin 5B in Children With Early-onset Cholestasis.

OBJECTIVES: Mutations in Myosin 5B (MYO5B) are known to be associated with microvillous inclusion disease (MVID) a genetic cause of neonatal intractable diarrhoea. More recently, they have been reported in children with cholestasis but without typical gastrointestinal symptoms of MVID. We describe our series of children with cholestasis and mutations in MYO5B. METHODS: Clinical, laboratory, and histological data were collected from patients with cholestasis and pathogenic mutations in MYO5B, found by next generation sequencing (NGS) but with minimal gastrointestinal disease. RESULTS: Six patients (3 boys) were identified. Median age at presentation was 19 months (range, 3-92). Presenting features were jaundice, pale stools, pruritus, and failure to thrive. Patients 5 and 6 had intractable diarrhoea until the age of 3 and 7 years, respectively, but currently are on full enteral diet with no intestinal symptoms. Median values for serum total bilirubin were 55 µmol/L (2-500), alanine aminotransferase 73I IU/L (32-114), γ-glutamyltransferase 7 IU/L (7-10), and serum bile acids 134 µmol/L (18-274). Three patients underwent 1 or more types of biliary diversion for symptom control. Median follow-up was 5 years (2-22). At most recent follow-up, they all reported pruritus while on antipruritics. Patient 1 had a liver transplant. CONCLUSIONS: We identified 6 patients, with mutations in MYO5B, early-onset cholestasis and pruritus, with variable response to biliary diversion without typical MVID.

TRAF1/C5, eNOS, C1q, but not STAT4 and PTPN22 gene polymorphisms are associated with genetic susceptibility to systemic lupus erythematosus in Turkey.

A significant source of variability in the literature on systemic lupus erythematosus (SLE) susceptibility genes has been the inability to replicate genetic findings across different racial or ethnic groups. We investigated whether a single nucleotide polymorphism (SNP) of the STAT4 (rs7574865), PTPN22 (rs2476601), TRAF1/C5 (rs10818488), and C1q (rs292001) genes as well as the 27-bp VNTR polymorphism on intron 4 of eNOS, previously associated with SLE in other populations, are also associated with SLE risk in Turkey. A group of 158 SLE patients and 155 healthy controls were included in this study. A genetic association of the TRAF1/C5, C1q, and eNOS gene polymorphism, but not of STAT4 and PTPN22, was found to confer a degree of risk for SLE. These data highlight the importance of comparative studies in different populations to confirm the previously detected genetic associations.

Innate immunity in systemic lupus erythematosus: sensing endogenous nucleic acids.

Historically, the involvement of complement - an integral part of the innate immune response- in the pathogenesis of lupus was recognized early. Emphasis shifted quickly however to the specific immunity with scientists concentrating on the adaptive immune response (autoantigens, autoreactive T cells and autoantibodies). Similarly, the detection of interferon alpha (IFNα), another key mediator of innate immunity, in the sera of active lupus patients by Hooks and Moutsopoulos in 1979 was poorly understood and thus ignored for many years. More recently however, the realization that a) endogenous ligands ("stressors") derived from a "stressed" host can be potent inducers of inflammatory mediators, and b) a cross-talk exists between the innate and the specific immune response, has motivated investigators to take a closer look at innate immunity. To this end, studies have revealed novel inducers, sensors, mediators and effectors in the innate arm of immunity of key relevance to the pathogenesis of lupus. According to the current paradigm, nucleosomes containing nucleic acids (RNA and/or DNA) and other endogenous danger ligands that can bind to pathogen associated molecular pattern receptors are incorporated in apoptotic blebs, which in turn promote the activation of dendritic and B cells and the production of IFNα and autoantibodies, respectively. These molecules find their way to specific receptors (toll-like receptors, TLRs; the nucleotide binding and oligomerization domain receptors, NLRs; and the retinoid acid inducible gene-I-like receptors, RLRs) some of which are located intracellularly. Thus in lupus, apoptotic material is not only a source of autoantigens and molecules with adjuvant activity, but also a source of endogenous molecules that can be potent inducers of inflammatory cytokines.