ResearchPad - 316 https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis]]> https://www.researchpad.co/article/elastic_article_15300 Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by scattered fibrotic lesions in the lungs. The pathogenesis and genetic basis of IPF remain poorly understood. Here, we show that a homozygous missense mutation in SFTPA1 caused IPF in a consanguineous Japanese family. The mutation in SFTPA1 disturbed the secretion of SFTPA1 protein. Sftpa1 knock-in (Sftpa1-KI) mice that harbored the same mutation as patients spontaneously developed pulmonary fibrosis that was accelerated by influenza virus infection. Sftpa1-KI mice showed increased necroptosis of alveolar epithelial type II (AEII) cells with phosphorylation of IRE1α leading to JNK-mediated up-regulation of Ripk3. The inhibition of JNK ameliorated pulmonary fibrosis in Sftpa1-KI mice, and overexpression of Ripk3 in Sftpa1-KI mice treated with a JNK inhibitor worsened pulmonary fibrosis. These findings provide new insight into the mechanisms of IPF in which a mutation in SFTPA1 promotes necroptosis of AEII cells through JNK-mediated up-regulation of Ripk3, highlighting the necroptosis pathway as a therapeutic target for IPF.

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<![CDATA[A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function]]> https://www.researchpad.co/article/elastic_article_15293

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<![CDATA[A DNAH17 missense variant causes flagella destabilization and asthenozoospermia]]> https://www.researchpad.co/article/Nae35663e-5912-4cba-a585-b87e3da1bc84

Using mice modelling patients’ variant, this study demonstrates that a homozygous DNAH17 missense variant causes asthenozoospermia and specifically destabilizes microtubule doublets 4–7 in flagella, which could be largely due to the storage of sperm in epididymis.

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<![CDATA[Inherited IL-18BP deficiency in human fulminant viral hepatitis]]> https://www.researchpad.co/article/Ne7f3a1f6-1e5b-4764-8b97-962cbded256d

We report autosomal recessive IL-18BP deficiency in a child who died of fulminant hepatitis upon infection with hepatitis A virus. Deficiency of IL-18BP leads to excessive IL-18 activity and uncontrolled IL-18–mediated hepatotoxicity in the infected liver.

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<![CDATA[The human CIB1–EVER1–EVER2 complex governs keratinocyte-intrinsic immunity to β-papillomaviruses]]> https://www.researchpad.co/article/5c910786d5eed0c4841a4439

de Jong et al. show that loss-of-function mutations in CIB1 are responsible for epidermodysplasia verruciformis, a cutaneous disease caused by human β-papillomavirus (β-HPV) infections, and that CIB1 forms a complex with EVER proteins, acting as a restriction factor against HPV.

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<![CDATA[hCALCRL mutation causes autosomal recessive nonimmune hydrops fetalis with lymphatic dysplasia]]> https://www.researchpad.co/article/5c91079ed5eed0c4841a465d

Using genetic, pharmacological and animal model approaches, we elucidate a novel human mutation in a G protein coupled receptor that impairs receptor oligomerization and trafficking leading to fatal, non-immune hydrops fetalis associated with arrested lymphatic development.

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<![CDATA[Germline-activating mutations in PIK3CD compromise B cell development and function]]> https://www.researchpad.co/article/5c69ecb5d5eed0c48414e1fc

PIK3CD mutations cause immune dysregulation. By studying humans and a novel mouse model, we show these mutations intrinsically impair B-cell development and function. These findings reveal mechanisms of compromised humoral immunity due to PIK3CD mutations, and opportunities to pharmacologically restore these defects.

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<![CDATA[A20 and ABIN-1 team up against intestinal epithelial cell death]]> https://www.researchpad.co/article/5c368386d5eed0c4841f4084

A20 and its binding partner ABIN-1 are genetically linked to inflammatory diseases. In this issue of JEM, Kattah et al. demonstrate that simultaneous deletion in a mouse model leads to instantaneous cell death in the intestinal epithelium and mortality.

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<![CDATA[Mutations in the X-linked ATP6AP2 cause a glycosylation disorder with autophagic defects]]> https://www.researchpad.co/article/5c01f8d4d5eed0c4842bee1f

Rujano et al. report mutations in ATP6AP2 leading to liver disease, immunodeficiency, and psychomotor impairment. ATP6AP2 deficiency impairs the assembly and function of the V-ATPase proton pump, causing defects in protein glycosylation and autophagy.

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<![CDATA[A p190BRhoGAP mutation and prolonged RhoB activation in fatal systemic capillary leak syndrome]]> https://www.researchpad.co/article/5c01f8c9d5eed0c4842bebeb

Pierce et al. describe a pediatric patient with a fatal systemic capillary leak syndrome (Clarkson’s disease). They identify a point mutation in p190BRhoGAP and show that patient-derived microvascular endothelial cells show prolonged activation RhoB that correlates with impaired barrier recovery after treatment with TNF compared with control cultures.

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