Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation.

BACKGROUND: Hereditary angioedema (HAE) is a potentially fatal disorder resulting in recurrent attacks of severe swelling. It may be associated with a genetic deficiency of functional C1 inhibitor (C1-INH) or with normal C1-INH (HAEnCI). In families with HAEnCI, HAE-linked mutations in the F12, PLG, KNG1, ANGPT1, or MYOF genes have been identified. In many families with HAEnCI the genetic cause of the disease is currently unknown. OBJECTIVE: The aim of this study was to identify a novel disease-linked mutation for HAEnCI. METHODS: Methods comprised whole exome sequencing (WES), Sanger sequencing analysis, pedigree analysis, bioinformatical analysis of the mutation, and biochemical analysis of parameters of the kallikrein-kinin (contact) system. RESULTS: By performing WES on a multi-generation family with HAEnCI we identified the HS3ST6 mutation c.430A>T (p.Thr144Ser) in all three affected family members that were sequenced. This gene encodes the heparan sulfate glucosamine 3-O-sulfotransferase 6 (3-OST-6) which is involved in the last step of heparan sulfate biosynthesis. The p.Thr144Ser mutation is likely to affect the interaction between two beta sheets stabilizing the active center of the 3-OST-6 protein. CONCLUSIONS: We conclude that mutant 3-OST-6 fails to transfer sulfo groups to the 3-OH position of heparan sulfate, resulting in incomplete heparan sulfate biosynthesis. This is likely to affect cell surface interactions of key players in angioedema formation and is a novel mechanism for disease development

Cockayne syndrome without UV-sensitivity in Vietnamese siblings with novel <em>ERCC8</em> variants.

Cockayne syndrome (CS) is a rare progeroid disorder characterized by growth failure, microcephaly, photosensitivity, and premature aging, mainly arising from biallelic ERCC8 (CS-A) or ERCC6 (CS-B) variants. In this study we describe siblings suffering from classical Cockayne syndrome but without photosensitivity, which delayed a clinical diagnosis for 16 years. By whole-exome sequencing we identified the two novel compound heterozygous ERCC8 variants c.370_371del (p.L124Efs*15) and c.484G&gt;C (p.G162R). The causality of the ERCC8 variants, of which one results in a frameshift and the other affects the WD3 domain, was tested and confirmed by a rescue experiment investigating DNA repair in H2O2 treated patient fibroblasts. Structural modeling of the p.G162R variant indicates effects on protein-protein interaction. This case shows the importance to test for ERCC6 and ERCC8 variants even if patients do not present with a complete CS phenotype

Hepatitis B virus envelope proteins can serve as therapeutic targets embedded in the host cell plasma membrane.

Hepatitis B virus (HBV) infection is a major health threat causing 880,000 deaths each year. Available therapies control viral replication, but do not cure HBV leaving patients at risk to develop hepatocellular carcinoma. Here we show that HBV envelope proteins (HBs) - besides their integration into endosomal membranes - become embedded in the plasma membrane where they can be targeted by redirected T-cells. HBs was detected on the surface of HBV-infected cells, in livers of mice replicating HBV and in HBV-induced hepatocellular carcinoma. Staining with HBs-specific recombinant antibody MoMab recognizing a conformational epitope indicated that membrane-associated HBs remains correctly folded in HBV-replicating cells in cell culture and in livers of HBV-transgenic mice in vivo. MoMab coated onto superparamagnetic iron oxide nanoparticles allowed to detect membrane-associated HBs after HBV infection by electron microscopy in distinct stretches of the hepatocyte plasma membrane. Last not least we demonstrate that HBs located to the cell surface allows therapeutic targeting of HBV-positive cells by T-cells either engrafted with a chimeric antigen receptor or redirected by bispecific, T-cell engager antibodies. This article is protected by copyright. All rights reserved