Discovery and functional analysis of a novel ALPK1 variant in ROSAH syndrome.

Retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and migraine headache (ROSAH) syndrome is an autosomal dominant disorder and to date is known to be caused by either the Thr237Met or Tyr254Cys variant in the protein kinase ALPK1. Here, we identify a family in which ROSAH syndrome is caused by a novel variant in which Ser277 is changed to Phe. All six patients examined display ocular inflammation and optic nerve elevation, four have retinal degeneration and four are registered blind.

Haploinsufficiency in PTPN2 leads to early-onset systemic autoimmunity from Evans syndrome to lupus.

An exome sequencing strategy employed to identify pathogenic variants in patients with pediatric-onset systemic lupus or Evans syndrome resulted in the discovery of six novel monoallelic mutations in PTPN2. PTPN2 is a phosphatase that acts as an essential negative regulator of the JAK/STAT pathways. All mutations led to a loss of PTPN2 regulatory function as evidenced by in vitro assays and by hyperproliferation of patients' T cells.

Deciphering the clinical spectrum of gastric disease in patients with juvenile polyposis syndrome.

Background And Aims: Juvenile polyposis syndrome (JPS) is a rare hereditary autosomal dominant cancer-predisposition syndrome caused by germline pathogenic variants (PVs) located in SMAD4 or BMPR1A genes. Accurate clinical and endoscopic data regarding the evolution of gastric lesions remain sparse.

Methods: Clinical, endoscopic, genetic, and pathologic data from patients with SMAD4 or BMPR1A PVs included between 2007 and 2020 in the French network on rare digestive polyposis (RENAPOL [French National Polyposis Register]) database were prospectively collected to address uncertainties regarding gastric involvement.

Mendelian Causes of Autoimmunity: the Lupus Phenotype.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by its large heterogeneity in terms of clinical presentation and severity. The pathophysiology of SLE involves an aberrant autoimmune response against various tissues, an excess of apoptotic bodies, and an overproduction of type-I interferon. The genetic contribution to the disease is supported by studies of monozygotic twins, familial clustering, and genome-wide association studies (GWAS) that have identified numerous risk loci.

Genome sequencing identify chromosome 9 inversions disrupting ENG in 2 unrelated HHT families.

Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber disease, is a dominant inherited vascular disorder. The clinical diagnosis is based on the Curaçao criteria and pathogenic variants in the ENG and ACVRL1 genes are responsible for most cases of HHT. Four families with a negative targeted gene panel and selected by a multidisciplinary team were selected and whole-genome sequencing was performed according to the recommendations of the French National Plan for Genomic Medicine.

Rescue of Pap-Mas in Systemic JIA Using Janus Kinase Inhibitors, Case Report and Systematic Review.

Introduction: Biological disease-modifying anti-rheumatic drugs (bDMARDs) targeting interleukin (IL)-6 and IL-1β represent a steroid-sparing first-line therapy used in systemic-onset juvenile idiopathic arthritis (sJIA). Recently, the occurrence of pulmonary alveolar proteinosis (PAP) in sJIA patients was reported with early-onset and exposure to bDMARDs as potential risk factors. We report on a new case with longitudinal immunomonitoring successfully treated by Janus Kinase inhibitors (JAKi) and review past clinical descriptions of this new entity.

DOCK11 deficiency in patients with X-linked actinopathy and autoimmunity.

Dedicator of cytokinesis (DOCK) proteins play a central role in actin cytoskeleton regulation. This is highlighted by the DOCK2 and DOCK8 deficiencies leading to actinopathies and immune deficiencies. DOCK8 and DOCK11 activate CDC42, a Rho-guanosine triphosphate hydrolases involved in actin cytoskeleton dynamics, among many cellular functions.

"P2RY8-son" break of tolerance promotes SLE.

In this issue of JEM, He et al. (2021. J.

Clinical significance of a single cerebrospinal fluid immunoglobulin band: A retrospective study.

Background: To demonstrate an inflammatory process in the central nervous system, the presence of at least two immunoglobulin (Ig) bands in the cerebrospinal fluid (CSF) is required. So far, the presence of a single abnormal Ig band is considered as negative.

Objective: The objective was to assess retrospectively the significance of a single CSF Ig band in clinical practice.

Early-onset autoimmunity associated with SOCS1 haploinsufficiency.

Autoimmunity can occur when a checkpoint of self-tolerance fails. The study of familial autoimmune diseases can reveal pathophysiological mechanisms involved in more common autoimmune diseases. Here, by whole-exome/genome sequencing we identify heterozygous, autosomal-dominant, germline loss-of-function mutations in the SOCS1 gene in ten patients from five unrelated families with early onset autoimmune manifestations.

Contribution of rare and predicted pathogenic gene variants to childhood-onset lupus: a large, genetic panel analysis of British and French cohorts.

Background: Systemic lupus erythematosus (SLE) is a rare immunological disorder and genetic factors are considered important in its causation. Monogenic lupus has been associated with around 30 genotypes in humans and 60 in mice, while genome-wide association studies have identified more than 90 risk loci. We aimed to analyse the contribution of rare and predicted pathogenic gene variants in a population of unselected cases of childhood-onset SLE.

In situ NADH laser fluorimetry during muscle contraction in humans.

The aim of the present study was to use nicotinamide adenine dinucleotide phosphate, reduced (NADH) fluorimetry, to investigate in situ NADH changes during muscle contraction in humans on an isokinetic dynamometer. Thirteen healthy male subjects each performed one maximal voluntary contraction (MVC) with the knee extensor muscle. The NADH muscle fluorescence was monitored by a double beam laser fluorimeter which uses an optical fibre, percutaneously inserted through a needle into the vastus lateral muscle, to guide the light.