Monogenic deficiency diseases provide unique opportunities to define the contributions of individual molecules to human physiology and to identify pathologies arising from their dysfunction. Here we describe a deficiency disease in two human siblings that presented with severe bleeding, frequent infections and osteopetrosis at an early age. These symptoms are consistent with but more severe than those reported for people with leukocyte adhesion deficiency III (LAD-III). Mechanistically, these symptoms arose from an inability to activate the integrins expressed on hematopoietic cells, including platelets and leukocytes. Immortalized lymphocyte cell lines isolated from the two individuals showed integrin activation defects. Several proteins previously implicated in integrin activation, including Ras-associated protein-1 (RAP1) 1 and calcium and diacylglycerol-regulated guanine nucleotide exchange factor-1 (CALDAG-GEF1) 2 , were present and functional in these cell lines. The genetic basis for this disease was traced to a point mutation in the coding region of the KINDLIN3 (official gene symbol FERMT3) gene 3 . When wild-type KINDLIN-3 was expressed in the immortalized lymphocytes, their integrins Correspondence should be addressed to T.V.B. (byzovat@ccf.org). 6 These authors contributed equally to this work.Note: Supplementary information is available on the Nature Medicine website. AUTHOR CONTRIBUTIONS N.L.M. identified the Kindlin-3 mutation, performed molecular biology and protein biochemistry studies and wrote the manuscript; L.Z. contributed to study design and experiments on primary leukocytes from subjects; J.C. performed assays with EGFP-Kindlin-3 rescue and siRNA-mediated KINDLIN3 knockdown and western blotting; A.C. performed microscopy studies and FACS analysis; O.R. performed cell culture work and molecular biology; Y.-Q.M. performed molecular biology and Kindlin-3-specific antibody preparation; E.A.P. performed platelet studies; M.T. performed neutrophil analysis; D.P.L. and A.I.C. performed osteogenesis assays; S.B.S. originally described the subjects, designed clinical studies and wrote the manuscript; E.F.P. designed the studies, interpreted the results and wrote the manuscript; T.V.B. performed experiments with platelets and leukocytes, designed the general strategy, interpreted data and wrote the manuscript. Kindlin-3 is one of the three-member kindlin family of intracellular proteins that are linked to the actin cytoskeleton 3 . The family is evolutionarily conserved with an ortholog, UNC-112, found in Caenorhabditis elegans 4 . Each kindlin contains a C-terminal FERM domain that is most similar to that of talin, another cytoskeletal protein involved in integrin regulation. Kindlins and talin bind to nonoverlapping sites in the cytoplasmic tails of integrins 5 . Kindler disease, associated with a deficiency of Kindlin-1, has multiple symptoms, including skin blistering and poikiloderma 6 . Kindlin-2 deficiency is embryonically lethal in zebrafish and mice but has not been described in hu...

In December 2019, the 2019 novel coronavirus disease (COVID‐19) caused by Severe Acute Respiratory Syndrome Coronavirus‐2 (SARS‐CoV‐2) first emerged in Wuhan, China. This has now spread worldwide and was declared a pandemic by March 2020. Initially, the pediatric population was described as low risk for severe COVID‐19. However, reports have emerged recently of cases of COVID‐19 in children with a systemic inflammatory disease, with features that overlap with Kawasaki Disease (KD). We describe the first 15 cases with multi‐system inflammatory syndrome in children (MIS‐C), temporally related to COVID‐19, who presented for care to a tertiary pediatric referral center in New York City. We discuss the disproportionate burden of disease among Hispanic/Latino and black/African‐American ancestry, the distinct cytokine signature across the disease spectrum (IL‐1/IL‐6), and the potential role and pathogenesis of SARS‐CoV‐2 in this new clinical entity. This article is protected by copyright. All rights reserved.

An inherited syndrome characterized by recurrent or progressive necrotic soft-tissue infections, diminished pus formation, impaired wound healing, granulocytosis, and/or delayed umbilical cord severance was recognized in four male and four female patients. As shown with subunit-specific monoclonal antibodies in immunofluorescence flow cytometry and 125I immunoprecipitation techniques, in addition to a NaB3H4-galactose oxidase labeling assay, granulocytes, monocytes, or lymphocytes from these individuals had a "moderate" or "severe" deficiency of Mac-1, LFA-1, or p150,95 (or a combination)--three structurally related "adhesive" surface glycoproteins. Two distinct phenotypes were defined on the basis of the quantity of antigen expressed. Three patients with severe deficiency and four patients with moderate deficiency expressed less than 0.3% and 2.5%-31% of normal amounts of these molecules on granulocyte surfaces, respectively. The severity of clinical infectious complications among these patients was directly related to the degree of glycoprotein deficiency. More profound abnormalities of tissue leukocyte mobilization, granulocyte-directed migration, hyperadherence, phagocytosis of iC3b-opsonized particles, and complement- or antibody-dependent cytotoxicity were found in individuals with severe, as compared with moderate, deficiency. It is proposed that in vivo abnormalities of leukocyte mobilization reflect the critical roles of Mac-1 glycoproteins in adhesive events required for endothelial margination and tissue exudation. The recognition of phenotypic variation among patients with Mac-1, LFA-1 deficiency may be important with respect to therapeutic strategies.

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