Combined immunodeficiency and hypoglycemia associated with mutations in hypoxia upregulated 1

• Published in: Journal of allergy and clinical immunology Vol. 139; no. 4; pp. 1391 - 1393.e11
• Main Authors: Haapaniemi, Emma M, Fogarty, Christopher L, Keskitalo, Salla, Katayama, Shintaro, Vihinen, Helena, Ilander, Mette, Mustjoki, Satu, Krjutškov, Kaarel, Lehto, Markku, Hautala, Timo, Eriksson, Ove, Jokitalo, Eija, Velagapudi, Vidya, Varjosalo, Markku, Seppänen, Mikko, Kere, Juha
• Format: Journal Article
• Language: English
• Published: United States Elsevier Limited 01.04.2017
• Subjects: Accumulation; Adult; Albinism; Anemia; Antigen presentation; Apoptosis; Bacteria; Bacterial infections; Cytotoxicity; Dendritic cells; Endoplasmic reticulum; Female; Fibroblasts; Glucose; Hematopoiesis; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - immunology; Humans; Hypoglycemia; Hypoglycemia - genetics; Hypoglycemia - immunology; Hypoxia; Immune response; Immune system; Immunoglobulins; Immunologic Deficiency Syndromes - genetics; Immunologic Deficiency Syndromes - immunology; Immunology; Infections; Lymphocytes T; Mass spectrometry; Medicin och hälsovetenskap; Metabolism; Metabolites; Mitochondria; Mutation; Neutropenia; Neutrophils; Pathogenesis; Pathogens; Primary immunodeficiencies; Proteins; Proteomes; Scientific imaging; Transportation systems
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2016.09.050

Because of a suspected novel primary immunodeficiency, we performed whole-exome sequencing. HYOU1 further belongs to herpes infection-induced proteome.8 We hypothesized that mutations in HYOU1 ATPase domain would impair ATP hydrolysis, thereby hampering the conformational changes required for HYOU1 chaperone function.4,5 Consequently, this could lead to altered substrate binding. Both mutants bound with high affinity to a range of proteins that did not bind to WT HYOU1 (Fig 1, C). [...]the binding profiles of the mutated HYOU1 proteins seemed altered, leading to ectopic protein binding. [...]we describe a novel immunometabolic syndrome caused by recessive HYOU1 mutations. Gene ELANE HAX1 VPS45 JAGN1 G6P3 HYOU1 LAMTOR2 AP3B1 RAB27A Clinical characteristics Inheritance AR, AD AR AR AR AR AR AR AR AR Infection susceptibility Bacteria Bacteria Bacteria Bacteria Bacteria Bacteria, herpesvirus Bacteria Bacteria Bacteria Immunology Neutropenia, cyclic neutropenia Neutropenia Neutropenia, hypergammaglob ulinemia, myelofibrosis Neutropenia Neutropenia, thrombocytopenia Granulocytopenia,thrombocytopenia,anemia, B-celldeficiency, dendriticcell deficiency Neutropenia, hypogammaglobuli nemia Granulocytopenia, coagulation defects, decreased NK and T-cell cytotoxicity Neutropenia, decreased NK and T-cell cytotoxicity Other features - Neurological impairment (some cases) Hepato-, spleno-, & nephromegaly (extramedullary hematopoiesis) Bone and dental anomalies Syndromic patients Hypoglycemia, mildbone anomalies Oculocutaneous albinism Oculocutaneous albinism Oculocutaneous albinism Malignancy predisposition + + + − − − − − − Molecular pathogenesis Cellular compartment ER Mitochondria ER, vesicular system ER ER ER, mitochondria Vesicular transport system Vesicular transport system Vesicular transport system Pathogenic mechanism ELANE accumulation in the ER, UPR induction, & neutrophil apoptosis Mitochondrial destabilization, disturbed stress signaling -> neutrophil apoptosis Defective endosomal trafficking Protein accumulation in...