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Predicted loss and gain of function mutations in ACO1 are associated with erythropoiesis.

ABSTRACT: Hemoglobin is the essential oxygen-carrying molecule in humans and is regulated by cellular iron and oxygen sensing mechanisms. To search for novel variants associated with hemoglobin concentration, we performed genome-wide association studies of hemoglobin concentration using a combined set of 684,122 individuals from Iceland and the UK. Notably, we found seven novel variants, six rare coding and one common, at the ACO1 locus associating with either decreased or increased hemoglobin concentration. Of these variants, the missense Cys506Ser and the stop-gained Lys334Ter mutations are specific to eight and ten generation pedigrees, respectively, and have the two largest effects in the study (EffectCys506Ser?=?-1.61?SD, CI95?=?[-1.98, -1.35]; EffectLys334Ter?=?0.63?SD, CI95?=?[0.36, 0.91]). We also find Cys506Ser to associate with increased risk of persistent anemia (OR?=?17.1, P?=?2?×?10-14). The strong bidirectional effects seen in this study implicate ACO1, a known iron sensing molecule, as a major homeostatic regulator of hemoglobin concentration.

SUBMITTER: Oskarsson GR

PROVIDER: S-EPMC7181819 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Predicted loss and gain of function mutations in ACO1 are associated with erythropoiesis.

Oskarsson Gudjon R GR Oddsson Asmundur A Magnusson Magnus K MK Kristjansson Ragnar P RP Halldorsson Gisli H GH Ferkingstad Egil E Zink Florian F Helgadottir Anna A Ivarsdottir Erna V EV Arnadottir Gudny A GA Jensson Brynjar O BO Katrinardottir Hildigunnur H Sveinbjornsson Gardar G Kristinsdottir Anna M AM Lee Amy L AL Saemundsdottir Jona J Stefansdottir Lilja L Sigurdsson Jon K JK Davidsson Olafur B OB Benonisdottir Stefania S Jonasdottir Aslaug A Jonasdottir Adalbjorg A Jonsson Stefan S Gudmundsson Reynir L RL Asselbergs Folkert W FW Tragante Vinicius V Gunnarsson Bjarni B Masson Gisli G Thorleifsson Gudmar G Rafnar Thorunn T Holm Hilma H Olafsson Isleifur I Onundarson Pall T PT Gudbjartsson Daniel F DF Norddahl Gudmundur L GL Thorsteinsdottir Unnur U Sulem Patrick P Stefansson Kari K

Communications biology 20200423 1

Hemoglobin is the essential oxygen-carrying molecule in humans and is regulated by cellular iron and oxygen sensing mechanisms. To search for novel variants associated with hemoglobin concentration, we performed genome-wide association studies of hemoglobin concentration using a combined set of 684,122 individuals from Iceland and the UK. Notably, we found seven novel variants, six rare coding and one common, at the ACO1 locus associating with either decreased or increased hemoglobin concentrati ...[more]

PMID: 32327693

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Project description:Background: Germline mutations in signal transducer and activator of transcription 1 (STAT1), which lead to primary immunodeficiency, are classified as defects in intrinsic and innate immunity. To date, no comprehensive overview comparing GOF with LOF in early-onset immunodeficiency has been compiled. Objective: To collect and systematically review all studies reporting STAT1 GOF and LOF cases, and to describe the clinical, diagnostic, molecular, and therapeutic characteristics of all the conditions. Methods: A systematic review of the PubMed, EMBASE, Web of Science, Scopus, and Cochrane to identify articles published before May 23, 2020. Data pertaining to patients with a genetic diagnosis of STAT1 GOF or LOF germline mutations, along with detailed clinical data, were reviewed. Results: The search identified 108 publications describing 442 unique patients with STAT1 GOF mutations. The patients documented with chronic mucocutaneous candidiasis (CMC; 410/442), lower respiratory tract infections (210/442), and autoimmune thyroid disease (102/442). Th17 cytopenia was identified in 87.8% of those with GOF mutations. Twenty-five patients with GOF mutations received hematopoietic stem cell transplantation (HSCT), and 10 died several months later. Twelve of 20 patients who received JAK inhibitor therapy showed improved symptoms. Twenty-one publications described 39 unique patients with STAT1 LOF mutations. The most common manifestations were Mendelian susceptibility to mycobacterial diseases (MSMD) (29/39), followed by osteomyelitis (16/39), and lymphadenopathy (9/39). Missense, indel, and frameshift mutations were identified as LOF mutations. There were no obvious defects in lymphocyte subsets or immunoglobulin levels. Eighteen patients required antimycobacterial treatment. Three patients received HSCT, and one of the three died from fulminant EBV infection. Conclusions: STAT1 GOF syndrome is a clinical entity to consider when confronted with a patient with early-onset CMC, bacterial respiratory tract infections, or autoimmune thyroid disease as well as Th17 cytopenia and humoral immunodeficiency. HSCT is still not a reasonable therapeutic choice. Immunoglobulin replacement therapy and JAK inhibitors are an attractive alternative. STAT1 LOF deficiency is a more complicated underlying cause of early-onset MSMD, osteomyelitis, respiratory tract infections, and Herpesviridae infection. Anti-mycobacterial treatment is the main therapeutic choice. More trials are needed to assess the utility of HSCT.

Dataset Information

Predicted loss and gain of function mutations in ACO1 are associated with erythropoiesis.

Publications

Predicted loss and gain of function mutations in ACO1 are associated with erythropoiesis.

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