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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:Glycine receptors (GlyRs) containing the α2 subunit govern cell fate, neuronal migration and synaptogenesis in the developing cortex and spinal cord. Rare missense variants and microdeletions in the X-linked GlyR α2 subunit gene (GLRA2) have been associated with human autism spectrum disorder (ASD), where they typically cause a loss-of-function via protein truncation, reduced cell-surface trafficking and/or reduced glycine sensitivity (e.g., GLRA2Δex8-9 and extracellular domain variants p.N109S and p.R126Q). However, the GlyR α2 missense variant p.R323L in the intracellular M3-M4 domain results in a gain-of-function characterized by slower synaptic decay times, longer duration active periods and increases in channel conductance. This study reports the functional characterization of four missense variants in GLRA2 associated with ASD or developmental disorders (p.V-22L, p.N38K, p.K213E, p.T269M) using a combination of bioinformatics, molecular dynamics simulations, cellular models of GlyR trafficking and electrophysiology in artificial synapses. The GlyR α2V-22L variant resulted in altered predicted signal peptide cleavage and a reduction in cell-surface expression, suggestive of a partial loss-of-function. Similarly, GlyR α2N38K homomers showed reduced cell-surface expression, a reduced affinity for glycine and a reduced magnitude of IPSCs in artificial synapses. By contrast, GlyR α2K213E homomers showed a slight reduction in cell-surface expression, but IPSCs were larger, with faster rise/decay times, suggesting a gain-of-function. Lastly, GlyR α2T269M homomers exhibited a high glycine sensitivity accompanied by a substantial leak current, suggestive of an altered function that could dramatically enhance glycinergic signaling. These results may explain the heterogeneity of clinical phenotypes associated with GLRA2 mutations and reveal that missense variants can result in a loss, gain or alteration of GlyR α2 function. In turn, these GlyR α2 missense variants are likely to either negatively or positively deregulate cortical progenitor homeostasis and neuronal migration in the developing brain, leading to changes in cognition, learning, and memory.

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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