C2orf69 mutations disrupt mitochondrial function and cause a multisystem human disorder with recurring autoinflammation

Lausberg, Eva; Gießelmann, Sebastian; Dewulf, Joseph; Wiame, Elsa; Holz, Anja; Salvarinova, Ramona; Karnebeek, Clara D. van; Klemm, Patricia; Ohl, Kim; Mull, Michael; Braunschweig, Till; Weis, Joachim; Sommer, Clemens; Demuth, Stephanie; Haase, Claudia M.; Stollbrink-Peschgens, Claudia; Debray, François-Guillaume; Libioulle, Cécile; Choukair, Daniela; Oommen, Prasad T.; Surowy, Harald; Wieczorek, Dagmar; Wagner, Norbert; Meyer, Robert; Eggermann, Thomas; Begemann, Matthias; Schaftingen, Emile Van; Häusler, Martin; Tenbrock, Klaus; Heuvel, Lambert van den; Elbracht, Miriam; Kurth, Ingo; Kraft, Florian

doi:10.1172/jci143078

Cited by 14 publications

(14 citation statements)

References 34 publications

(17 reference statements)

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“…Notably, C2orf69-Brain Caudate basal ganglia gene-trait pair was the only one observed overlapping gene-tissue pair between smoking status and HF. C2orf69 is an evolutionarily conserved gene whose function needs to be further clarified, but recent studies have shown its association with a fatal autoinflammatory syndrome that disrupts the development/homeostasis of the immune and central nervous systems (102,103), which may contribute to the link between smoking and HF.…”

Section: Discussionmentioning

confidence: 99%

Smoking Status and Type 2 Diabetes, and Cardiovascular Disease: A Comprehensive Analysis of Shared Genetic Etiology and Causal Relationship

et al. 2022

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ObjectiveThis study aimed to explore shared genetic etiology and the causality between smoking status and type 2 diabetes (T2D), cardiovascular diseases (CVDs), and related metabolic traits.MethodsUsing summary statistics from publicly available genome-wide association studies (GWASs), we estimated genetic correlations between smoking status and T2D, 6 major CVDs, and 8 related metabolic traits with linkage disequilibrium score regression (LDSC) analysis; identified shared genetic loci with large-scale genome-wide cross-trait meta-analysis; explored potential shared biological mechanisms with a series of post-GWAS analyses; and determined causality with Mendelian randomization (MR).ResultsWe found significant positive genetic associations with smoking status for T2D (Rg = 0.170, p = 9.39 × 10−22), coronary artery disease (CAD) (Rg = 0.234, p = 1.96 × 10−27), myocardial infarction (MI) (Rg = 0.226, p = 1.08 × 10−17), and heart failure (HF) (Rg = 0.276, p = 8.43 × 10−20). Cross-trait meta-analysis and transcriptome-wide association analysis of smoking status identified 210 loci (32 novel loci) and 354 gene–tissue pairs jointly associated with T2D, 63 loci (12 novel loci) and 37 gene–tissue pairs with CAD, 38 loci (6 novel loci) and 17 gene–tissue pairs with MI, and 28 loci (3 novel loci) and one gene–tissue pair with HF. The shared loci were enriched in the exo-/endocrine, cardiovascular, nervous, digestive, and genital systems. Furthermore, we observed that smoking status was causally related to a higher risk of T2D (β = 0.385, p = 3.31 × 10−3), CAD (β = 0.670, p = 7.86 × 10−11), MI (β = 0.725, p = 2.32 × 10−9), and HF (β = 0.520, p = 1.53 × 10−6).ConclusionsOur findings provide strong evidence on shared genetic etiology and causal associations between smoking status and T2D, CAD, MI, and HF, underscoring the potential shared biological mechanisms underlying the link between smoking and T2D and CVDs. This work opens up a new way of more effective and timely prevention of smoking-related T2D and CVDs.

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Section: Discussionmentioning

confidence: 99%

Smoking Status and Type 2 Diabetes, and Cardiovascular Disease: A Comprehensive Analysis of Shared Genetic Etiology and Causal Relationship

et al. 2022

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“…IKZF1 GOF [52]) (Table 4; Supplementary Table 1) • neutropenia CXCR2 [53,54] (Table 5, Supplementary Table 1) • innate immune defects resulting in susceptibility to mycobacterial/bacterial (TBX21 [55,56], IFNG [57], TLR8 [58,59]), viral (NOS2 [60], SNORA31 [61], ATG4A, MAP1LC3B2 [62], ZNFX1 [63][64][65], TLR7 [66][67][68]), and/or fungal infections (MAPK8 [69]) (Table 6; Supplementary Table 1); • Autoimmune/autoinflammatory disorders (TMEM173 [70], LSM11, RNU7-1 [71], CDC42 [72][73][74][75][76][77][78], STAT2 [79,80], ATAD3A [81], AR TBK1 [82], C2orf69 [83,84], RIPK1 [85,86], NCKAP1L [87][88][89], SYK [90], HCK1 [91], IKBKG…”

Section: Novel Inborn Errors Of Immunitymentioning

confidence: 99%

“…• The small nucleolar RNA SNORA31 plays a critical role in CNS-intrinsic immunity against HSV-2 infection, likely via production of type 1 IFN, yet the exact mechanism remains unknown [61]. • The hitherto uncharacterized protein-coding gene C2orf69 has a multitude of roles across numerous biological systems, including regulating autoinflammation [83,84].…”

Section: Iei Define Specific Roles For Known Genes and Reveal Immune-...mentioning

confidence: 99%

“…Total number of disorders in Table7: 56. New inborn errors of immunity: 14 (AR GOF TMEM173[70], LSM11, RNU7-1[71], CDC42[72][73][74][75][76][77][78], STAT2[79,80], ATAD3A[81], C2orf69[83,84], RIPK1[85,86], NCKAP1L[87][88][89], SYK[90], HCK1[91], PSMB9[95,96], IKBKG NEMO-Δex5, AR TBK1[82]) IFN interferon, HSM hepatosplenomegaly, CSF cerebrospinal fluid, SLE systemic lupus erythematosus, TORCH toxoplasmosis, other, rubella, cytomegalovirus, and herpes infections, SNHL sensorineural hearing loss, AGS Aicardi-Goutières syndrome, BSN bilateral striatal necrosis, FCL familial chilblain lupus, ICC intracranial calcification, IFN interferon type I, pDCs plasmacytoid dendritic cells, SP spastic paraparesis, SMS Singleton-Merten syndrome, ss single-stranded DNA *Variants in PSMB4, PSMB9, PSMA3, and POMP have been proposed to cause a similar CANDLE phenotype in compound heterozygous monogenic (PSMB4), digenic (PSMA3/PSMB8, PSMB9/PSMB4, PSMB4/PSMB8) and AD monogenic (POMP) models[115] …”

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confidence: 99%

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Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee

et al. 2022

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We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 55 novel monogenic gene defects, and 1 phenocopy due to autoantibodies, that have either been discovered since the previous update (published January 2020) or were characterized earlier but have since been confirmed or expanded in subsequent studies. While variants in additional genes associated with immune diseases have been reported in the literature, this update includes only those that the committee assessed that reached the necessary threshold to represent novel inborn errors of immunity. There are now a total of 485 inborn errors of immunity. These advances in discovering the genetic causes of human immune diseases continue to significantly further our understanding of molecular, cellular, and immunological mechanisms of disease pathogenesis, thereby simultaneously enhancing immunological knowledge and improving patient diagnosis and management. This report is designed to serve as a resource for immunologists and geneticists pursuing the molecular diagnosis of individuals with heritable immunological disorders and for the scientific dissection of cellular and molecular mechanisms underlying monogenic and related human immune diseases.

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“…We also noted pronounced upregulation of C2orf69, a regulator of mitochondrial function (Lausberg et al, 2021; Wong et al, 2021), in both SCZ (LFC = 2.02, FDR-adj. P: = 0.004) and BP synapses (LFC = 2.06; FDR-adj.…”

Section: Resultsmentioning

confidence: 78%

Deep proteomics identifies shared molecular pathway alterations in synapses of schizophrenia and bipolar disorder patients and mouse model

Aryal

Bonanno

Song

et al. 2022

Preprint

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Synaptic dysfunction is implicated in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BP). We used quantitative mass-spectrometry to carry out deep and unbiased profiling of the proteome of synapses purified from the dorsolateral prefrontal cortex of 35 cases of SCZ, 35 cases of BP, and 35 controls. Compared to controls, SCZ and BP synapses showed substantial and similar proteomic alterations. Network and gene set enrichment analyses revealed upregulation of proteins associated with autophagy and certain vesicle transport pathways, and downregulation of proteins related to synaptic, mitochondrial, and ribosomal function in the synapses of individuals with SCZ or BP. Some of the same pathways (e.g., upregulation of vesicle transport, downregulation of mitochondrial and ribosomal proteins) were similarly dysregulated in the synaptic proteome of mutant mice deficient in Akap11, a recently discovered shared risk gene for SCZ and BP. Our work provides novel biological insights into molecular dysfunction at the synapse in SCZ and BP and serves as a resource for understanding the pathophysiology of these debilitating neuropsychiatric disorders.

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C2orf69 mutations disrupt mitochondrial function and cause a multisystem human disorder with recurring autoinflammation

Cited by 14 publications

References 34 publications

Smoking Status and Type 2 Diabetes, and Cardiovascular Disease: A Comprehensive Analysis of Shared Genetic Etiology and Causal Relationship

Smoking Status and Type 2 Diabetes, and Cardiovascular Disease: A Comprehensive Analysis of Shared Genetic Etiology and Causal Relationship

Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee

Deep proteomics identifies shared molecular pathway alterations in synapses of schizophrenia and bipolar disorder patients and mouse model

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