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. 

/pdf/human-inborn-errors-of-immunity-2022-update-on-the-2lbpypmg.pdf

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

Mitochondrial abnormalities are primarily seen in morphology, structure and function. They can cause damage to organs, including the heart, brain and muscle, by various mechanisms, such as oxidative stress, abnormal energy metabolism, or genetic mutations. Identifying and detecting pathophysiological alterations in mitochondria is the principal means of studying mitochondrial abnormalities. The present study reviewed methods in mitochondrial research and focused on three aspects: Mitochondrial extraction and purification, morphology and structure and function. In addition to classical methods, such as electron microscopy and mitochondrial membrane potential monitoring, newly developed methods, such as mitochondrial ultrastructural determination, mtDNA mutation assays, metabolomics and analyses of regulatory mechanisms, have also been utilized in recent years. These approaches enable the accurate detection of mitochondrial abnormalities and provide guidance for the diagnosis and treatment of related diseases.

/pdf/common-methods-in-mitochondrial-research-review-3cagkzq5.pdf

Common methods in mitochondrial research (Review)

http://www.cell.com/article/S2211124723005089/pdf

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

Objective This 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. Methods Using 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). Results We 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). Conclusions Our 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.

/pdf/smoking-status-and-type-2-diabetes-and-cardiovascular-aat4kpxw.pdf

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

PURPOSE OF REVIEW
Primary immunodeficiency diseases (PIDs), also called inborn errors of immunity (IEI), are genetic disorders characterized by increased susceptibility to infection and/or aberrant regulation of immunological pathways. This review summarizes and highlights the new IEI disorders in the International Union of Immunological Societies (IUIS) 2022 report and current trends among new PIDs.


RECENT FINDINGS
Since the 2019 IUIS report and the 2021 IUIS interim update, the IUIS IEI classification now includes 485 validated IEIs. Increasing utilization of genetic testing and advances in the strategic evaluation of genetic variants has continued to drive the identification of, not only novel IEI disorders, but additional genetic etiologies for known IEI disorders and phenotypes.


SUMMARY
The recognition of new IEIs continues to advance at a rapid pace, which is due in part to increased performance and application of genetic modalities as well as expansion of the underlying science that is applied to convincingly establish causality. These disorders, as a whole, continue to emphasize the specificity of immunity, complexity of immune mechanisms, and the fine balance that defines immune homeostasis.

New primary immunodeficiencies 2023 update.

Human C2orf69 is an evolutionarily conserved gene whose function is unknown. Here, we report eight unrelated families from which 20 children presented with a fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. C2ORF69 bears homology to esterase enzymes, and orthologs can be found in most eukaryotic genomes, including that of unicellular phytoplankton. We found that endogenous C2ORF69 (1) is loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. We show that CRISPR-Cas9-mediated inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures, which is preceded by persistent brain inflammation. Collectively, our results delineate an autoinflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems.

Loss of C2orf69 defines a fatal autoinflammatory syndrome in humans and zebrafish that evokes a glycogen storage-associated mitochondriopathy

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Loss of C2orf69 defines a fatal autoinflammatory syndrome in humans and zebrafish that evokes a glycogen storage-associated mitochondriopathy