HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease

Cook, Sara; Comrie, William A.; Poli, Cecilia; Similuk, Morgan; Oler, Andrew J.; Faruqi, Aiman J; Kuhns, Douglas B.; Yang, Sheng; Vargas-Hernández, Alexander; Carisey, Alexandre F.; Fournier, Benjamin; Anderson, David E.; Price, Susan; Smelkinson, Margery; Chahla, Wadih Abou; Forbes, Lisa R.; Mace, Emily M.; Cao, Tram N.; Coban‐Akdemir, Zeynep; Jhangiani, Shalini N.; Muzny, Donna M.; Gibbs, Richard A.; Lupski, James R.; Orange, Jordan S.; Cuvelier, Geoffrey D.E.; Hassani, Moza Al; Kaabi, Nawal Al; Yafei, Zain Al; Jyonouchi, Soma; Raje, Nikita; Caldwell, John S.; Huang, Yanping; Burkhardt, Janis K.; Latour, Sylvain; Chen, Baoyu; ElGhazali, Gehad; Rao, V. Koneti; Chinn, Iván K.; Lenardo, Michael J.

doi:10.1126/science.aay5663

Cited by 77 publications

(121 citation statements)

References 43 publications

(58 reference statements)

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“…Loss of Hem1 and thus WRC function has severe and complex organismic consequences in mice 13,50,65 (see also Figure 1E) and men, 50,66,67 resulting in autoinflammation. Inefficiently cleared pathogens and apoptotic or necrotic cell bodies constitute major sources of inflammation and autoantibodies.…”

Section: Articlementioning

confidence: 99%

Loss of Hem1 disrupts macrophage function and impacts migration, phagocytosis, and integrin-mediated adhesion

et al. 2021

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Section: Articlementioning

confidence: 99%

Loss of Hem1 disrupts macrophage function and impacts migration, phagocytosis, and integrin-mediated adhesion

et al. 2021

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“…Recently, an immune dysregulation disorders characterized by deficit of the hematopoietic-specific WAVE complex regulator HEM1, coded by the NCKAP1L gene, has been characterized (no. 16 in Table 1 and Figure 1) (88). Patients with HEM1 deficiency suffer from recurrent infections, asthma and lymphoproliferation.…”

Section: Branching Defectsmentioning

confidence: 99%

Actin Remodeling Defects Leading to Autoinflammation and Immune Dysregulation

et al. 2021

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A growing number of monogenic immune-mediated diseases have been related to genes involved in pathways of actin cytoskeleton remodeling. Increasing evidences associate cytoskeleton defects to autoinflammatory diseases and primary immunodeficiencies. We reviewed the pathways of actin cytoskeleton remodeling in order to identify inflammatory and immunological manifestations associated to pathological variants. We list more than twenty monogenic diseases, ranging from pure autoinflammatory conditions as familial Mediterranean fever, mevalonate kinase deficiency and PAPA syndrome, to classic and novel primary immunodeficiencies as Wiskott-Aldrich syndrome and DOCK8 deficiency, characterized by the presence of concomitant inflammatory and autoimmune manifestations, such as vasculitis and cytopenia, to severe and recurrent infections. We classify these disorders according to the role of the mutant gene in actin cytoskeleton remodeling, and in particular as disorders of transcription, elongation, branching and activation of actin. This expanding field of rare immune disorders offers a new perspective to all immunologists to better understand the physiological and pathological role of actin cytoskeleton in cells of innate and adaptive immunity.

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“…For example, these technologies provided the association of homozygous mutations in Nck-associated protein 1-like (NCKAP1L) also known as Hem-1, a component of actin cytoskeleton machinery, with immune dysregulation and lympoproliferation. Proteomic studies in this case revealed an unsuspected interaction between Hem-1 and mTOR pathway [81].…”

Section: Genetic Diagnosis and Functional Validation Of Novel Ieimentioning

confidence: 77%

Functional Genetics in Inborn Errors of Immunity

Rey-Jurado

Poli

2021

Future Rare Dis.

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Inborn errors of immunity are genetic defects of the immune system, causing increased susceptibility to infection, autoinflammation, autoimmunity and immune dysregulation. Next-generation sequencing has enabled exponential identification of novel inborn errors of immunity due to mutations in genes encoding for proteins that participate in the immune response. However, genomic sequencing often yields multiple variants in potential candidate genes, hence functional validation of these genetic defects becomes paramount to achieve diagnosis and discovery. Genome-editing technologies such as CRISPR-Cas9 have allowed exponential advances on discovery of new primary immunodeficiencies, enabling appropriate diagnosis and treatment. This review summarizes the heterogeneous clinical presentation of primary immunodeficiencies and contextualizes the rationale for functional validation studies to achieve diagnosis and discovery, subsequently leading to the application of directed therapies.

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HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease

Cited by 77 publications

References 43 publications

Loss of Hem1 disrupts macrophage function and impacts migration, phagocytosis, and integrin-mediated adhesion

Loss of Hem1 disrupts macrophage function and impacts migration, phagocytosis, and integrin-mediated adhesion

Actin Remodeling Defects Leading to Autoinflammation and Immune Dysregulation

Functional Genetics in Inborn Errors of Immunity

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