HEM1 deficiency disrupts mTORC2 and F-actin control in inherited immunodysregulatory disease
Open accessAbstract
An inherited disorder makes WAVEs: The WAVE regulatory complex (WRC) is a multiunit complex that regulates actin cytoskeleton formation. Although other actin-regulatory proteins modulate human immune responses, the precise role for the WRC has not yet been established. Cook et al. studied five patients from four unrelated families who harbor missense variants of the gene encoding the WRC component HEM1. These patients presented with recurrent infections and poor antibody responses, along with enhanced allergic and autoimmune disorders. HEM1 was found to be required for the regulation of cortical actin and granule release in T cells and also interacted with a key metabolic signaling complex contributing to the disease phenotype. By linking these interactions to immune function, this work suggests potential targets for future immunotherapies. Science , this issue p. 202
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NCKAP1L mutations in humans and HEM1 deletion in mice cause broad immune dysregulation.
“NCKAP1L mutations in humans and HEM1 deletion in mice cause broad immune dysregulation130–132.”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [130]
The Abstract reports that NCKAP1L mutations in patients cause immunodeficiency alongside atopy, lymphoproliferation, and cytokine overproduction. It also notes lymphopenia, neutrophilia, or bone marrow failure in HEM1-deficient mice, but does not specify that HEM1 was deleted in those mice or establish the same broad immune phenotype in both species. (LLM, conf=0.82)
Experimental — accuracy not yet measuredMost reported pathogenic NCKAP1L variants are biallelic missense variants resulting in destabilizing amino acid substitutions: p.R129W in exon 4, p.V141F in exon 5, p.R258L in exon 7, and p.P359L and p.M371V in exon 11.
“Most are biallelic missense variants resulting in destabilizing amino acid substitutions: p.R129W in exon 4, p.V141F in exon 5, p.R258L in exon 7, and p.P359L and p.M371V in exon 11 [8, 9].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The paper’s patient-description passage (section labeled Abstract; page not provided) reports biallelic NCKAP1L missense variants in all five patients studied, but does not establish that most reported pathogenic variants have this form or give the claimed variant-to-exon list. Its biochemical-analysis passage (same section; page not provided) says most patients had WRC destabilization, but M371V retained normal WRC protein expression and instead disrupted Arf1-mediated activation. Thus the claim incorrectly treats M371V as destabilizing. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThree HEM1-deficient patients with features such as fever, splenomegaly, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, and increased soluble IL-2 receptor met diagnostic criteria for hemophagocytic lymphohistiocytosis.
“Three patients with features such as fever, splenomegaly, hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, and increased soluble IL-2 receptor met diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH) [8, 10, 28, 29]”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The patient-description passage (section labeled Abstract; page unavailable) reports five HEM1-deficient patients and chronic hepatosplenomegaly, supporting the splenomegaly feature. It does not report that three patients met HLH diagnostic criteria or document the listed fever and laboratory findings; searches for HLH and those findings found no supporting passage. (LLM, conf=0.81)
Experimental — accuracy not yet measuredHEM1 deficiency was first described in 2019 and has been reported in nine individuals from seven kindreds.
“HEM1 deficiency was first described in 2019 and has been reported in nine individuals from seven kindreds [8–10, 25].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredLoss of the WRC, one of the two primary Arp2/3 nucleation promoting factors, contributes to impaired specific immunity and concomitant nonspecific immune system hyperactivation.
“One study showed how loss of the WRC, one of the two primary actin-related proteins 2/3 (Arp2/3) nucleation promoting factors (NPF), contributes to the complex picture of impaired specific immunity and concomitant nonspecific immune system hyperactivation [8].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The Abstract reports that HEM1 mutations destabilize or impair activation of the WRC, causing immunodeficiency alongside cytokine overproduction and immune hyperresponsiveness. It also identifies the WRC as controlling Arp2/3-mediated actin nucleation, but does not establish the claim’s more specific description of it as one of two primary Arp2/3 nucleation-promoting factors. (LLM, conf=0.84)
Experimental — accuracy not yet measured
HEM1-deficient patients may have systemic lupus erythematosus-like disease with positive anti-nuclear antibodies and double-stranded DNA autoantibodies, and associated immune complex glomerulonephritis.
“Patients may have systemic lupus erythematosus–like disease with positive anti-nuclear antibodies (ANA) and double-stranded (ds) DNA autoantibodies, and associated immune complex glomerulonephritis [8–10].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The patient-description passage (indexed as Abstract; page unavailable) reports autoimmune manifestations in HEM1-deficient patients. It does not identify lupus-like disease, positive ANA or anti-dsDNA antibodies, or immune-complex glomerulonephritis; searches for those specific features found no supporting passage in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredOther bacterial infections in HEM1-deficient patients have included cellulitis, septic arthritis, and cholecystitis.
“Other bacterial infections have included cellulitis, septic arthritis, and cholecystitis [8–10].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The paper’s patient-description passage (labeled Abstract; page unavailable) reports recurrent bacterial and viral skin infections in HEM1-deficient patients, supporting the general infection context. It does not identify cellulitis, septic arthritis, or cholecystitis; searches for the listed conditions found no matching passage in our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measuredAll HEM1-deficient patients suffer from recurrent infections such as otitis media, upper respiratory infections, pneumonia, and abscesses.
“All patients suffer from recurrent infections such as otitis media, upper respiratory infections, pneumonia, and abscesses [8–10].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The passage labeled Abstract (page unavailable) reports recurrent skin and severe respiratory infections, including pneumonia, in five HEM1-deficient patients. It does not specifically report otitis media, upper respiratory infections, or abscesses, and its five-patient cohort does not establish that all HEM1-deficient patients have recurrent infections. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTwo siblings carried compound heterozygous deleterious mutations encoding the p.P359L variant as well as a p.V519L variant in exon 16.
“Two siblings carried compound heterozygous deleterious mutations encoding the p.P359L variant as well as a p.V519L variant in exon 16 [8].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The patient-description passage (indexed under Abstract; no page supplied) reports five patients from four families with bi-allelic NCKAP1L missense mutations predicted to be damaging. It does not identify two siblings as compound heterozygotes or specify p.P359L, p.V519L, or exon 16; searches for those variants, siblings, and exon 16 found no confirming passage. (LLM, conf=0.83)
Experimental — accuracy not yet measuredReported viral infections in HEM1-deficient patients have included disseminated herpes simplex virus, Epstein-Barr virus viremia, and gastroenteritis.
“Reported viral infections have included disseminated herpes simplex virus, Epstein-Barr virus viremia, and gastroenteritis [8–10].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The passage describing the five patients (section labeled Abstract; page unavailable) reports recurrent viral skin infections in HEM1-deficient patients. It does not identify disseminated herpes simplex virus, Epstein–Barr virus viremia, or gastroenteritis; searches for those terms found no matching passage in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredAtopic disease in the form of food allergy, allergic rhinitis, and asthma occurs in more than half of the HEM1-deficient patient cohort.
“Atopic disease in the form of food allergy, allergic rhinitis, and asthma occurs in more than half of the patient cohort, highlighting exaggerated atopic inflammatory responses against environmental allergens and irritants [8–10].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The passage labeled Abstract (page unavailable) reports atopic disease among five HEM1-deficient patients. It does not specify food allergy, allergic rhinitis, or asthma, or establish that atopy affected more than half of the cohort; searches for those conditions found no supporting passage. (LLM, conf=0.84)
Experimental — accuracy not yet measuredImpaired specific antibody production after vaccinations or EBV infection was observed in six HEM1-deficient patients.
“Impaired specific antibody production after vaccinations or EBV infection was observed in six patients [8, 10].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The patient-description passage (section labeled Abstract; page unavailable) reports poor specific antibody responses in five HEM1-deficient patients, supporting the core finding. It does not specify whether those responses followed vaccination or EBV infection, and it reports five patients rather than six. (LLM, conf=0.90)
Experimental — accuracy not yet measuredElevated IgE is frequently observed in HEM1-deficient patients, especially in those with asthma or atopic symptoms.
“Elevated IgE is frequently observed, especially in those with asthma or atopic symptoms [8, 10].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The clinical description (indexed under Abstract; page unavailable) reports atopic disease and says the five HEM1-deficient patients sometimes had elevated IgE or IgG. It does not establish that elevated IgE was frequent or especially observed in patients with asthma or atopic symptoms. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPatient cells demonstrated reduced mTOR activity in the absence of WRC.
“data from patient cells reliably demonstrated reduced mTOR activity in the absence of WRC [8, 9].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The passage on TCR signaling (section labeled Abstract; page unavailable) reports reduced phosphorylation of the mTORC2 substrate AKT Ser473 in HEM1-deficient patient T cells, supporting reduced mTORC2 signaling. But the paper distinguishes HEM1’s role in mTORC2 regulation from its role in the WRC; it does not establish that absence of the WRC itself reduced mTOR activity. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPhysical interaction between WRC and mTORC subunits suggests direct modulation of kinase or actin polymerization activity.
“suggesting direct modulation of kinase or actin polymerization activity [8, 41].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The paper’s interaction passage (indexed under Abstract; page unavailable) reports that HEM1, a WRC component, co-immunoprecipitated with the mTORC2 component RICTOR and suggests that HEM1 regulates mTORC2. But it says the interaction likely occurs when HEM1 is outside the WRC; WAVE2 did not co-immunoprecipitate with RICTOR. It therefore does not establish a physical interaction between the assembled WRC and mTORC2 subunits or direct modulation of actin polymerization through that interaction. (LLM, conf=0.87)
Experimental — accuracy not yet measuredKnockdown of HEM1 in pan-T cells followed by reactivation increased soluble granzymes, IFNγ, IL-4, and IL-6.
“Knockdown of HEM1 in pan-T cells and subsequent reactivation resulted in increased levels of soluble granzymes, interferon gamma (IFNγ), IL-4, and IL-6”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The passage discussing IL-2 stimulation (section labeled Abstract; page unavailable) reports that HEM1-knockdown cells hypersecreted granzymes and that reducing HEM1 in primary T cells increased release of cytokines or granule contents. It does not identify IFNγ, IL-4, or IL-6 as increased, or establish the specified pan-T-cell reactivation condition. (LLM, conf=0.82)
Experimental — accuracy not yet measuredMultiple investigations found elevated surface CD107a levels after CD8+ T cell degranulation and lower cortical actin thickness.
“Multiple investigations found elevated surface CD107a levels after CD8 + T cell degranulation and lower cortical actin thickness”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The passage on HEM1-deficient patient cells (section labeled Abstract; page unavailable) reports reduced cortical F-actin and higher surface CD107a on T cells, especially after induced degranulation. It does not specify that the CD107a finding was in CD8+ T cells or report a measurement of cortical actin thickness; it describes reduced F-actin instead. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn vitro studies of activated patient CD8+ T cells revealed hypersecretion of cytotoxic cytokines, including perforin and granzymes A and B.
“Despite failure to properly initiate adaptive responses, in vitro studies of activated patient CD8+ T cells revealed hypersecretion of cytotoxic cytokines, including perforin and granzymes A and B [8].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The paper reports that IL-2-stimulated patient cells hypersecreted perforin and granzymes. But it also reports normal granzyme A, granzyme B, and perforin release from patient CD8+ T cells; the claim does not preserve this distinction between experimental conditions. Both passages are labeled Abstract in our copy, with no page number provided. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNatural killer cells were either normal or decreased across the HEM1-deficient cohort.
“Natural killer (NK) cells were either normal or decreased across the cohort [8–10].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The passage discussing NK-cell measurements (section labeled Abstract; no page provided) reports decreased NK-cell abundance in patients for whom sufficient samples were available. It does not report normal NK-cell counts or establish the pattern across the entire five-patient cohort. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMore than half of HEM1-deficient patients had elevated IgG levels without a clear relationship to autoimmune manifestations.
“More than half of the patients had elevated IgG levels without a clear relationship to autoimmune manifestations [8, 10].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The patient-description passage (labeled Abstract; page unavailable) reports that the five HEM1-deficient patients sometimes had elevated IgG and autoimmune manifestations. It does not establish that more than half had elevated IgG or that IgG levels had no clear relationship to autoimmune manifestations. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn HEM1-deficient patients, phosphorylation of AKT at serine 473 in response to various stimuli (CD3/28 TCR stimulation, IgM BCR stimulation, fibronectin, and ICAM-1) is diminished in T and B cells.
“Phosphorylation of AKT at serine 473, a specific target of the mTORC2 kinase complex, in response to various stimuli (CD3/28 TCR stimulation, IgM BCR stimulation, fibronectin, and ICAM-1) was diminished in T and B cells from patients [8, 9].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The passage discussing Fig. 4A and fig. S11A–C (page unavailable) reports defective TCR-induced AKT Ser473 phosphorylation in HEM1-deficient patient T cells. Our copy does not report the same phosphorylation result in B cells or after IgM, fibronectin, or ICAM-1 stimulation; its ICAM-1 passage concerns binding, not AKT phosphorylation. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPathogenic variants in NCKAP1L, a hematopoietically restricted gene encoding the HEM1 protein component of the WRC, define a novel disease involving recurrent bacterial and viral infections, autoimmunity, and excessive inflammation (OMIM 141180).
“Recently, three reports investigating novel mutations in NCKAP1L, a hematopoietically restricted gene encoding the HEM1 protein component of the WAVE regulatory complex (WRC), established how improper actin networks lead to a clinical syndrome involving recurrent bacterial and viral infections and autoimmunity (OMIM 141180) [8–10].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The p.M371V substitution drastically reduced WRC activation by the upstream GTPase ARF1, thus impairing WRC function without destabilizing the complex.
“By contrast, the p.M371V substitution drastically reduced WRC activation by the upstream GTPase ARF1, thus impairing WRC function without destabilizing the complex [8].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
Physical interaction between WRC and mTORC subunits was observed.
“physical interaction between WRC and mTORC subunits was observed”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
Reduced integrity of the mechanical actin barrier facilitates vesicular hypersecretion.
“indicating that reduced integrity of the mechanical actin barrier facilitates vesicular hypersecretion [8, 10, 12, 33].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
HEM1 deficiency reduces mTORC activity.
“in vitro data suggesting that HEM1 deficiency reduces mTORC activity [8, 41].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
HEM1-deficient T cells show reduced CD25 and CD69 upregulation and poor proliferative responses after TCR engagement in vitro.
“This manifests as reduced CD25 and CD69 upregulation and poor proliferative responses in patient cells after TCR engagement in vitro [8, 9].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
Most HEM1-deficient patients (six out of nine) displayed increased total B cells.
“Most patients (six out of nine) displayed increased total B cells [8–10].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The passage describing the patient cohort (section labeled Abstract; page unavailable) reports five HEM1-deficient patients and poor antibody responses, but does not give total B-cell counts. Searches for increased total B cells and for “B cells” found no passage supporting the six-of-nine figure. Because the sentence cites multiple sources, this does not establish where that figure came from. (LLM, conf=0.74)
Experimental — accuracy not yet measuredThose three HEM1-deficient patients demonstrated transaminitis or sinusoidal dilatation on liver biopsy.
“and demonstrated transaminitis or sinusoidal dilatation on liver biopsy [8, 10].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The patient-description passage (labeled Abstract; page unavailable) reports chronic hepatosplenomegaly in a study of five HEM1-deficient patients. Searches for transaminitis, sinusoidal dilatation, liver biopsy, and related terms found no passage establishing either claimed finding in the three patients. (LLM, conf=0.73)
Experimental — accuracy not yet measuredFailure to thrive was noted in two HEM1-deficient patients.
“Failure to thrive was noted in two patients [8, 9].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The patient-description passage in our copy (labeled Abstract; page unavailable) identifies five HEM1-deficient patients and lists infections, atopy, and inflammatory manifestations, but does not mention failure to thrive. Searches for “failure to thrive,” poor growth, weight gain, and growth retardation found no passage establishing that two patients had this finding. (LLM, conf=0.72)
Experimental — accuracy not yet measuredSeveral dysmorphic and developmental syndromic features may be observed in HEM1-deficient patients, such as intracerebral ventricular dilation, tricuspid valve deficiency, bicuspid aortic valve, ventricular septal defects, pectus carinatum, and poor dentition.
“Interestingly, several dysmorphic and developmental syndromic features may be observed, such as intracerebral ventricular dilation, tricuspid valve deficiency, bicuspid aortic valve, ventricular septal defects, pectus carinatum, and poor dentition [8].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The patient-description passage (indexed under Abstract; no page supplied) reports infections, atopy, inflammation, and lymphadenopathy, but does not address the listed dysmorphic or developmental features. Searches for the named ventricular, valve, chest, and dental findings, and for related congenital abnormalities, found no passage in our copy that addresses them. (LLM, conf=0.74)
Experimental — accuracy not yet measuredAutoimmune thrombocytopenia in one HEM1-deficient patient occurred after measles, mumps, and rubella vaccination.
“Autoimmune thrombocytopenia in one patient occurred after measles, mumps, and rubella vaccination [8].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The patient-description passage (section labeled Abstract; page unavailable) mentions autoimmune manifestations among the HEM1-deficient patients, but does not identify thrombocytopenia or a vaccination preceding it. Searches for thrombocytopenia and for measles, mumps, and rubella vaccination found no passage addressing the reported event. (LLM, conf=0.72)
Experimental — accuracy not yet measuredInterstitial lung disease is described in HEM1-deficient patients without a clear etiology but may be related to viral infections or chronic inflammation.
“Interstitial lung disease is also described without a clear etiology but may be related to viral infections or chronic inflammation [8, 27].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The passage describing the five patients (section labeled Abstract; page unavailable) reports respiratory infections, pneumonia, bronchiectasis, and inflammatory disease, but does not describe interstitial lung disease. Searches for interstitial lung disease and for a viral or inflammatory etiology found no passage linking either proposed cause to that condition. (LLM, conf=0.73)
Experimental — accuracy not yet measuredSiblings of patients from three of the seven kindreds died before 3 years of age from unknown causes or known infections, possibly because of HEM1 deficiency.
“Notably, siblings of patients from three of the seven kindreds died before 3 years of age from unknown causes or known infections, possibly because of HEM1 deficiency [8, 9].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The Abstract describes five patients from four unrelated families who had serious infections, but it does not report deaths among their siblings. Searches for siblings, deaths before age three, and seven kindreds found no passage addressing those details; the two citations may together cover more families than this paper alone. (LLM, conf=0.73)
Experimental — accuracy not yet measuredTwo unrelated HEM1-deficient patients displayed persistently elevated proportions of αβ double-negative T cells.
“Two unrelated patients displayed persistently elevated proportions of αβ double-negative T (DNT) cells, an interesting comparison to the hallmark expansion of DNTs in autoimmune lymphoproliferative syndrome [8, 31, 32].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The patient-description passage (section labeled Abstract; page unavailable) reports five HEM1-deficient patients from four unrelated families, but does not describe αβ double-negative T cells. Searches for “double-negative,” “αβ double negative,” and the corresponding CD4/CD8-negative phenotype found no passage documenting persistently elevated proportions in two patients. (LLM, conf=0.73)
Experimental — accuracy not yet measuredHEM1-deficient patients with severe autoimmune features display reduced proportions of naïve CD4+ and CD8+ T cell populations.
“Patients with severe autoimmune features display reduced proportions of naïve CD4+ and CD8+ T cell populations [8–10].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The patient-description passage (labeled Abstract; page unavailable) reports autoimmune manifestations in some HEM1-deficient patients, but does not give proportions of naïve CD4+ or CD8+ T cells. Searches for naïve T-cell subsets and CD45RA found no passage in our copy establishing the claimed reduction. (LLM, conf=0.73)
Experimental — accuracy not yet measuredNaïve CD8+ T cell populations were low in HEM1-deficient patients, and no consistent pattern has been observed with CD8+ memory cells.
“Naïve CD8+ T cell populations were low, and no consistent pattern has been observed with CD8+ memory cells [8–10].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The available patient T-cell passage (labeled Abstract; page unavailable) discusses activation, proliferation, and CD8+ cytotoxicity, but not naïve or memory CD8+ cell counts. Searches for naïve CD8+ cells, memory CD8+ cells, and lymphocyte-subset markers found no passage addressing either claimed pattern. (LLM, conf=0.72)
Experimental — accuracy not yet measuredLymph node biopsy from a different HEM1-deficient patient showed evidence of histiocytosis and emperipolesis suggesting Rosai-Dorfman disease.
“Lymph node biopsy from a different patient showed evidence of histiocytosis and emperipolesis suggesting Rosai-Dorfman disease [8].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The patient-description passage in our copy (section labeled Abstract; page unavailable) reports lymphadenopathy in HEM1-deficient patients, but does not describe a lymph node biopsy or its findings. Searches for emperipolesis, histiocytosis, and Rosai-Dorfman disease found no passage addressing the claimed biopsy result. (LLM, conf=0.73)
Experimental — accuracy not yet measuredOne HEM1-deficient patient displayed selective IgA deficiency in the context of celiac disease while others displayed mildly elevated IgA levels.
“One patient displayed selective IgA deficiency in the context of celiac disease while others displayed mildly elevated IgA levels [8, 10].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The patient-description passage (section labeled Abstract; page unavailable) reports poor specific antibody responses and sometimes elevated IgE or IgG, but does not address IgA levels or celiac disease. Searches for selective IgA deficiency, elevated IgA, and celiac disease found no passage supporting the attributed patient-level claim. (LLM, conf=0.74)
Experimental — accuracy not yet measuredHem1−/− mice have increased serum levels of IFNγ and IL-6.
“corresponding to increased serum levels of IFNγ and IL-6 observed in Hem1−/− mice [8, 9].”
From HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions (2022) · cites this paper as [8]
The section labeled Abstract mentions HEM1-deficient mice only in connection with lymphopenia, neutrophilia, or bone marrow failure. Searches for mouse serum IFNγ and IL-6 found no passage in our copy reporting those measurements; its cytokine findings concern patient or HEM1-knockdown cells instead. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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Cites
mTOR Signaling in Growth, Metabolism, and Disease
Saxton, R. A., & Sabatini, D. M. (2017) · Cell · doi:10.1016/j.cell.2017.02.004 · Cited by 7,555 · see citing works
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- [1]Cunningham-Rundles C, Ponda PP, Molecular defects in T- and B-cell primary immunodeficiency diseases. Nat Rev Immunol 5, 880– 892 (2005). 16261175
- [3]Guertin DA, Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 11, 859– 871 (2006). 17141160
- [4]Lee K, Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 32, 743– 753 (2010). 20620941 PMC2911434
- [5]Van de Velde LA, Murray PJ, Proliferating Helper T Cells Require Rictor/mTORC2 Complex to Integrate Signals from Limiting Environmental Amino Acids. J Biol Chem 291, 25815– 25822 (2016). 27799302 PMC5207057
- [6]Chen B, Padrick SB, Henry L, Rosen MK, Biochemical reconstitution of the WAVE regulatory complex. Methods Enzymol 540, 55– 72 (2014). 24630101 PMC4110903
- [7]Stradal TE, Regulation of actin dynamics by WASP and WAVE family proteins. Trends Cell Biol 14, 303– 311 (2004). 15183187
- [8]Chen B, Rac1 GTPase activates the WAVE regulatory complex through two distinct binding sites. Elife 6, (2017). PMC5614565 28949297
- [9]Chen Z, Structure and control of the actin regulatory WAVE complex. Nature 468, 533– 538 (2010). 21107423 PMC3085272
- [10]Shao L, The Wave2 scaffold Hem-1 is required for transition of fetal liver hematopoiesis to bone marrow. Nat Commun 9, 2377 (2018). 29915352 PMC6006146
- [11]Litschko C, Differential functions of WAVE regulatory complex subunits in the regulation of actin-driven processes. Eur J Cell Biol 96, 715– 727 (2017). 28889942
- [12]Lebensohn AM, Kirschner MW, Activation of the WAVE complex by coincident signals controls actin assembly. Mol Cell 36, 512– 524 (2009). 19917258 PMC2818508
- [13]Burns SO, Zarafov A, Thrasher AJ, Primary immunodeficiencies due to abnormalities of the actin cytoskeleton. Curr Opin Hematol 24, 16– 22 (2017). 27749373
- [14]Kircher M, A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46, 310– 315 (2014). 24487276 PMC3992975
- [15]Park H, A point mutation in the murine Hem1 gene reveals an essential role for Hematopoietic protein 1 in lymphopoiesis and innate immunity. J Exp Med 205, 2899– 2913 (2008). 19015308 PMC2585840
- [16]Leithner A, Diversified actin protrusions promote environmental exploration but are dispensable for locomotion of leukocytes. Nat Cell Biol 18, 1253– 1259 (2016). 27775702
- [17]Basquin C, Membrane protrusion powers clathrin-independent endocytosis of interleukin-2 receptor. EMBO J 34, 2147– 2161 (2015). 26124312 PMC4557667
- [18]Gil-Krzewska A, An actin cytoskeletal barrier inhibits lytic granule release from natural killer cells in patients with Chediak-Higashi syndrome. J Allergy Clin Immunol 142, 914– 927 e916 (2018). 29241728 PMC5995607
- [19]Carisey AF, Mace EM, Saeed MB, Davis DM, Orange JS, Nanoscale Dynamism of Actin Enables Secretory Function in Cytolytic Cells. Curr Biol 28, 489– 502 e489 (2018). 29398219 PMC5835143
- [20]Murugesan S, Formin-generated actomyosin arcs propel T cell receptor microcluster movement at the immune synapse. J Cell Biol 215, 383– 399 (2016). 27799367 PMC5100289
- [21]Nolz JC, The WAVE2 complex regulates actin cytoskeletal reorganization and CRAC-mediated calcium entry during T cell activation. Curr Biol 16, 24– 34 (2006). 16401421 PMC1779663
- [22]Weiner OD, Hem-1 complexes are essential for Rac activation, actin polymerization, and myosin regulation during neutrophil chemotaxis. PLoS Biol 4, e38 (2006). 16417406 PMC1334198
- [23]Nolz JC, WAVE2 regulates high-affinity integrin binding by recruiting vinculin and talin to the immunological synapse. Mol Cell Biol 27, 5986– 6000 (2007). 17591693 PMC1952166
- [24]Nolz JC, The WAVE2 complex regulates T cell receptor signaling to integrins via Abl- and CrkL-C3G-mediated activation of Rap1. J Cell Biol 182, 1231– 1244 (2008). 18809728 PMC2542481
- [25]Sarbassov DD, Guertin DA, Ali SM, Sabatini DM, Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098– 1101 (2005). 15718470
- [26]Diz-Munoz A, Membrane Tension Acts Through PLD2 and mTORC2 to Limit Actin Network Assembly During Neutrophil Migration. PLoS Biol 14, e1002474 (2016). 27280401 PMC4900667
- [27]Treanor B, The membrane skeleton controls diffusion dynamics and signaling through the B cell receptor. Immunity 32, 187– 199 (2010). 20171124 PMC2984614
- [28]Iwata TN, Ramirez-Komo JA, Park H, Iritani BM, Control of B lymphocyte development and functions by the mTOR signaling pathways. Cytokine Growth Factor Rev 35, 47– 62 (2017). 28583723 PMC5559228
- [29]Yang C, mTORC1 and mTORC2 differentially promote natural killer cell development. Elife 7, (2018). PMC5976438 29809146
- [30]Paila U, Chapman BA, Kirchner R, Quinlan AR, GEMINI: integrative exploration of genetic variation and genome annotations. PLoS Comput Biol 9, e1003153 (2013). 23874191 PMC3715403
- [31]Lek M, Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285– 291 (2016). 27535533 PMC5018207
- [32]Sanborn KB, Myosin IIA associates with NK cell lytic granules to enable their interaction with F-actin and function at the immunological synapse. J Immunol 182, 6969– 6984 (2009). 19454694 PMC2835774
- [33]Sanborn KB, Rak GD, Mentlik AN, Banerjee PP, Orange JS, Analysis of the NK cell immunological synapse. Methods Mol Biol 612, 127– 148 (2010). 20033638
- [34]Banerjee PP, Orange JS, Quantitative measurement of F-actin accumulation at the NK cell immunological synapse. J Immunol Methods 355, 1– 13 (2010). 20171970 PMC2854315
- [35]Schindelin J, Fiji: an open-source platform for biological-image analysis. Nat Methods 9, 676– 682 (2012). 22743772 PMC3855844
- [36]Chen B, Padrick SB, Henry L, Rosen MK, Biochemical reconstitution of the WAVE regulatory complex. Methods Enzymol 540, 55– 72 (2014). 24630101 PMC4110903
- [37]Chen B, Rac1 GTPase activates the WAVE regulatory complex through two distinct binding sites. Elife 6, (2017). PMC5614565 28949297
- [38]O’Shea EK, Lumb KJ, Kim PS, Peptide ‘Velcro’: design of a heterodimeric coiled coil. Curr Biol 3, 658– 667 (1993). 15335856
- [39]Keilhauer EC, Hein MY, Mann M, Accurate protein complex retrieval by affinity enrichment mass spectrometry (AE-MS) rather than affinity purification mass spectrometry (AP-MS). Mol Cell Proteomics 14, 120– 135 (2015). 25363814 PMC4288248
- [40]Boersema PJ, Raijmakers R, Lemeer S, Mohammed S, Heck AJ, Multiplex peptide stable isotope dimethyl labeling for quantitative proteomics. Nat Protoc 4, 484– 494 (2009). 19300442
- [41]Cox J, Mann M, MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol 26, 1367– 1372 (2008). 19029910
- [42]Lin Y, Sodium laurate, a novel protease- and mass spectrometry-compatible detergent for mass spectrometry-based membrane proteomics. PLoS One 8, e59779 (2013). 23555778 PMC3610932
- [43]Rappsilber J, Mann M, Ishihama Y, Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat Protoc 2, 1896– 1906 (2007). 17703201
- [44]Perrin C, Ohta B, Kuperman J, Beta-deuterium isotope effects on amine basicity, “inductive” and stereochemical. J Am Chem Soc 125, 15008– 9. (2003) 14653734
Cited by
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HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions
Cook, S., Lenardo, M. J., & Freeman, A. F. (2022) · Journal of Clinical Immunology · doi:10.1007/s10875-022-01327-0 · Cited by 24 · see citing works
Self-citationThe WAVE complex in developmental and adulthood brain disorders
Kim, H.-G., Berdasco, C., Nairn, A. C., & Kim, Y. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01386-w · Cited by 8 · see citing works
- Authors
- Cook, S. A., Comrie, W. A., Poli, M. C., Similuk, M., Oler, A. J., Faruqi, A. J., Kuhns, D. B., Yang, S., Vargas-Hernández, A., Carisey, A. F., Fournier, B., Anderson, D. E., Price, S., Smelkinson, M., Abou Chahla, W., Forbes, L. R., Mace, E. M., Cao, T. N., Coban-Akdemir, Z. H., Jhangiani, S. N., Muzny, D. M., Gibbs, R. A., Lupski, J. R., Orange, J. S., Cuvelier, G. D. E., Al Hassani, M., Al Kaabi, N., Al Yafei, Z., Jyonouchi, S., Raje, N., Caldwell, J. W., Huang, Y., Burkhardt, J. K., Latour, S., Chen, B., ElGhazali, G., Rao, V. K., Chinn, I. K., & Lenardo, M. J.
- Affiliations
- National Institutes of Health (US)
- Baylor College of Medicine (US)
- Frederick National Laboratory for Cancer Research (US)
- Iowa State University (US)
- Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
- Inserm (FR)
- Department of Pediatric Hematology, Jeanne de Flandre Hospital, Centre Hospitalier Universitaire (CHU), Lille, France.
- Columbia University Irving Medical Center (US)
- Baylor-Hopkins Center for Mendelian Genomics, Houston, TX, USA.
- Section of Pediatric Hematology/Oncology/BMT, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada.
- Sheikh Khalifa Medical City, Abu Dhabi Healthcare Company (SEHA), Abu Dhabi, United Arab Emirates.
- Children's Hospital of Philadelphia (US)
- Children's Mercy Hospital (US)
- Wake Forest University Health Sciences (US)
- Shaikh Khalifa Medical City (AE)
- Corresponding author
- Cook, Sarah A.
- Comrie, William A.
- Lenardo, Michael J.
- ORCID
- Cook, Sarah A.
- Comrie, William A.
- Poli, M. Cecilia
- Similuk, Morgan
- Oler, Andrew J.
- Faruqi, Aiman J.
- Kuhns, Douglas B.
- Yang, Sheng
- Carisey, Alexandre F.
- Fournier, Benjamin
- Anderson, D. Eric
- Price, Susan
- Smelkinson, Margery
- Abou Chahla, Wadih
- Forbes, Lisa R.
- Mace, Emily M.
- Coban-Akdemir, Zeynep H.
- Jhangiani, Shalini N.
- Muzny, Donna M.
- Gibbs, Richard A.
- Lupski, James R.
- Orange, Jordan S.
- Cuvelier, Geoffrey D. E.
- Jyonouchi, Soma
- Raje, Nikita
- Caldwell, Jason W.
- Huang, Yanping
- Burkhardt, Janis K.
- Latour, Sylvain
- Chen, Baoyu
- ElGhazali, Gehad
- Rao, V. Koneti
- Chinn, Ivan K.
- Lenardo, Michael J.
- Venue
- Science
- Published
- 2020-07-10
- Volume
- 369
- Issue
- 6500
- Pages
- 202-207
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC8383235
- OpenAlex
- W3041635606
- Cited by
- 102
- References
- 1
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 18 · 2023: 13 · 2022: 19 · 2021: 28 · 2020: 2
- FWCI
- 5.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Iowa State University Digital Repository (Iowa State University) (submittedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- National Institutes of Health (AI120989)
- American Diabetes Association (1-16-PDF-025)
- National Cancer Institute (No. HHSN261200800001E)
- National Institute of General Medical Sciences
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- NIGMS (1FI2GM119979-01)
- nih-nhgri (UM1 HG006542)
- The Jeffrey Modell Foundation Translational Research Award
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- WAVE regulatory complex, Arf1, mTORC2, F-actin, actin polymerization, inherited immunodeficiency, Akt phosphorylation, T cell proliferation, cytokine production, leukocyte migration, cortical actin network
- MeSH terms
- Mechanistic Target of Rapamycin Complex 2, Actins, Humans, Immunologic Deficiency Syndromes, Lymphoproliferative Disorders, Membrane Proteins, Pedigree, Phosphorylation, CD4-Positive T-Lymphocytes, Cytokines, ADP-Ribosylation Factor 1, Cell Proliferation, Wiskott-Aldrich Syndrome Protein Family
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