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ARPC5 deficiency leads to severe early-onset systemic inflammation and mortality.

ABSTRACT: The Arp2/3 complex drives the formation of branched actin networks that are essential for many cellular processes. In humans, the ARPC5 subunit of the Arp2/3 complex is encoded by two paralogous genes (ARPC5 and ARPC5L) with 67% identity. Through whole-exome sequencing, we identified a biallelic ARPC5 frameshift variant in a female child who presented with recurrent infections, multiple congenital anomalies, diarrhea and thrombocytopenia, and suffered early demise from sepsis. Her consanguineous parents also had a previous child who died with similar clinical features. Using CRISPR/Cas9-mediated approaches, we demonstrate that loss of ARPC5 affects actin cytoskeleton organization and function in vitro. Homozygous Arpc5-/- mice do not survive past embryonic day 9 owing to developmental defects, including loss of the second pharyngeal arch, which contributes to craniofacial and heart development. Our results indicate that ARPC5 is important for both prenatal development and postnatal immune signaling, in a non-redundant manner with ARPC5L. Moreover, our observations add ARPC5 to the list of genes that should be considered when patients present with syndromic early-onset immunodeficiency, particularly if recessive inheritance is suspected.

SUBMITTER: Sindram E

PROVIDER: S-EPMC10387347 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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ARPC5 deficiency leads to severe early-onset systemic inflammation and mortality.

Sindram Elena E Caballero-Oteyza Andrés A Kogata Naoko N Chor Mei Huang Shaina S Alizadeh Zahra Z Gámez-Díaz Laura L Fazlollhi Mohammad Reza MR Peng Xiao X Grimbacher Bodo B Way Michael M Proietti Michele M

Disease models & mechanisms 20230720 7

The Arp2/3 complex drives the formation of branched actin networks that are essential for many cellular processes. In humans, the ARPC5 subunit of the Arp2/3 complex is encoded by two paralogous genes (ARPC5 and ARPC5L) with 67% identity. Through whole-exome sequencing, we identified a biallelic ARPC5 frameshift variant in a female child who presented with recurrent infections, multiple congenital anomalies, diarrhea and thrombocytopenia, and suffered early demise from sepsis. Her consanguineous ...[more]

PMID: 37382373

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Project description:ObjectivesWe tested the hypothesis that a C-reactive protein and ferritin-based systemic inflammation contingency table can track mortality risk in pediatric severe sepsis.DesignProspective cohort study.SettingTertiary PICU.PatientsChildren with 100 separate admission episodes of severe sepsis were enrolled.InterventionsBlood samples were attained on day 2 of sepsis and bi-weekly for biomarker batch analysis. A 2 × 2 contingency table using C-reactive protein and ferritin thresholds was developed.Measurements and main resultsA C-reactive protein of 4.08 mg/dL and a ferritin of 1,980 ng/mL were found to be optimal cutoffs for outcome prediction at first sampling (n = 100) using the Youden index. PICU mortality was increased in the "high-risk" C-reactive protein greater than or equal to 4.08 mg/dL and ferritin greater than or equal to 1,980 ng/mL category (6/13 [46.15%]) compared with the "intermediate-risk" C-reactive protein greater than or equal to 4.08 mg/dL and ferritin less than 1,980 ng/mL or C-reactive protein less than 4.08 mg/dL and ferritin greater than or equal to 1,980 ng/mL categories (2/43 [4.65%]), and the "low-risk" C-reactive protein less than 4.08 mg/dL and ferritin less than 1,980 ng/mL category (0/44 [0%]) (odds ratio, 36.43 [95% CI, 6.16-215.21]). The high-risk category was also associated with the development of immunoparalysis (odds ratio, 4.47 [95% CI, 1.34-14.96]) and macrophage activation syndrome (odds ratio, 24.20 [95% CI, 5.50-106.54]). Sixty-three children underwent sequential blood sampling; those who were initially in the low-risk category (n = 24) and those who subsequently migrated (n = 19) to the low-risk category all survived, whereas those who remained in the "at-risk" categories had increased mortality (7/20 [35%]; p < 0.05).ConclusionsA C-reactive protein- and ferritin-based contingency table effectively assessed mortality risk. Reduction in systemic inflammation below a combined threshold C-reactive protein of 4.08 mg/dL and ferritin of 1,980 ng/mL appeared to be a desired response in children with severe sepsis.

Project description:BackgroundVitamin D deficiency and systemic inflammation share common pathological mechanisms in muscle loss, cardio-pulmonary function decline, and abnormal metabolism, which are linked to chronic conditions, senescence, and early mortality. However, their combined effect on mortality in older adults has not been well established. This study longitudinal aimed to explore the independent and combined associations of serum 25-hydroxyvitamin D [25(OH)D] and high sensitivity C-reactive protein (hs-CRP) with mortality risk in Chinese community-based older people.Methods3072 older adults (86.07 ± 11.87 years, 54.52% female) from the Chinese Longitudinal Healthy Longevity Survey (2012-2018) were enrolled. Baseline 25(OH)D and hs-CRP levels were collected, and survival information was recorded in the 2014 and 2018 follow-up waves. Cox proportional hazard regressions were conducted to explore the associations between 25(OH)D, hs-CRP, and mortality. Demographic characteristics, health behaviors, and chronic disease biomarkers were adjusted.ResultsDuring 10,622.3 person-years of follow-up (median: 3.51 years), 1321 older adults died, including 448 deaths due to cardiovascular disease (CVD). Increased mortality risk was associated with lower 25(OH)D and higher hs-CRP quantiles, even after adjusting for each other and multiple covariates (all P-trend < 0.05). In combined analyses, the highest all-cause mortality (HR: 2.18, 95% CI: 1.73 ~ 2.56), CVD mortality (HR: 2.30, 95% CI: 1.64 ~ 3.21), and non-CVD mortality (HR: 2.19, 95% CI: 1.79 ~ 2.49) were obtained in participants with both 25(OH)D deficiency (< 50 nmol/L) and high hs-CRP (≥ 3.0 mg/L), respectively. We observed significant additive interactions of 25(OH)D and hs-CRP on all-cause mortality and non-CVD mortality (RERIS>0).ConclusionsLow 25(OH)D and high hs-CRP, both independently and jointly, increase mortality risk in Chinese community-dwelling older adults. Thus, priority should be given to early detection and appropriate intervention in older individuals with combined vitamin D deficiency and systemic inflammation. Molecular mechanisms of related adverse health effect are worthy of further investigation.

Dataset Information

ARPC5 deficiency leads to severe early-onset systemic inflammation and mortality.

Publications

ARPC5 deficiency leads to severe early-onset systemic inflammation and mortality.

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