Impaired heme synthesis in a family with Pelger‐Huët anomaly, recurrent abdominal pain attacks and impaired neutrophil motility in vitro

Abstract

Heme synthesis was studied by measuring the activity of δ‐aminolevulinic acid synthase (AmLev synthase) in granulocytes, the activity of δ‐aminolevulinic acid dehydratase (AmLev dehydratase) and of uroporphyrinogen I synthase in erythrocytes as well as the concentrations of coproporphyrin and protoporphyrin in erythrocytes of 6 patients with Pelger‐Huët anomaly. 3 of these patients from the same kindred had a syndrome of recurrent attacks of fever and abdominal pains, a tendency to skin infections, delayed wound healing and impaired neutrophil motility. The other 3 patients were asymptomatic. The activity of AmLev synthase was depressed in all 3 symptomatic patients and normal in the asymptomatic patients. 1 symptomatic patient had a decreased erythrocyte protoporphyrin concentration. These findings indicate a derangement of heme synthesis in the symptomatic patients. Their abdominal pain attacks could be due to heme depletion. The findings suggest that the abdominal pains of patients with porphyria could be due to decreased heme synthesis rather than due to accumulation of porphyrin precursors in tissues. The cause of the impaired neutrophil motility may be a defect in energy metabolism due to decreased supply of heme for oxidative metabolism.

Gain-of-function CEBPE mutation causes noncanonical autoinflammatory inflammasomopathy

“…The index family has been studied since the 1970s. [16][17][18] A systems-level approach combining genomics, transcriptomics, and proteomics finally made it possible to unravel the causative pathogenic mechanisms. In conclusion, CAIN reveals GOF mechanisms resulting in autoinflammation and immunodeficiency, which are potentially relevant for various transcription factor-related diseases.…”

“…14 Early studies in Cebpe knockout mice showed Cebpe to be integral for maintenance of constitutive levels of several cytokines, including IFN-g. 15 We report an autosomal recessive GOF PID, C/EBPε-associated autoinflammation and immune impairment of neutrophils (CAIN), in a family with a genetically uncharacterized autoinflammatory syndrome. [16][17][18] According to our results, C/EBPε acts as a regulator of both the inflammasome and interferome. Homozygous missense mutations in CEBPE (14:23586886 C->T;p.Arg219His) resulted in markedly decreased C/EBPε association with transcriptional repressors and increased occupancy on chromatin, leading to dysregulated C/EBPε-mediated transcription of interleukin and interferon response genes in neutrophils.…”

“…In the 1970s, affected members of the index family were thought to have atypical Pelger-Hu€ et anomaly because they presented with neutrophil hyposegmentation, aberrant neutrophil responsiveness, and impaired chemotaxis. [16][17][18] Patients experienced recurrent attacks of abdominal pain, aseptic fever, and systemic inflammation lasting 4 to 5 days. These were accompanied by an acute-phase response and occasionally by nailbed, tongue, submandibular and gluteal abscesses; intra-abdominal granulomas; pyoderma gangrenosum; and buccal ulcerations.…”

“…The novel homozygous CEBPE 14:23586886 C>T mutation cosegregated perfectly with the disease phenotype (Fig 1, A, and see Fig E1 in this article's Online Repository at www.jacionline.org). [16][17][18] Arg219His was predicted to be detrimental and not listed in major public or in-house databases. It resided in the highly conserved basic zipper region's carboxyl terminal DNA-binding domain shared by all 4 C/EBPε isoforms (Fig 1, B and C).…”