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Case Reports
. 2024 May 22;44(6):129.
doi: 10.1007/s10875-024-01733-6.

Variable Syndromic Immunodeficiency in Patients with Biallelic PRIM1 Mutations

Vasil Toskov  1 , Petra Kaiser-Labusch  2 , Min Ae Lee-Kirsch  3 ; PRIM1 study group; Stephan Ehl  4 , Oliver Wegehaupt  5   6
Collaborators, Affiliations
Case Reports

Variable Syndromic Immunodeficiency in Patients with Biallelic PRIM1 Mutations

Vasil Toskov et al. J Clin Immunol. .

Abstract

Mutations in genes of the DNA polymerase complex have been linked to impaired immunological function next to distinct syndromic features. Biallelic mutations in PRIM1 are associated with a primordial dwarfism syndrome with variable hypogammaglobulinemia. The disease is mostly lethal in infancy due to pulmonary infections as well as hepatic cirrhosis. We studied 3 novel patients with PRIM1-deficiency with a focus on immunological consequences. All three shared dysmorphic features including a prominent forehead, triangular face and bilateral cryptorchidism. P1 carried the novel homozygous PRIM1 splice variant c.103+2T>G, allowing residual protein expression and associated with a mild clinical phenotype. P2 and P3 carried the known homozygous variant c.638+36C>G and died in infancy. Paradoxically, B cell lymphopenia was most pronounced in P1. No other significant lymphocyte abnormalities were detected. Interestingly, all 3 patients showed variable, but intermittently excessive Type I interferon signatures. In summary, the B-cell deficiency in PRIM1-deficiency is markedly variable and the severity of syndromic manifestations is not predictive of the immunological phenotype. We highlight a potential contribution of pathological type I interferon activation to disease pathogenesis which warrants further investigations.

Keywords: B cell deficiency; PRIM1; agammaglobulinemia; immunodeficiency; interferonopathy; primordial dwarfism; type I interferon.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Genetic and immunological features of 2 patients with known and 1 patient with novel homozygous PRIM1 mutations. A Pedigrees of two unrelated families with PRIM1 patients. “ + “ denotes the reference PRIM1 allele, V1 and V2 the mutated variants. B PRIM1 specific RT-PCR of RNA isolated from P1 and healthy donor (HD) PBMCs that were stimulated with PHA and IL-2 for 3 days. Primers cover the intronic region between exon 1 and exon 2 (WT 187 bp). The two lanes labeled P1 were loaded with the same sample. P1 has a larger transcript due to the insertion shown in (C). Other weaker bands are presumably unspecific transcripts due to strong stimulation with PHA/IL-2. C Sanger sequencing reads of cDNA covering the Exon1/2 boundary of PRIM1 from P1 and a HD. The PRIM1 variant c.103 + 2 T > G in P1 causes a 9 bp insertion. Illustration created with BioRender. D Immunoblotting of whole cell lysates of P1 and HD PBMCs that were stimulated with PHA and IL-2 for 3 days. E BrdU cell cycle assay. Left panel: percentage of CD4 + and CD8 + T-lymphocytes in S-Phase of P1 and HD after 3 days of stimulation with PHA and IL-2. Four independent stimulation experiments with cells from P1 and healthy controls are shown. Individual experiments are depicted by different open symbols. Black symbols represent values from HD obtained in independent experiments. Statistics: ordinary unpaired one-way ANOVA, significance level p < 0.05. Right panel: representative FACS plots of cell cycle distribution in CD3 + CD8 + cells. F CFSE dilution assay of PBMC incubated for 5 days with medium (gray lines) or PHA (black lines) gated on CD4 + or CD8 + T cells. G Upper part: IFN-γ production of CD3-CD56 + NK cells in response to stimulation with IL-15/IL-18 in comparison to a healthy control. Lower part: CD107 expression of NK cells upon stimulation of PBMC with NK-sensitive target K562 cells. H IFN signatures in PBMCs of patients P1, P2 and P3. Shown is the fold increase in the IFN score compared with historical positive controls (patients with Aicardi-Goutières Syndrom (AGS)). An IFN score of 12.49 (red dashed line) indicates the median of 10 healthy controls plus 2 SD
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References

    1. Starokadomskyy P, et al. DNA polymerase-α regulates the activation of type I interferons through cytosolic RNA:DNA synthesis. Nat Immunol. 2016;17(5):495–504. doi: 10.1038/ni.3409. - DOI - PMC - PubMed
    1. Conde CD, et al. Polymerase δ deficiency causes syndromic immunodeficiency with replicative stress. J Clin Invest. 2019;129(10):4194–4206. doi: 10.1172/JCI128903. - DOI - PMC - PubMed
    1. Logan CV, et al. DNA polymerase epsilon deficiency causes IMAGe syndrome with variable immunodeficiency. Am J Hum Genet. 2018;103(6):1038–1044. doi: 10.1016/j.ajhg.2018.10.024. - DOI - PMC - PubMed
    1. Parry DA, et al. PRIM1 deficiency causes a distinctive primordial dwarfism syndrome. Genes Dev. 2020;34(21–22):1520–1533. doi: 10.1101/gad.340190.120. - DOI - PMC - PubMed
    1. Starokadomskyy P, et al. NK cell defects in X-linked pigmentary reticulate disorder. JCI Insight. 2019;4(21):e125688. doi: 10.1172/jci.insight.125688. - DOI - PMC - PubMed

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