NK cell defects in X-linked pigmentary reticulate disorder

Starokadomskyy, Petro; Wilton, Katelynn M.; Krzewski, Konrad; Lopez, Adam M.; Sifuentes-Dominguez, Luis; Overlee, Brittany L.; Chen, Qing; Ray, Ann; Gil-Krzewska, Aleksandra; Peterson, Mary; Kinch, Lisa N.; Rohena, Luis; Grunebaum, Eyal; Zinn, Andrew R.; Grishin, Nick V.; Billadeau, Daniel D.; Burstein, Ezra

doi:10.1172/jci.insight.125688

Cited by 19 publications

(30 citation statements)

References 40 publications

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“…Follicular T helper cells and memory B cells were also normal in our patient. It has recently been shown that NK cells are quantitatively and functionally altered in patients with XLPDR [3]. In line with these data, our patient had slight NK cell cytopenia and a relative paucity of mature CD56 dim NK cells in peripheral blood.…”

supporting

confidence: 89%

“…The relative proportion of immature CD56 hi NK cells was 2-fold elevated compared to the two controls ( Fig. S2), in keeping what has been described in other XLPDR patients [3]. NK function was assessed flow cytometrically by measuring intracellular IFN-γ and CD107a in response to receptordependent (K562 cells) and receptor-independent (PMA/ ionomycin) activation (Fig.…”

supporting

confidence: 84%

“…Functionally, NK cell degranulation, as assessed by CD107a expression, was more preserved than IFN-γ formation following receptor-dependent activation. Receptor-independent-NK cell activation was normal, suggesting a defect in the immune synapse formation that depends on the surface receptors [3]. We have not experimentally studied synapse formation which has been demonstrated to be abnormal in NK cells of XLPDR patients.…”

mentioning

confidence: 92%

“…B and T cell subpopulations were normal for age, and the oxidative burst test (DHR123) revealed normal neutrophil burst activity ( Table 1). It has been recently demonstrated that NK cells are dysfunctional in patients with XLPDR [3]. Therefore, the NK cell phenotype and function in the XLPDR patient were evaluated compared to a simultaneously recruited healthy (adult) control and an adult patient with recurrent infections with possible, but not yet further evaluated primary immunodeficiency (Disease control).…”

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confidence: 99%

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JAK Inhibition in a Patient with X-Linked Reticulate Pigmentary Disorder

et al. 2020

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To the editor, X-linked reticulate pigmentary disorder (XLPDR) is a very rare inherited disease with prominent skin hyperpigmentation and multiorgan involvement dominated by autoinflammatory manifestations in the eyes, the urinary tract, and recurrent infections, particularly in the respiratory tract. In 2016, the causative genetic mutation for XLPDR was located to the POLA1 gene, which encodes the catalytic subunit of DNA polymerase A1 [1]. An intronic POLA1 mutation (c.1375-354A>G), causing altered POLA1 gene splicing, leads to reduced transcript and protein levels. It has been demonstrated that POLA1 deficiency is directly linked to the activation of type I interferons (IFNs) and upregulation of interferonstimulated genes (ISG), classifying XLPDR as an interferonopathy [1]. In affected males, the disease typically manifests in the first months of life with failure to thrive, recurrent pneumonias, persistent diarrhea in infancy, and pathognomonic diffuse hyperpigmentation and characteristic facies [2]. The patient described here was born in 2008 into a Caucasian, non-consanguineous family via spontaneous vaginal delivery at term. The index patient has two older, healthy brothers and healthy parents. His mother lacked pigmentary changes along Blaschko's lines. At the age of four weeks, he was admitted to the hospital due to low weight for age (Fig. S1). During the admission, he developed mild bloody diarrhea. All laboratory tests performed at that time (blood count, electrolytes, liver parameters, clotting time, thyroid function, viral serologies, screening for inborn metabolic disorders, stool screenings for malabsorption, and infections) were within reference ranges. The hypothesis of a cow's milk protein allergy was made, the formula was swapped to an amino acid based one, the symptoms resolved, and the patient started to gain weight. Since the age of six months, his weight follows percentiles 3-15 (Supplementary Fig. 1). On clinical examination during the hospitalization, a mild muscular hypotonia was noticed and further tests (MRI of the head, abdominal ultrasound, EEG, and referral to the ophthalmologist) were arranged-all with normal results. Neuropediatric follow-up was arranged due to the mild muscular hypotonia but was stopped at the age of 2 years because a normal development was objectified. Over the next years, the patient suffered from recurrent otitis media, sinusitis, and several pneumonias. Despite t he p erformance of an ade noidectomy, Corinne Légeret and Benedikt J. Meyer contributed equally to this work.

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supporting

confidence: 89%

supporting

confidence: 84%

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confidence: 92%

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confidence: 99%

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JAK Inhibition in a Patient with X-Linked Reticulate Pigmentary Disorder

et al. 2020

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“…This is another rare syndrome with recurrent infections caused by pathogenic variants in POLA1 which leads to reduced pol α expression ( Figure 8 ) [ 86 ]. In addition to recurrent infections, affected individuals have hypogonadism, hyperpigmentation, corneal dystrophy, photophobia, unique facial features and multiorgan inflammation due to the role of pol α in modulating the interferon response [ 86 , 87 , 88 , 89 , 90 ]. Recurrent infections are due to reduced NK cell numbers and reduced cytotoxicity of peripheral NK cells, although the NK cells in these individuals do not stay consistently low enough to make the diagnosis of CNKD [ 90 ].…”

Section: Diseasesmentioning

confidence: 99%

Congenital Diseases of DNA Replication: Clinical Phenotypes and Molecular Mechanisms

Schmit

Bielinsky

2021

IJMS

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Deoxyribonucleic acid (DNA) replication can be divided into three major steps: initiation, elongation and termination. Each time a human cell divides, these steps must be reiteratively carried out. Disruption of DNA replication can lead to genomic instability, with the accumulation of point mutations or larger chromosomal anomalies such as rearrangements. While cancer is the most common class of disease associated with genomic instability, several congenital diseases with dysfunctional DNA replication give rise to similar DNA alterations. In this review, we discuss all congenital diseases that arise from pathogenic variants in essential replication genes across the spectrum of aberrant replisome assembly, origin activation and DNA synthesis. For each of these conditions, we describe their clinical phenotypes as well as molecular studies aimed at determining the functional mechanisms of disease, including the assessment of genomic stability. By comparing and contrasting these diseases, we hope to illuminate how the disruption of DNA replication at distinct steps affects human health in a surprisingly cell-type-specific manner.

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