Prevalence of CECR1 mutations in pediatric patients with polyarteritis nodosa, livedo reticularis and/or stroke

The objective of this paper is to: describe the phenotype compound heterozygote for mutations in CECR1 in two children. We describe the clinical and immunological phenotype, including the assessment of ADA2 activity, cytokine expression, interferon-stimulated and neutrophil-stimulated gene signatures, and the results of CECR1 sequencing. The first patient presented with intermittent fever, cutaneous vasculitis, myalgia and muscle inflammation on MRI leading to a provisional diagnosis of periarteritis nodosa. Subsequently, two cerebral lacunar lesions were identified following a brain stroke. Clinical features improved on anti-tumour necrosis factor therapy. The first patient's sister demonstrated early-onset, long-lasting anaemia with mild biological inflammation; at the ages of 3 and 5 years, she had presented 2 acute, transient neurological events with lacunar lesions on MRI. CECR1 sequencing identified both sisters to be compound heterozygous for a p.Tyr453Cys mutation and a previously undescribed deletion of exon 7. ADA2 activity was reduced by 50%. Neutrophil-stimulated genes were not overexpressed, but interferon-stimulated genes were. The expression of a panel of other cytokine transcripts was not significantly altered. In conclusion, searching for CECR1 mutation or assessing ADA2 activity should be considered in patients with an atypical presentation of inflammatory disease.

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“… 10 However, this report and others underline the fact that marked phenotypic variability can occur even in the same family. 11 …”

Section: Discussionmentioning

confidence: 99%

ADA2 deficiency: case report of a new phenotype and novel mutation in two sisters

Uettwiller

Sarrabay²,

Rodero

et al. 2016

RMD Open

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ADA2 is a lysosomal DNase regulating the type-I interferon response

Boehler

Bartok

Krausz

et al. 2020

Preprint

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Deficiency of adenosine deaminase 2 (DADA2) is a severe, congenital syndrome, which manifests with hematologic, immunologic and inflammatory pathologies. DADA2 is caused by biallelic mutations in ADA2, but the function of ADA2, and the mechanistic link between ADA2 deficiency and the severe inflammatory phenotype remains unclear. Here, 5 we show that monocyte-derived proteomes from DADA2 patients are highly enriched in interferon response proteins. Using immunohistochemistry and detailed glycan analysis we demonstrate that ADA2 is post-translationally modified for sorting to the lysosomes. At acidic, lysosomal pH, ADA2 acts as a novel DNase that degrades cGAS/Sting-activating ligands. Furthermore, we define a clear structure-function relationship for this acidic

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Prevalence of CECR1 mutations in pediatric patients with polyarteritis nodosa, livedo reticularis and/or stroke

Cited by 2 publications

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ADA2 deficiency: case report of a new phenotype and novel mutation in two sisters

ADA2 deficiency: case report of a new phenotype and novel mutation in two sisters

ADA2 is a lysosomal DNase regulating the type-I interferon response

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