Wouters Marjon, Ehlers Lisa, Van Eynde Wout, Kars Meltem Ece, Delafontaine Selket, Kienapfel Verena, Dzhus Mariia, Schrijvers Rik, De Haes Petra, Struyf Sofie, Bucciol Giorgia, Itan Yuval, Bolze Alexandre, Voet Arnout, Hombrouck Anneleen, Moens Leen, Ogunjimi Benson, Meyts Isabelle
Laboratory Inborn errors of Immunity, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium.
Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charite - Universitatsmedizin Berlin, corporate member of Freie Universitat Berlin and Humboldt-Universitat zu Berlin, Berlin, Germany.
medRxiv. 2024 Dec 11:2024.12.09.24317629. doi: 10.1101/2024.12.09.24317629.
Human ADA2 deficiency (DADA2) is an inborn error of immunity with a broad clinical phenotype which encompasses vasculopathy including livedo racemosa and lacunar strokes, as well as hemato-immunological features. Diagnosis is based on the combination of decreased serum ADA2 activity and the identification of biallelic deleterious alleles in the gene. DADA2 carriers harbor a single pathogenic variant in and are mostly considered healthy and asymptomatic. However, some DADA2 carriers present a phenotype compatible with DADA2. Here, we report ten patients from seven kindreds presenting with a phenotype indicative of DADA2, in whom only a single pathogenic variant (p.G47R, p.G47V, p.R169Q, p.H424N) was identified. To test whether being heterozygote for specific variants could explain the patients' phenotype, we investigated the effect of the ADA2 missense variants p.G47A, p.G47R, p.G47V, p.G47W, p.R169Q, p.E328K, p.T360A, p.N370K, p.H424N and p.Y453C on ADA2 protein expression, secretion and enzymatic activity. Functional studies indicate that they exert a dominant negative effect on ADA2 enzymatic activity, dimerization and/or secretion. At the molecular level, heterozygosity for these variants mimics what is observed in DADA2. We conclude that humans with heterozygous dominant negative missense variants in ADA2 are at risk of DADA2.
人类腺苷脱氨酶2缺乏症（DADA2）是一种先天性免疫缺陷病，具有广泛的临床表型，包括血管病变，如网状青斑和腔隙性脑卒中等，以及血液免疫学特征。诊断基于血清ADA2活性降低以及该基因中双等位基因有害变异的鉴定。DADA2携带者在该基因中存在一个致病性变异，大多被认为是健康且无症状的。然而，一些DADA2携带者表现出与DADA2相符的表型。在此，我们报告了来自七个家系的十名患者，他们表现出提示DADA2的表型，其中仅鉴定出一个致病性变异（p.G47R、p.G47V、p.R169Q、p.H424N）。为了测试特定变异的杂合性是否可以解释患者的表型，我们研究了ADA2错义变异p.G47A、p.G47R、p.G47V、p.G47W、p.R169Q、p.E328K、p.T360A、p.N370K、p.H424N和p.Y453C对ADA2蛋白表达、分泌和酶活性的影响。功能研究表明，它们对ADA2酶活性、二聚化和/或分泌具有显性负效应。在分子水平上，这些变异的杂合性模拟了DADA2中观察到的情况。我们得出结论，ADA2中具有杂合性显性负错义变异的人类有患DADA2的风险。
