126350
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In 3 patients from 2 unrelated families with autoinflammatory-pancytopenia syndrome (AIPCS; 619858), Rodero et al. (2017) identified homozygous missense mutations affecting conserved residues in the DNASE2 gene (G116A, 126350.0001 and D121V, 126350.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Neither was present in the gnomAD database. In vitro functional expression studies in patient fibroblasts and transfected HEK293 cells showed that the mutations caused reduced DNASE2 activity compared to controls. Expression of the wildtype protein in patient fibroblasts restored the DNASE2 activity. RNA-seq analysis of patient blood cells showed an upregulation of interferon-stimulated genes (ISGs), and patient serum showed increased levels of interferon-alpha (IFNA1; 147660) compared to controls. SiRNA-mediated knockdown of DNASE2 in control fibroblasts also resulted in increased ISG expression. These defects could be reversed in patient fibroblasts with expression of wildtype DNASE2. Unstimulated CD3+ T cells and CD14+ monocytes derived from the patients showed increased phosphorylation of STAT1 (600555) and STAT3 (102582), consistent with an inflammatory state. Rodero et al. (2017) noted that mice with homozygous loss of DNase2 accumulate undigested DNA from erythroblasts in the lysosomes of macrophages, which then chronically activates type I interferon production to result in a lethal perinatal anemia (see ANIMAL MODEL). Similar features of ineffective erythropoiesis were observed in the patients; liver biopsy in 1 patient showed increased numbers of Kupffer cells staining for hemosiderin, indicating increased phagocytosis of red blood cells. These findings suggested an important role for DNASE2 in hematopoiesis.
In a 14-year-old girl, born of consanguineous Somali parents, with AIPCS, Hong et al. (2020) identified a homozygous missense mutation in the DNASE2 gene (Y95C; 126350.0003). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies in COS7 cells showed that the Y95C mutation completely abolished DNASE2 activity, and patient-derived monocytes and macrophages showed impaired DNA clearance ability in lysosomes compared to controls. These findings were consistent with a loss of function.
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