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  • Introduction The lysosomal storage disorder Gaucher disease

    2024-04-02

    Introduction The lysosomal storage disorder Gaucher disease (Mendelian Inheritance in Man, OMIM #230800) results from the recessively inherited deficiency of lysosomal glucocerebrosidase (GCase, EC 3.2.1.45), caused by mutations in the gene GBA1 (MIM# 606463) located on chromosome 1q21. The enzymatic deficiency causes accumulation of the substrates glucosylceramide and glucosylsphingosine, primarily in cells of the reticuloendothelial system. Histologically, the disorder is characterized by the presence of lipid-laden Gaucher macrophages (Gaucher cells) in the spleen, liver, and bone marrow. These cells are believed to be primarily responsible for the visceral, hematologic, and bone pathology in affected individuals [1,2]. There are both non-neuronopathic (type 1) and neuronopathic (types 2 and 3) forms of Gaucher disease. Patients present with vast phenotypic heterogeneity, ranging from asymptomatic adults to early lethality. Enzyme Replacement Therapy and Substrate Reduction Therapy are effective in reversing disease manifestations in non-neuronopathic Gaucher disease, although response to therapy differs between patients and even siblings. There are over 300 known mutations in GBA1, with certain relevant genotype-phenotype associations, but in many cases, genotype cannot be used to predict prognosis or the response to therapy [3]. Because of this variability in phenotypes, there is a great need for biomarkers that might correlate with prognosis [4]. Several blood biomarkers have been identified for the biochemical monitoring of Gaucher disease [5]. Three of those most commonly used to reflect disease activity are chitotriosidase [6], angiotensin I-converting enzyme and 8-CPT-2Me-cAMP, sodium salt phosphatase – reviewed in [7]. Furthermore, studies in blood from patients with Gaucher disease also demonstrate >10-fold elevation in chemokines PARC/CCL18 [8] and macrophage inflammatory proteins (MIP)-1-α and MIP-1-β [9]. Most recently glucosylsphingosine was reported as a biomarker closely correlating with disease activity [10]. Of these markers, angiotensin I-converting enzyme (ACE, CD143, EC 3.4.15.1), a Zn2+ carboxydipeptidase with two catalytic centers [11], is a key regulator of blood pressure, and also participates in the development of vascular pathology and remodeling [12,13]. The somatic isoform of ACE is highly expressed as a type-I membrane glycoprotein in endothelial [14,15], epithelial and neuroepithelial cells [16,17], as well as in immune cells including macrophages and dendritic cells [18,19]. ACE is also known as CD143 [20,21]. In addition to membrane-bound ACE, a variable amount of soluble ACE lacking the transmembrane domain is present in blood and other biological fluids [22]. In a healthy individual, ACE found in blood originates primarily from the vast pulmonary microvasculature, which exhibits 100% ACE expression, compared to capillaries in the systemic circulation, which are 10–15% ACE-positive [15]. ACE enters the circulation via proteolytic treatment (shedding) from the endothelial cell surface by a yet unidentified ACE secretase [23]. In healthy individuals, the level of ACE in the blood is stable [24], whereas it is increased, 3–5-fold, in blood of subjects with sarcoidosis [25] or Gaucher disease [26,27], and it has been used as a clinical biomarker of disease severity [28,29]. A panel of 16 monoclonal antibodies (mAbs) has been developed that recognize different conformational epitopes on human ACE [30–32]. It has been shown that the pattern of mAb binding to ACE is a very sensitive marker of local ACE conformation. This pattern, known as the “conformational fingerprint of ACE”, reflects changes in the epitopes for the distinct mAbs, due to partial denaturation of the ACE globule, chemical modification, inhibitor binding, mutations, and different glycosylation/deglycosylation patterns [33–36]. Moreover, it was previously shown that this conformational fingerprint may detect conformationally changed ACE derived from different cell/tissue origins, including ACE from macrophages/dendritic cells [33], epithelial cells [35] or heart [37], versus ACE from lung endothelial cells. In disease states, such as sarcoidosis [33] or uremia [34], an altered ACE conformational fingerprint is observed.