APOLD1

Inheritance Pattern: AD

Disease ID:MONDO:0021181

Submitter: ClinGen

The APOLD1 gene encodes an endothelial cell early response protein induced after ischemia and expected to regulate endothelial cell signaling and vascular function One variant, c.145_146delinsTA (p.Arg49Ter) in APOLD1 was reported in 4 members of a family with an unclassified bleeding disorder (Stritt et al., PMID:35638551). This variant results from a combination in cis of the common c.146G>A; p.R49Q (rs4763876) and the rare missense c.145C>T; p.R49W (rs757476941) nucleotide substitution in APOLD1. The mechanism of disorder is not completely clear, however, it has been proposed that loss of APOLD1 results in dysmorphic endothelial cells with reduced cell-cell junctions and increased permeability, potentially leading to a bleeding disorder. Evidence supporting this gene-disease relationship includes genetic evidences (case-level data) and experimental evidences (expression; functional alteration in non-patient cells, non-human model organisms). Summary of Case Level Data: 1.5 POINTS Variants in this gene have been reported in 4 probands in 1 publication (PMID: 35638551). Affected patients show an unusual type of spontaneous and trauma-related bleeding defect as they have normal coagulation and platelet function test parameters and do not respond to classical treatment with tranexamic acid or platelet transfusion. The use of vasodilators or aspirin worsened their bleeding tendency, and they developed microcirculatory symptoms, such as livedo reticularis after the administration of desmopressin and Raynaud syndrome. Summary of Experimental Data: 3.5 POINTS Regard B et al. showed that APOLD1 is rapidly induced in endothelial cells of cerebral vessels by seizures. APOLD1 mRNA is expressed in capillaries and in the cells lining the inner surface of veins and arteries, suggesting expression by endothelial cells (PMID 15102925). Stritt et al. showed that APOLD1 localizes to cell-cell junctions and Weibel-Palade bodies in endothelial cells and in platelet alpha granules (PMID 35638551). The same authors showed that APOLD1 silencing causes increase in cell size, altered shape, endothelial cell junction dismantling (reduction in the tight junction protein CLDN5 and PECAM1), markedly enhanced fibronectin fibrillogenesis and actin stress fiber formation, reminiscent of endothelial cell activation, and increased endothelial permeability to FITC-dextran. Fan et al demonstrated that Apold1 KO mice show impaired angiogenesis in the ischemic stroke border zone (PMID:36933174). In summary, we obtained limited association of APOLD1 with unclassified bleeding disorder. This classification was approved by the ClinGen Hemostasis Thrombosis Working Group on DATE (SOP Version 10).

Inheritance Pattern: AD

Disease ID:MONDO:0958229

Submitter: PanelApp Australia