GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension

Abstract

Portal hypertension is a major contributor to decompensation and death from liver disease, a global health problem. Here, we demonstrate homozygous damaging mutations in GIMAP5, a small organellar GTPase, in four families with unexplained portal hypertension. We show that GIMAP5 is expressed in hepatic endothelial cells and that its loss in both humans and mice results in capillarization of liver sinusoidal endothelial cells (LSECs); this effect is also seen when GIMAP5 is selectively deleted in endothelial cells. Single-cell RNA-sequencing analysis in a GIMAP5-deficient mouse model reveals replacement of LSECs with capillarized endothelial cells, a reduction of macrovascular hepatic endothelial cells, and places GIMAP5 upstream of GATA4, a transcription factor required for LSEC specification. Thus, GIMAP5 is a critical regulator of liver endothelial cell homeostasis and, when absent, produces portal hypertension. These findings provide new insight into the pathogenesis of portal hypertension, a major contributor to morbidity and mortality from liver disease.

GIMAP6 regulates autophagy, immune competence, and inflammation in mice and humans

“…A potentially life-threatening aspect of Pt 1’s disease is pulmonary hypertension. This is observed in immunodeficiency diseases and other GIMAP deficiencies ( Drzewiecki et al, 2021 ; Johnston et al, 2004 ). For GIMAP6, recurrent lung infections may cause aberrant lung vasculature leading to hypertension.…”

Challenges associated with diagnostic exome sequencing in liver diseases

“…To facilitate the WES analysis, we developed a list of 502 genes associated with a Mendelian disease with potential liver phenotypes ( Figure 3 ). Several new genetic disorders, such as TULP3 [41], KIF12, USP54 [42], KCNN3 [43,44], GIMAP5 [9] and so on, were discovered and recently reported to cause liver phenotypes. These discoveries coupled with their detailed annotated phenotypes provide an important resource to look for a genetic diagnosis for those patients with a related clinical phenotype and available WES result.…”

“…This work constitutes an initial attempt at a gene list for monogenic liver disease, but the list will have to be continuously annotated and updated to include new information about genes and variants. For example, we updated the list to include several genes ( TULP3 40 , KIF12, USP54 41 , KCNN3 42,43 , GIMAP5 9 ) which have been implicated in monogenic disorders associated with liver phenotypes during the performance of this study.…”

“…Subsequently, the cloning, mapping, and functional characterization of homeostatic iron regulator (HFE) gene in the 1990s paved a unique pathway for the diagnosis of hemochromatosis [3]. The advent of next-generation sequencing (NGS) approaches have led to the discovery of many novel genetic alterations causing liver phenotypes such as fibrolamellar hepatocellular carcinoma [4], recurrent acute liver failure [5][6][7], or idiopathic non-cirrhotic portal hypertension [8,9]. These findings demonstrate the power of NGS for identifying novel and poorly understood rare liver diseases.…”

NLR’s Analogs with Young Blood Cells in Monitoring of Toxicity of Long-Term Preventing Immunosuppression in the Liver Transplant’s Recipients

“…a shift may indicate the prevailing of capillarization over endothelial fenestration, fraught with portal hypertension[25]. Nevertheless, the main benefit of cytotoxic treatment appears to this time, i.e.…”