Portal_Hypertension_Noncirrhotic_2

Mendelian MONDO:0030397 Pathograph 27 Show in embeddings browser

Noncirrhotic portal hypertension 2 is an autosomal recessive disorder caused by biallelic loss-of-function variants in GIMAP5, which encodes a small organellar GTPase expressed selectively in lymphocytes and endothelial cells. It is distinctive on two counts. First, the portal hypertension arises from a primary endothelial lesion rather than from hepatocellular injury or fibrosis: losing GIMAP5 reduces GATA4, the transcription factor that specifies liver sinusoidal endothelial cell identity, and the sinusoids capillarize, raising intrahepatic vascular resistance in a liver that is not cirrhotic. Second, the same molecular lesion produces an inborn error of immunity in parallel, with lymphopenia, recurrent infection and autoimmune cytopenias, because GIMAP5 is required for lymphocyte survival as well. A unifying upstream step has been proposed for both arms: GIMAP5 restrains protein kinase CK2, and without it ceramide synthases run unchecked and long-chain ceramides accumulate, driving cellular senescence. The two arms are nonetheless mechanistically independent, which matters clinically - endothelial-specific deletion reproduces the capillarization on its own, and mice lacking mature lymphocytes still develop the liver disease, so transplanting the immune system is not expected to reverse established portal hypertension.

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1
Inheritance
8
Pathophys.
1
Histopath.
13
Phenotypes
2
Gaps
27
Pathograph
1
Genes
5
Variants
4
Medical Actions
3
Differentials
2
Models
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Two damaged alleles are required. Most reported index families are consanguineous with homozygous variants, and monoallelic carriers are generally healthy.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:33956074 SUPPORT Human Clinical
"we demonstrate homozygous damaging mutations in GIMAP5, a small organellar GTPase, in four families with unexplained portal hypertension"
Establishes the recessive, homozygous basis across four independent families.
PMID:42358996 SUPPORT Human Clinical
"Biallelic loss-of-function mutations in the GTPase of immunity-associated protein 5 (GIMAP5) cause a severe syndrome"
States the biallelic requirement directly.
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Discussions and Knowledge Gaps

2
Does correcting the haematopoietic compartment alter the course of the hepatic vascular disease in GIMAP5 deficiency?
KNOWLEDGE GAP OPEN hsct_will_not_reverse_portal_hypertension
Attached to
pathophysiology#Sinusoidal Capillarization treatments#Hematopoietic Cell Transplantation
The mouse evidence says the two arms are independent: endothelial-specific deletion reproduces the capillarization on its own, and the hepatic pathology persists in a Rag2-deficient background lacking mature B, T and NK cells, and cannot be adoptively transferred with marrow. The prediction is that haematopoietic transplantation will not reverse established portal hypertension. But this has not been tested in patients, and the untested question that matters is whether transplantation performed early, before capillarization is established, changes the hepatic trajectory. Because HSCT carries real mortality and is being weighed for the immune arm anyway, this gap sits directly on a clinical decision rather than beside one.
Show evidence (2 references)
PMID:18796632 SUPPORT Model Organism
"This pathology persists in a Rag2-deficient background in the absence of mature B, T, or NK cells and cannot be adoptively transferred by transplanting gimap5(-/-) bone marrow into wild-type recipients"
The lymphocyte-independence result on which the prediction rests.
PMID:33956074 SUPPORT Model Organism
"this effect is also seen when GIMAP5 is selectively deleted in endothelial cells"
The complementary result showing the endothelium alone is sufficient.
Does the CK2-ceramide senescence pathway account for the endothelial arm, or only the lymphocyte arm?
KNOWLEDGE GAP OPEN ceramide_pathway_to_endothelial_phenotype
Attached to
pathophysiology#Long-Chain Ceramide Accumulation pathophysiology#Reduced GATA4 in Liver Sinusoidal Endothelial Cells
The CK2-ceramide axis was demonstrated in T cells, where inhibiting CK2 or ceramide synthase rescues the cells. It is presented as a unifying mechanism for both arms of the disease, but the endothelial half of that claim is an extrapolation: no study has shown ceramide accumulation in liver sinusoidal endothelial cells, nor that CK2 or ceramide synthase inhibition prevents capillarization or reduces GATA4 loss. This matters because CK2 and ceramide-synthase inhibitors are the leading candidate targeted therapies, and whether they could address the portal hypertension or only the immune disease turns on exactly this question.
Proposed experiments
Ceramide profiling and CK2 inhibition in GIMAP5-deficient liver endothelium
lsec_ceramide_and_ck2_rescue
Measure long-chain ceramide species in liver sinusoidal endothelial cells isolated from endothelial-specific Gimap5 knockout mice against littermate controls, then test whether CK2 or ceramide-synthase inhibition prevents GATA4 loss and capillarization in the same model.
Readouts
Long-chain ceramide abundance in isolated LSECs
pathophysiology#Long-Chain Ceramide Accumulation
Direction: INCREASED
Interpretation: Accumulation in endothelium would extend the pathway beyond lymphocytes.
GATA4 expression after CK2 inhibition
pathophysiology#Reduced GATA4 in Liver Sinusoidal Endothelial Cells
Direction: RESTORED
Interpretation: Restoration would place the ceramide pathway upstream of the endothelial transcriptional defect.
Would support
pathophysiology#Long-Chain Ceramide Accumulation
Would refute
pathophysiology#Long-Chain Ceramide Accumulation
Supporting outcome
  • Ceramides accumulate in GIMAP5-deficient liver sinusoidal endothelial cells, and CK2 or ceramide-synthase inhibition preserves GATA4 expression and prevents capillarization.
Refuting outcome
  • Ceramide levels are unchanged in GIMAP5-deficient liver endothelium, or inhibition rescues lymphocytes while leaving capillarization and GATA4 loss unaffected, showing the endothelial arm runs through a different pathway.
Show evidence (1 reference)
PMID:38172257 SUPPORT In Vitro
"Inhibition of CK2 and CER synthase rescues GIMAP5-deficient T cells by preventing CER overaccumulation and cell deterioration"
The rescue is demonstrated in T cells; the endothelial equivalent is what is missing.
⚙

Pathophysiology

8
Biallelic GIMAP5 Loss of Function
Two damaged GIMAP5 alleles leave little or no functional GTPase. GIMAP5 is expressed selectively in lymphocytes and endothelial cells, which is what confines the disease to those two compartments despite the gene being lost everywhere.
Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION
GTPase activity GO:0003924 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves GTPase activity (GO:0003924), qualified as loss of function. GO:0003924 is a molecular function from the Gene Ontology. ⇓ LOSS OF FUNCTION
lysosomal membrane GO:0005765 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves lysosomal membrane (GO:0005765). GO:0005765 is a cellular component from the Gene Ontology.
Downstream
Unrestrained CK2 Activation of Ceramide Synthases GIMAP5 normally binds CK2 and attenuates its activation of ceramide synthases, so losing GIMAP5 removes that restraint.
Lymphocyte Apoptosis and Impaired Proliferation In lymphocytes, GIMAP5 loss also leaves GSK3-beta constitutively active, which constrains c-Myc induction and NFATc1 nuclear import and limits productive proliferation independently of the ceramide route.
Show evidence (1 reference)
PMID:38172257 SUPPORT In Vitro
"deficiency of GIMAP5, an evolutionarily conserved GTPase selectively expressed in lymphocytes and endothelial cells"
Establishes the restricted expression pattern that determines which tissues the disease affects. Graded IN_VITRO rather than HUMAN_CLINICAL because the quoted clause reports where the protein is expressed, which is an expression result, not a clinical observation about patients.
Unrestrained CK2 Activation of Ceramide Synthases
Without GIMAP5 to attenuate it, protein kinase CK2 over-activates ceramide synthases. This is the shared upstream step proposed for both arms of the disease.
ceramide metabolic process GO:0006672 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased ceramide metabolic process (GO:0006672). GO:0006672 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Long-Chain Ceramide Accumulation Over-active ceramide synthases produce ceramide faster than it is cleared.
Show evidence (1 reference)
PMID:38172257 SUPPORT In Vitro
"GIMAP5 controls CER abundance by interacting with protein kinase CK2 (CK2), attenuating its ability to activate CER synthases"
Identifies CK2 and the ceramide synthases as the immediate downstream effectors.
Long-Chain Ceramide Accumulation
Pathological accumulation of long-chain ceramides, the defining metabolic signature of GIMAP5 deficiency. That inhibiting either CK2 or ceramide synthase rescues the cells is what makes this a causal step rather than a correlate.
Downstream
Cellular Senescence in Endothelium and Lymphocytes Ceramide overaccumulation drives the senescent phenotype in the two cell types that express GIMAP5.
Show evidence (1 reference)
PMID:38172257 SUPPORT In Vitro
"Inhibition of CK2 and CER synthase rescues GIMAP5-deficient T cells by preventing CER overaccumulation and cell deterioration"
The rescue experiment establishing that the ceramide accumulation causes the cellular deterioration rather than accompanying it.
Cellular Senescence in Endothelium and Lymphocytes
Senescence and organelle dysfunction in the GIMAP5-expressing compartments. From here the disease divides into a hepatic vascular arm and an immune arm, which proceed independently of each other.
endothelial cell CL:0000115 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell (CL:0000115). CL:0000115 is a cell type from the Cell Ontology.
cellular senescence GO:0090398 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cellular senescence (GO:0090398). GO:0090398 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Reduced GATA4 in Liver Sinusoidal Endothelial Cells GIMAP5 is placed upstream of GATA4 by single-cell transcriptomics, but the steps connecting the ceramide and senescence pathway to GATA4 have not been demonstrated.
Show evidence (1 reference)
PMID:38172257 SUPPORT Human Clinical
"a new human genetic disease that causes cell senescence, liver and immune dysfunction, and early mortality"
Establishes senescence as the cellular endpoint of the shared pathway.
Reduced GATA4 in Liver Sinusoidal Endothelial Cells
Loss of GATA4, the transcription factor required to specify liver sinusoidal endothelial cell identity. This is the step that turns a generic endothelial defect into a specifically hepatic one.
liver sinusoidal endothelial cell CL:1000398 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves liver sinusoidal endothelial cell, annotated with endothelial cell of hepatic sinusoid (CL:1000398). CL:1000398 is a cell type from the Cell Ontology.
endothelial cell differentiation GO:0045446 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased endothelial cell differentiation (GO:0045446). GO:0045446 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Sinusoidal Capillarization Without GATA4 the sinusoidal endothelium loses its specialized identity and takes on a continuous, capillary-like phenotype.
Show evidence (1 reference)
PMID:33956074 SUPPORT Model Organism
"places GIMAP5 upstream of GATA4, a transcription factor required for LSEC specification"
Identifies GATA4 and its role in specifying the affected cell type.
Sinusoidal Capillarization
The specialized fenestrated sinusoidal endothelium is replaced by capillarized endothelium, and macrovascular hepatic endothelial cells are reduced. Critically this happens when GIMAP5 is deleted in endothelium alone, which is what establishes the lesion as endothelial-intrinsic rather than a consequence of the immune disease.
liver sinusoidal endothelial cell CL:1000398 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves liver sinusoidal endothelial cell, annotated with endothelial cell of hepatic sinusoid (CL:1000398). CL:1000398 is a cell type from the Cell Ontology.
hepatic sinusoid UBERON:0001281 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in hepatic sinusoid (UBERON:0001281). UBERON:0001281 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Endothelial-specific Gimap5 knockout mouse Mouse recapitulates Reproduces the defining endothelial phenotype without any haematopoietic manipulation, which is the cleanest available demonstration that the liver disease does not require the immune disease.
Downstream
Increased Intrahepatic Vascular Resistance Capillarized sinusoids, with nodular regenerative hyperplasia and obliterative portal venopathy, raise resistance to portal flow. The quantitative contribution of each histological change has not been partitioned.
Show evidence (2 references)
PMID:33956074 SUPPORT Model Organism
"this effect is also seen when GIMAP5 is selectively deleted in endothelial cells"
The endothelial-specific deletion experiment establishing cell-intrinsic causation.
PMID:33956074 SUPPORT Model Organism
"reveals replacement of LSECs with capillarized endothelial cells, a reduction of macrovascular hepatic endothelial cells"
Describes the cellular composition change by single-cell sequencing.
Increased Intrahepatic Vascular Resistance
Raised resistance to portal venous flow within a liver that is not cirrhotic. This is the defining haemodynamic abnormality, and the absence of cirrhosis, fibrosis and portal vein thrombosis is what makes the entity noncirrhotic portal hypertension rather than ordinary chronic liver disease.
portal vein UBERON:0002017 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in portal vein (UBERON:0002017). UBERON:0002017 is an anatomical location from the Uberon multi-species anatomy ontology. liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Germline Gimap5 knockout mouse Mouse fails to recapitulate The whole-body null develops liver failure through hepatocyte apoptosis and chronic hepatic haematopoiesis, not through the sinusoidal capillarization and portal hypertension that define the human disease.
Downstream
Portal hypertension The raised resistance is the portal hypertension.
Splenomegaly Portal congestion enlarges the spleen. The universal splenomegaly and the raised portal pressure are both reported, but no source states the causal step between them, so it is curated as an inference.
Esophageal varix Portosystemic collaterals decompress the hypertensive portal system through the oesophageal veins.
Nodular regenerative hyperplasia of liver The characteristic hepatic histology of the disorder, found on biopsy in the absence of cirrhosis.
Show evidence (1 reference)
PMID:33956074 SUPPORT Human Clinical
"He was found to have an increased portal pressure of 14 mm Hg (normal portal venous pressure ranges between 5 and 10 mm Hg)"
The one directly measured portal pressure in the cohort, establishing the haemodynamic abnormality rather than inferring it.
Lymphocyte Apoptosis and Impaired Proliferation
Spontaneous T and NK cell apoptosis with impaired proliferation. GIMAP5 has long been recognized as an anti-apoptotic factor required for lymphocyte survival, and this arm of the disease was characterized in rodents well before the human portal hypertension phenotype was described.
T cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology. natural killer cell CL:0000623 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves natural killer cell (CL:0000623). CL:0000623 is a cell type from the Cell Ontology.
negative regulation of apoptotic process GO:0043066 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of apoptotic process (GO:0043066). GO:0043066 is a biological process from the Gene Ontology. ↓ DECREASED T cell homeostasis GO:0043029 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased T cell homeostasis (GO:0043029). GO:0043029 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Germline Gimap5 knockout mouse Mouse recapitulates Impaired intrathymic maturation and compromised survival of postthymic CD4 and CD8 cells, with a block in NK and NKT development.
Downstream
Decreased total lymphocyte count Failure of lymphocyte survival and proliferation manifests as lymphopenia.
Recurrent infections Lymphopenia and T-cell exhaustion leave the patient susceptible to infection.
Autoimmune hemolytic anemia Immune dysregulation produces autoimmune cytopenias; how a survival defect in lymphocytes gives rise to autoimmunity rather than simple immunodeficiency is not resolved.
Show evidence (2 references)
PMID:18796632 SUPPORT Model Organism
"selective gene ablation of the mouse gimap5 gene impairs the final intrathymic maturation of CD8 and CD4 T cells and compromises the survival of postthymic CD4 and CD8 cells"
Establishes the survival defect in T cells on Gimap5 loss.
PMID:29382851 SUPPORT Human Clinical
"a human patient with a GIMAP5 loss-of-function mutation has lymphopenia and impaired T cell proliferation in vitro that can be rescued with GSK3 inhibitors"
Confirms the proliferation defect in a human patient and identifies a pharmacological rescue.
✶

Histopathology

1
Sinusoidal CD34 positivity with nodular regenerative hyperplasia
Liver biopsy shows nodular regenerative hyperplasia without cirrhosis, and CD34 immunostaining is positive in the sinusoidal endothelium. That CD34 stain is the histological correlate of the capillarization node in this entry: normal sinusoidal endothelium does not express CD34, so its appearance marks the loss of sinusoidal identity directly.
Show evidence (3 references)
PMID:33956074 SUPPORT Human Clinical
"CD34 immunostaining showed increased staining in the sinusoidal endothelium suggesting capillarization of the sinusoids"
The histological demonstration of capillarization in patient liver tissue.
PMID:33956074 SUPPORT Human Clinical
"The reticulin stain highlights the nodularity with zones of widened two-cell-thick plates bounded by a narrow, compressed cell plate consistent with nodular regenerative hyperplasia"
Documents the nodular regenerative hyperplasia on reticulin staining.
PMID:33956074 SUPPORT Human Clinical
"None had cirrhosis, splanchnic venous thrombosis, or other extrahepatic causes of portal hypertension"
The exclusion that makes the portal hypertension noncirrhotic, stated for the whole cohort.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Portal_Hypertension_Noncirrhotic_2 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

13
Blood 3
Thrombocytopenia VERY_FREQUENT HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33956074 SUPPORT Human Clinical
"thrombocytopenia, elevated transaminases, and esophageal varices were nearly universal (Table 1)"
Gives the near-universal frequency in the founding cohort, which is what the frequency grade rests on.
Decreased total lymphocyte count VERY_FREQUENT HP:0001888 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased total lymphocyte count (HP:0001888). HP:0001888 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29382851 SUPPORT Human Clinical
"a human patient with a GIMAP5 loss-of-function mutation has lymphopenia and impaired T cell proliferation in vitro"
Documents lymphopenia in a human patient.
Autoimmune hemolytic anemia OCCASIONAL HP:0001890 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autoimmune hemolytic anemia (HP:0001890). HP:0001890 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42358996 SUPPORT Human Clinical
"The 11-year-old proband presented with autoimmune cytopenias, severe viral infections, and early biochemical liver anomalies"
Documents autoimmune cytopenias in a genetically confirmed patient.
Cardiovascular 2
Portal hypertension OBLIGATE HP:0001409 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Portal hypertension (HP:0001409). HP:0001409 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33956074 SUPPORT Human Clinical
"four families with unexplained portal hypertension"
The presenting feature in every index family.
Splenomegaly VERY_FREQUENT HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744). HP:0001744 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33956074 SUPPORT Human Clinical
"All affected subjects have splenomegaly"
Gives both the finding and its frequency in the founding cohort of nine patients.
PMID:38055739 SUPPORT Model Organism
"caused lymphopenia, splenomegaly, progressive liver pathology, and extramedullary hematopoiesis (EMH)"
The orthologous lesion reproduces the splenomegaly in the model system, corroborating the human finding rather than standing in for it.
Digestive 5
Esophageal varix VERY_FREQUENT HP:0002040 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Esophageal varix (HP:0002040). HP:0002040 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33956074 SUPPORT Human Clinical
"thrombocytopenia, elevated transaminases, and esophageal varices were nearly universal (Table 1)"
Gives the frequency directly in the founding cohort.
Nodular regenerative hyperplasia of liver FREQUENT HP:0011954 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nodular regenerative hyperplasia of liver (HP:0011954). HP:0011954 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42358996 SUPPORT Human Clinical
"GIMAP5 deficiency drives a distinct vascular remodeling characterized by nodular regenerative hyperplasia (NRH) and porto-sinusoidal vascular disorder (PSVD), frequently progressing to non-cirrhotic portal hypertension"
States the histology and its progression to portal hypertension for this disease specifically.
Hepatomegaly FREQUENT HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33956074 SUPPORT Human Clinical
"He was found to have hepatosplenomegaly at 2 yr of age"
Records hepatomegaly directly, in a genetically confirmed patient and at the age it was detected.
Ascites OCCASIONAL HP:0001541 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ascites (HP:0001541). HP:0001541 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33956074 SUPPORT Human Clinical
"from liver failure and portal hypertension complications, including hyperbilirubinemia, ascites, and encephalopathy"
Records ascites among the portal-hypertension complications in this cohort.
Hepatocellular carcinoma OCCASIONAL HP:0001402 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatocellular carcinoma (HP:0001402). HP:0001402 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33956074 SUPPORT Human Clinical
"one 2-cm hepatic lesion with arterial enhancement and portal venous washout highly suspicious for hepatocellular carcinoma"
The finding as reported, with the source's own hedge that it is suspicious on imaging rather than confirmed.
Immune 1
Recurrent infections FREQUENT HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42358996 SUPPORT Human Clinical
"cause a severe syndrome characterized by altered immunity, lymphoproliferation, and progressive hepatopathy"
Establishes altered immunity as a core component.
Metabolism 2
Elevated circulating hepatic transaminase concentration VERY_FREQUENT HP:0002910 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating hepatic transaminase concentration (HP:0002910). HP:0002910 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33956074 SUPPORT Human Clinical
"thrombocytopenia, elevated transaminases, and esophageal varices were nearly universal (Table 1)"
Gives the near-universal frequency in the founding cohort.
Elevated gamma-glutamyltransferase level OCCASIONAL HP:0030948 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated gamma-glutamyltransferase level (HP:0030948). HP:0030948 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33956074 SUPPORT Human Clinical
"His laboratory tests were remarkable for pancytopenia and elevation of liver transaminases and γ-glutamyl transferase"
Records the GGT elevation in a confirmed patient.
🧬

Genetic Associations

1
GIMAP5
Gene: GIMAP5 hgnc:18005 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GIMAP5 (hgnc:18005). hgnc:18005 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:33956074 SUPPORT Human Clinical
"we demonstrate homozygous damaging mutations in GIMAP5, a small organellar GTPase, in four families with unexplained portal hypertension"
The gene-discovery study.
PMID:33956074 SUPPORT Human Clinical
"Notably, all four mutations (p.I47T, p.P109L, p.L204P, and p.L223F) lead to loss of GIMAP5 protein expression"
The mechanistically important convergence. Four different missense substitutions, in four different kindreds, all produce the same consequence of absent protein, which is what makes this a clean loss of function rather than a set of allele-specific effects.
Variants (5)
p.Leu204Pro
The recurrent allele, seen homozygously and in compound heterozygosity across independent reports. It is the most frequent of the reported variants in population databases, which is why it is the one most likely to be encountered.
Functional effects
GIMAP5 GTPase activity
Loss of function; the substitution maps to the AIG1-type G domain.
Show evidence (1 reference)
PMID:42358996 SUPPORT Human Clinical
"Genetic analysis identified compound heterozygous variants (p.Leu204Pro and p.Arg214Ter) in GIMAP5 gene resulting in absent protein expression"
Reports this allele in compound heterozygosity with a nonsense allele, leaving no detectable protein.
p.Ile47Thr
Homozygous in two affected siblings of kindred 1, the offspring of a first-cousin union. Absent from gnomAD.
Functional effects
GIMAP5 GTPase activity
Loss of function; abolishes GIMAP5 protein expression.
Show evidence (1 reference)
PMID:33956074 SUPPORT Human Clinical
"In kindred 1, two affected siblings, the offspring of a first cousin union, were homozygous for a variant encoding a p.I47T substitution"
Reports the allele, its zygosity and the consanguineous pedigree.
p.Leu223Phe
Homozygous in four affected members of kindred 2, the largest single sibship in the founding cohort. Note the source is internally inconsistent about this residue: the running text and the summary of all four mutations give p.L223F, while the pedigree figure legend gives p.L223P. The text form is used here and the discrepancy is recorded rather than silently resolved.
Functional effects
GIMAP5 GTPase activity
Loss of function; abolishes GIMAP5 protein expression.
Show evidence (1 reference)
PMID:33956074 SUPPORT Human Clinical
"Four affected subjects were homozygous for the p.L223F variant, which also has an allele frequency of 0 in gnomAD"
Reports the allele, the number of homozygotes and its absence from population databases.
p.Pro109Leu
Homozygous in a child of a first-cousin union with noncirrhotic portal hypertension. Seen once in more than 251,400 sequenced alleles.
Functional effects
GIMAP5 GTPase activity
Loss of function; abolishes GIMAP5 protein expression.
Show evidence (1 reference)
PMID:33956074 SUPPORT Human Clinical
"In kindred 3, a child of a first cousin union with noncirrhotic portal hypertension was homozygous for a p.P109L substitution"
Reports the allele and the phenotype it segregates with.
p.Arg214Ter
A nonsense allele reported in compound heterozygosity with p.Leu204Pro, in a combination that leaves no detectable GIMAP5 protein.
Functional effects
GIMAP5 GTPase activity
Loss of function through premature termination.
Show evidence (1 reference)
PMID:42358996 SUPPORT Human Clinical
"Genetic analysis identified compound heterozygous variants (p.Leu204Pro and p.Arg214Ter) in GIMAP5 gene resulting in absent protein expression"
Reports the allele pair and the absent-protein consequence directly.
💊

Medical Actions

4
Variceal Prophylaxis with Nonselective Beta-Blockade
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: propranolol CHEBI:8499 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses propranolol (CHEBI:8499). CHEBI:8499 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Nonselective beta-blockade to lower portal pressure and reduce variceal bleeding risk, alongside endoscopic surveillance and band ligation. This is standard portal-hypertension care rather than anything specific to GIMAP5 deficiency.
Mechanism Target:
Increased Intrahepatic Vascular Resistance — Beta-blockade reduces portal inflow and pressure; it does not act on the endothelial lesion.
Show evidence (1 reference)
PMID:33956074 SUPPORT INDIRECT Human Clinical
"Esophageal varices, a consequence of increased portal pressure, were confirmed in seven subjects by endoscopy"
Establishes the raised portal pressure and the varices that prophylaxis targets. The efficacy of beta-blockade in this disorder specifically has not been studied.
Show evidence (1 reference)
PMID:33956074 SUPPORT INDIRECT Human Clinical
"Notably, three affected individuals in kindred 2 are deceased; two of them died from complications of portal hypertension"
Establishes that portal-hypertension complications are lethal in this disease, which is what motivates prophylaxis. No GIMAP5-specific trial evidence exists.
Sirolimus for Autoimmune Cytopenias
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: sirolimus CHEBI:9168 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sirolimus (CHEBI:9168). CHEBI:9168 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
An mTOR inhibitor used for the immune arm, reported to achieve sustained remission of the autoimmune cytopenias in the most recently published case.
Mechanism Target:
Lymphocyte Apoptosis and Impaired Proliferation — Acts on the immune arm of the disease and not on the hepatic vascular arm.
Show evidence (1 reference)
PMID:42358996 SUPPORT Human Clinical
"Targeted therapies, particularly mTORC1 inhibitors like sirolimus, offer a compelling strategy to reverse the metabolic and senescent defects observed in patient lymphocytes"
States that the agent acts on the lymphocyte compartment, which is the arm this link targets.
Show evidence (1 reference)
PMID:42358996 SUPPORT Human Clinical
"the proband achieved sustained clinical remission of cytopenias through immunomodulation with the mTOR inhibitor sirolimus"
Reports the observed response of the autoimmune cytopenias to sirolimus.
Liver Transplantation
Action: Liver TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Liver Transplantation (NCIT:C15271). NCIT:C15271 is a clinical intervention from the NCI Thesaurus. NCIT:C15271
Platform: Surgery
Considered for end-stage hepatic disease. It is mechanistically rational here in a way it is not for many multisystem disorders, because the causal lesion for the hepatic arm is intrinsic to the liver endothelium and would be replaced along with the organ.
Mechanism Target:
Sinusoidal Capillarization — Replacing the liver replaces the capillarized endothelium that carries the lesion.
Show evidence (1 reference)
PMID:33956074 SUPPORT INDIRECT Model Organism
"this effect is also seen when GIMAP5 is selectively deleted in endothelial cells"
The endothelial-intrinsic nature of the lesion is what makes organ replacement a coherent strategy; no transplant outcome in this disease has been reported.
Show evidence (1 reference)
PMID:33956074 SUPPORT INDIRECT Human Clinical
"GIMAP5 is a critical regulator of liver endothelial cell homeostasis and, when absent, produces portal hypertension"
Establishes the hepatic-endothelial locus of disease that motivates transplantation.
Hematopoietic Cell Transplantation
Action: Hematopoietic Cell TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Hematopoietic Cell Transplantation (NCIT:C15431). NCIT:C15431 is a clinical intervention from the NCI Thesaurus. NCIT:C15431
Platform: Cell therapy
Considered definitive for the immune and haematological disease. The important caveat is mechanistic: because the hepatic lesion is endothelial-intrinsic and lymphocyte-independent, transplanting the haematopoietic system is not expected to reverse established portal hypertension, so the risk-benefit calculation cannot treat it as a cure for the whole disease.
Mechanism Target:
Lymphocyte Apoptosis and Impaired Proliferation — Replaces the GIMAP5-deficient lymphoid compartment, addressing the immune arm alone.
Show evidence (1 reference)
PMID:18796632 SUPPORT Model Organism
"Development of NK/NKT cells is restored on transfer of gimap5(-/-) bone marrow into a wild-type environment"
Shows the lymphoid defect is correctable by changing the haematopoietic environment, which is the principle transplantation relies on.
Show evidence (1 reference)
PMID:18796632 REFUTE Model Organism
"This pathology persists in a Rag2-deficient background in the absence of mature B, T, or NK cells and cannot be adoptively transferred by transplanting gimap5(-/-) bone marrow into wild-type recipients"
Contradicts the expectation that haematopoietic transplantation addresses the liver disease. The hepatic pathology occurs without mature lymphocytes and is not transferable with marrow.
🔬

Diagnosis

4
Exome or genome sequencing for biallelic GIMAP5 variants
The definitive diagnostic. The disorder was discovered by exome sequencing and there is no biochemical screening test, so molecular confirmation is how the diagnosis is made.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:33956074 SUPPORT Human Clinical
"Seven affected individuals from these families were subjected to whole-exome sequencing to high depth of coverage across all coding bases and flanking intronic segments"
The method by which the diagnosis was established in the founding cohort.
GIMAP5 protein expression by immunoblot
A genuinely discriminating functional test, because every reported disease allele converges on the same consequence: loss of GIMAP5 protein. That makes absent protein on immunoblot informative for a variant of uncertain significance in a way a sequence result alone is not.
protein expression analysis NCIT:C25294 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:33956074 SUPPORT Human Clinical
"Notably, all four mutations (p.I47T, p.P109L, p.L204P, and p.L223F) lead to loss of GIMAP5 protein expression"
The convergence of every reported allele on absent protein is what makes the immunoblot diagnostically useful.
PMID:42358996 SUPPORT Human Clinical
"Genetic analysis identified compound heterozygous variants (p.Leu204Pro and p.Arg214Ter) in GIMAP5 gene resulting in absent protein expression"
A later case in which the same absent-protein result was used alongside sequencing.
Direct portal venography
Measures the portal pressure itself. Performed in one patient of the founding cohort, and the only direct haemodynamic measurement reported in this disease.
portal venography NCIT:C190556 NCI Thesaurus (NCIT)
One patient only. The measured pressure was 14 mm Hg against a normal range of 5-10 mm Hg.
Show evidence (1 reference)
PMID:33956074 SUPPORT Human Clinical
"Subject P4-1 was the only individual in this cohort who underwent a direct portal venogram"
Records that the measurement was made, and in how many patients.
Upper endoscopy for variceal surveillance
Confirms and grades oesophageal varices, and is the surveillance test that drives prophylaxis decisions.
upper gastrointestinal endoscopy NCIT:C16546 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:33956074 SUPPORT Human Clinical
"Esophageal varices, a consequence of increased portal pressure, were confirmed in seven subjects by endoscopy"
Endoscopic confirmation in seven of nine patients.
📈

Progression

2
Childhood presentation with portal hypertension
Age: Early childhood to adolescence
Presentation is typically in childhood, with splenomegaly, cytopenias and variceal bleeding. One patient was found to have hepatosplenomegaly at two years of age and another was first evaluated at thirteen for ecchymosis.
Show evidence (1 reference)
PMID:33956074 SUPPORT Human Clinical
"He was found to have hepatosplenomegaly at 2 yr of age"
Gives the youngest documented age at detection in the founding cohort.
Progressive liver disease and death from portal-hypertension complications
The hepatic disease progresses. Three affected individuals in one kindred are deceased, two of them from complications of portal hypertension, and one patient developed direct hyperbilirubinemia and worsening coagulopathy after shunt surgery. This is what makes the disorder more than a haematological curiosity and is the reason transplantation is discussed at all.
Show evidence (2 references)
PMID:33956074 SUPPORT Human Clinical
"Notably, three affected individuals in kindred 2 are deceased; two of them died from complications of portal hypertension"
Establishes mortality from the hepatic arm of the disease.
PMID:33956074 SUPPORT Human Clinical
"His most recent blood work revealed direct hyperbilirubinemia and worsening coagulopathy consistent with progression of underlying liver disease"
Documents progression of the liver disease in an individual patient despite shunt surgery.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Roughly twenty to twenty-five patients have been reported. The largest single addition was four families in the gene-discovery study; a 2026 review collected twenty previously published patients alongside one new case. No population rate has been estimated.
Show evidence (1 reference)
PMID:42358996 SUPPORT Human Clinical
"reporting the first Italian pediatric case alongside his mono-allelic carrier twin, integrated with a review of twenty previously published patients"
Gives the published patient count at the time of the most recent review.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Portal_Hypertension_Noncirrhotic_2:

Other genetic causes of porto-sinusoidal vascular disorder
Overlapping Features A broad differential: more than thirty genes have been associated with porto-sinusoidal vascular disorder, some as part of syndromes and some as isolated disease. GIMAP5 sits among the isolated-PSVD genes, and the striking observation across the whole set is that these genes are predominantly expressed in immune cells.
Show evidence (2 references)
PMID:38900412 SUPPORT Human Clinical
"We identified 34 genes and 1 chromosomal abnormality associated with PSVD in the literature"
Gives the size of the genetic differential.
PMID:38900412 SUPPORT Human Clinical
"we found that these genes are predominantly expressed in immune cells, suggesting that these cells may play a more important role in the development of PSVD than previously thought"
Places the GIMAP5 immune-endothelial duality within a broader pattern across PSVD genes.
Drug-induced noncirrhotic portal hypertension
Overlapping Features Acquired phenocopies exist and must be excluded, notably didanosine exposure. The connection is not merely clinical: didanosine lowers deoxyguanosine kinase levels, which is the same protein whose loss causes the inherited NCPH1, so the acquired and inherited forms may converge mechanistically.
Show evidence (1 reference)
PMID:26874653 SUPPORT Human Clinical
"treatment of patients with human immunodeficiency viral infection with the nucleoside analogue didanosine is known to cause portal hypertension in a subset of patients and lowers deoxyguanosine kinase levels in vitro"
Documents the acquired phenocopy and the shared molecular target.
🐁

Animal Models

2
Endothelial-specific Gimap5 knockout mouse
The model that isolates the hepatic vascular arm. Deleting Gimap5 in endothelium alone reproduces the sinusoidal capillarization, which is what establishes the lesion as cell-intrinsic to the endothelium.
Species
Mouse
Genotype
Endothelial-cell-conditional Gimap5 deletion
Publication
PMID:33956074
Pathograph links
Sinusoidal Capillarization recapitulates fidelity: high Reproduces the defining endothelial phenotype without any haematopoietic manipulation, which is the cleanest available demonstration that the liver disease does not require the immune disease.
Limitations: A conditional deletion models the endothelial arm in isolation and therefore says nothing about the immune arm or about how the two interact in a patient carrying the variant in every cell.
Readouts
Liver sinusoidal endothelial cell capillarization
Direction: INCREASED
Interpretation: The defining histological readout of this node.
Show evidence (1 reference)
PMID:33956074 SUPPORT Model Organism
"this effect is also seen when GIMAP5 is selectively deleted in endothelial cells"
Reports the capillarization in the endothelial-specific deletion.
Show evidence (1 reference)
PMID:33956074 SUPPORT Model Organism
"Single-cell RNA-sequencing analysis in a GIMAP5-deficient mouse model reveals replacement of LSECs with capillarized endothelial cells"
The mouse measurement establishing that the model reproduces the endothelial phenotype under study.
Germline Gimap5 knockout mouse
The whole-body null, which carries both arms of the disease and was characterized well before the human portal hypertension phenotype was described. Its most informative result for this entry is a negative one: the liver pathology persists when mature lymphocytes are absent.
Species
Mouse
Genotype
Gimap5 germline knockout
Publication
PMID:18796632
Pathograph links
Lymphocyte Apoptosis and Impaired Proliferation recapitulates fidelity: high Impaired intrathymic maturation and compromised survival of postthymic CD4 and CD8 cells, with a block in NK and NKT development.
Limitations: Median survival is about fifteen weeks, which is too short to model a chronic progressive disease, and the dominant hepatic phenotype in this model is hepatocyte apoptosis and liver failure rather than the capillarization and portal hypertension seen in patients.
Readouts
Peripheral CD4 and CD8 T cell survival
Direction: DECREASED
Interpretation: The lymphocyte survival defect that defines this node.
Show evidence (1 reference)
PMID:18796632 SUPPORT Model Organism
"compromises the survival of postthymic CD4 and CD8 cells, replicating findings in the BB rat model"
Reports the survival defect and its concordance with the rat model.
Show evidence (1 reference)
PMID:18796632 SUPPORT Model Organism
"selective gene ablation of the mouse gimap5 gene impairs the final intrathymic maturation of CD8 and CD4 T cells"
Establishes the model as informative for the lymphoid node.
Increased Intrahepatic Vascular Resistance fails to recapitulate fidelity: low The whole-body null develops liver failure through hepatocyte apoptosis and chronic hepatic haematopoiesis, not through the sinusoidal capillarization and portal hypertension that define the human disease.
Limitations: This model dies at a median of fifteen weeks from a hepatocellular rather than a vascular lesion, so it cannot be used to study portal hypertension even though it is the most complete genetic null available. The endothelial-specific deletion is the model for that arm.
Show evidence (2 references)
PMID:18796632 REFUTE Model Organism
"in later stages show pronounced hepatocyte apoptosis, leading to liver failure"
The hepatic phenotype reported in this model is hepatocyte apoptosis and liver failure, which is not the noncirrhotic portal hypertension of the human disease.
+ 1 more reference
{ }

Source YAML

click to show 
name: Portal_Hypertension_Noncirrhotic_2
category: Mendelian
creation_date: '2026-09-01T23:50:00Z'
description: >-
  Noncirrhotic portal hypertension 2 is an autosomal recessive disorder caused
  by biallelic loss-of-function variants in GIMAP5, which encodes a small
  organellar GTPase expressed selectively in lymphocytes and endothelial cells.
  It is distinctive on two counts. First, the portal hypertension arises from a
  primary endothelial lesion rather than from hepatocellular injury or
  fibrosis: losing GIMAP5 reduces GATA4, the transcription factor that
  specifies liver sinusoidal endothelial cell identity, and the sinusoids
  capillarize, raising intrahepatic vascular resistance in a liver that is not
  cirrhotic. Second, the same molecular lesion produces an inborn error of
  immunity in parallel, with lymphopenia, recurrent infection and autoimmune
  cytopenias, because GIMAP5 is required for lymphocyte survival as well. A
  unifying upstream step has been proposed for both arms: GIMAP5 restrains
  protein kinase CK2, and without it ceramide synthases run unchecked and
  long-chain ceramides accumulate, driving cellular senescence. The two arms
  are nonetheless mechanistically independent, which matters clinically -
  endothelial-specific deletion reproduces the capillarization on its own, and
  mice lacking mature lymphocytes still develop the liver disease, so
  transplanting the immune system is not expected to reverse established portal
  hypertension.
disease_term:
  preferred_term: portal hypertension, noncirrhotic, 2
  term:
    id: MONDO:0030397
    label: portal hypertension, noncirrhotic, 2
synonyms:
- NCPH2
- PHNC2
- GIMAP5 deficiency
- GIMAP5-related noncirrhotic portal hypertension
- GIMAP5-related porto-sinusoidal vascular disorder
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Two damaged alleles are required. Most reported index families are
    consanguineous with homozygous variants, and monoallelic carriers are
    generally healthy.
  evidence:
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we demonstrate homozygous damaging mutations in GIMAP5, a small organellar
      GTPase, in four families with unexplained portal hypertension
    explanation: Establishes the recessive, homozygous basis across four independent
      families.
  - reference: PMID:42358996
    reference_title: "Unexpected genetically determined immune dysregulation with liver involvement: GIMAP5 therapeutic dilemmas between targeted therapy and HSCT."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Biallelic loss-of-function mutations in the GTPase of immunity-associated
      protein 5 (GIMAP5) cause a severe syndrome
    explanation: States the biallelic requirement directly.
genetic:
- name: GIMAP5
  gene_term:
    preferred_term: GIMAP5
    term:
      id: hgnc:18005
      label: GIMAP5
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we demonstrate homozygous damaging mutations in GIMAP5, a small organellar
      GTPase, in four families with unexplained portal hypertension
    explanation: The gene-discovery study.
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Notably, all four mutations (p.I47T, p.P109L, p.L204P, and p.L223F) lead
      to loss of GIMAP5 protein expression'
    explanation: >-
      The mechanistically important convergence. Four different missense
      substitutions, in four different kindreds, all produce the same consequence
      of absent protein, which is what makes this a clean loss of function rather
      than a set of allele-specific effects.
  variants:
  - name: p.Leu204Pro
    description: >-
      The recurrent allele, seen homozygously and in compound heterozygosity
      across independent reports. It is the most frequent of the reported
      variants in population databases, which is why it is the one most likely
      to be encountered.
    functional_effects:
    - function: GIMAP5 GTPase activity
      description: Loss of function; the substitution maps to the AIG1-type G domain.
    evidence:
    - reference: PMID:42358996
      reference_title: "Unexpected genetically determined immune dysregulation with liver involvement: GIMAP5 therapeutic dilemmas between targeted therapy and HSCT."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Genetic analysis identified compound heterozygous variants (p.Leu204Pro
        and p.Arg214Ter) in GIMAP5 gene resulting in absent protein expression
      explanation: Reports this allele in compound heterozygosity with a nonsense
        allele, leaving no detectable protein.
  - name: p.Ile47Thr
    description: Homozygous in two affected siblings of kindred 1, the offspring of
      a first-cousin union. Absent from gnomAD.
    functional_effects:
    - function: GIMAP5 GTPase activity
      description: Loss of function; abolishes GIMAP5 protein expression.
    evidence:
    - reference: PMID:33956074
      reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In kindred 1, two affected siblings, the offspring of a first cousin
        union, were homozygous for a variant encoding a p.I47T substitution
      explanation: Reports the allele, its zygosity and the consanguineous pedigree.
  - name: p.Leu223Phe
    description: >-
      Homozygous in four affected members of kindred 2, the largest single
      sibship in the founding cohort. Note the source is internally inconsistent
      about this residue: the running text and the summary of all four mutations
      give p.L223F, while the pedigree figure legend gives p.L223P. The text form
      is used here and the discrepancy is recorded rather than silently resolved.
    functional_effects:
    - function: GIMAP5 GTPase activity
      description: Loss of function; abolishes GIMAP5 protein expression.
    evidence:
    - reference: PMID:33956074
      reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Four affected subjects were homozygous for the p.L223F variant, which
        also has an allele frequency of 0 in gnomAD
      explanation: Reports the allele, the number of homozygotes and its absence from
        population databases.
  - name: p.Pro109Leu
    description: Homozygous in a child of a first-cousin union with noncirrhotic portal
      hypertension. Seen once in more than 251,400 sequenced alleles.
    functional_effects:
    - function: GIMAP5 GTPase activity
      description: Loss of function; abolishes GIMAP5 protein expression.
    evidence:
    - reference: PMID:33956074
      reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In kindred 3, a child of a first cousin union with noncirrhotic portal
        hypertension was homozygous for a p.P109L substitution
      explanation: Reports the allele and the phenotype it segregates with.
  - name: p.Arg214Ter
    description: A nonsense allele reported in compound heterozygosity with p.Leu204Pro,
      in a combination that leaves no detectable GIMAP5 protein.
    functional_effects:
    - function: GIMAP5 GTPase activity
      description: Loss of function through premature termination.
    evidence:
    - reference: PMID:42358996
      reference_title: "Unexpected genetically determined immune dysregulation with liver involvement: GIMAP5 therapeutic dilemmas between targeted therapy and HSCT."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Genetic analysis identified compound heterozygous variants (p.Leu204Pro
        and p.Arg214Ter) in GIMAP5 gene resulting in absent protein expression
      explanation: Reports the allele pair and the absent-protein consequence
        directly.
  notes: >-
    All reported disease alleles are germline and recessive, and most are
    missense substitutions in or near the AIG1-type G domain; at least one
    nonsense allele is reported. Every reported allele converges on loss of
    GIMAP5 protein expression, which is both the mechanism and the basis for the
    immunoblot as a diagnostic test. GIMAP5 is loss-of-function tolerant at the
    population level, which is consistent with heterozygous carriers being
    unaffected. Note that the stability of GIMAP5 depends on the lysosomal
    MFSD1-GLMP complex, so MFSD1 and GLMP are candidate biological modifiers
    rather than established ones.
pathophysiology:
- name: Biallelic GIMAP5 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Two damaged GIMAP5 alleles leave little or no functional GTPase. GIMAP5 is
    expressed selectively in lymphocytes and endothelial cells, which is what
    confines the disease to those two compartments despite the gene being lost
    everywhere.
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
  molecular_functions:
  - preferred_term: GTPase activity
    term:
      id: GO:0003924
      label: GTPase activity
    modifier: LOSS_OF_FUNCTION
  cellular_components:
  - preferred_term: lysosomal membrane
    term:
      id: GO:0005765
      label: lysosomal membrane
  evidence:
  - reference: PMID:38172257
    reference_title: "GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: deficiency of GIMAP5, an evolutionarily conserved GTPase selectively expressed
      in lymphocytes and endothelial cells
    explanation: >-
      Establishes the restricted expression pattern that determines which tissues
      the disease affects. Graded IN_VITRO rather than HUMAN_CLINICAL because the
      quoted clause reports where the protein is expressed, which is an expression
      result, not a clinical observation about patients.
  downstream:
  - target: Unrestrained CK2 Activation of Ceramide Synthases
    causal_link_type: DIRECT
    description: GIMAP5 normally binds CK2 and attenuates its activation of ceramide
      synthases, so losing GIMAP5 removes that restraint.
    evidence:
    - reference: PMID:38172257
      reference_title: "GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: GIMAP5 controls CER abundance by interacting with protein kinase CK2
        (CK2), attenuating its ability to activate CER synthases
      explanation: States the direct molecular interaction and what its loss releases.
  - target: Lymphocyte Apoptosis and Impaired Proliferation
    causal_link_type: DIRECT
    description: >-
      In lymphocytes, GIMAP5 loss also leaves GSK3-beta constitutively active,
      which constrains c-Myc induction and NFATc1 nuclear import and limits
      productive proliferation independently of the ceramide route.
    evidence:
    - reference: PMID:29382851
      reference_title: "Gimap5-dependent inactivation of GSK3\u03b2 is required for CD4(+) T cell homeostasis and prevention of immune pathology."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: In the absence of Gimap5, constitutive GSK3beta activity constrains
        c-Myc induction and NFATc1 nuclear import, thereby limiting productive CD4+
        T cell proliferation
      explanation: Gives the second, GSK3-beta-dependent route from GIMAP5 loss to
        the lymphocyte phenotype.
- name: Unrestrained CK2 Activation of Ceramide Synthases
  biological_scale: MOLECULAR
  description: >-
    Without GIMAP5 to attenuate it, protein kinase CK2 over-activates ceramide
    synthases. This is the shared upstream step proposed for both arms of the
    disease.
  biological_processes:
  - preferred_term: ceramide metabolic process
    term:
      id: GO:0006672
      label: ceramide metabolic process
    modifier: INCREASED
  evidence:
  - reference: PMID:38172257
    reference_title: "GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: GIMAP5 controls CER abundance by interacting with protein kinase CK2 (CK2),
      attenuating its ability to activate CER synthases
    explanation: Identifies CK2 and the ceramide synthases as the immediate downstream
      effectors.
  downstream:
  - target: Long-Chain Ceramide Accumulation
    causal_link_type: DIRECT
    description: Over-active ceramide synthases produce ceramide faster than it is
      cleared.
    evidence:
    - reference: PMID:38172257
      reference_title: "GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We show that GIMAP5 restricts the pathological accumulation of long-chain
        ceramides (CERs), thereby regulating longevity
      explanation: States the accumulation and its consequence for cell longevity.
- name: Long-Chain Ceramide Accumulation
  biological_scale: MOLECULAR
  description: >-
    Pathological accumulation of long-chain ceramides, the defining metabolic
    signature of GIMAP5 deficiency. That inhibiting either CK2 or ceramide
    synthase rescues the cells is what makes this a causal step rather than a
    correlate.
  chemical_entities:
  - preferred_term: ceramide
    term:
      id: CHEBI:17761
      label: ceramide
    modifier: INCREASED
  evidence:
  - reference: PMID:38172257
    reference_title: "GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Inhibition of CK2 and CER synthase rescues GIMAP5-deficient T cells by
      preventing CER overaccumulation and cell deterioration
    explanation: The rescue experiment establishing that the ceramide accumulation
      causes the cellular deterioration rather than accompanying it.
  downstream:
  - target: Cellular Senescence in Endothelium and Lymphocytes
    causal_link_type: DIRECT
    description: Ceramide overaccumulation drives the senescent phenotype in the two
      cell types that express GIMAP5.
    evidence:
    - reference: PMID:38172257
      reference_title: "GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: we report a new human genetic disease that causes cell senescence, liver
        and immune dysfunction, and early mortality that results from deficiency of
        GIMAP5
      explanation: Names cell senescence as the consequence, together with the two
        organ systems affected.
- name: Cellular Senescence in Endothelium and Lymphocytes
  biological_scale: CELLULAR
  description: >-
    Senescence and organelle dysfunction in the GIMAP5-expressing compartments.
    From here the disease divides into a hepatic vascular arm and an immune
    arm, which proceed independently of each other.
  biological_processes:
  - preferred_term: cellular senescence
    term:
      id: GO:0090398
      label: cellular senescence
    modifier: INCREASED
  cell_types:
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  evidence:
  - reference: PMID:38172257
    reference_title: "GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a new human genetic disease that causes cell senescence, liver and immune
      dysfunction, and early mortality
    explanation: Establishes senescence as the cellular endpoint of the shared pathway.
  downstream:
  - target: Reduced GATA4 in Liver Sinusoidal Endothelial Cells
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      GIMAP5 is placed upstream of GATA4 by single-cell transcriptomics, but the
      steps connecting the ceramide and senescence pathway to GATA4 have not
      been demonstrated.
    evidence:
    - reference: PMID:33956074
      reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: places GIMAP5 upstream of GATA4, a transcription factor required for
        LSEC specification
      explanation: Establishes the ordering without demonstrating the intervening
        mechanism.
- name: Reduced GATA4 in Liver Sinusoidal Endothelial Cells
  biological_scale: CELLULAR
  description: >-
    Loss of GATA4, the transcription factor required to specify liver
    sinusoidal endothelial cell identity. This is the step that turns a
    generic endothelial defect into a specifically hepatic one.
  cell_types:
  - preferred_term: liver sinusoidal endothelial cell
    term:
      id: CL:1000398
      label: endothelial cell of hepatic sinusoid
  biological_processes:
  - preferred_term: endothelial cell differentiation
    term:
      id: GO:0045446
      label: endothelial cell differentiation
    modifier: DECREASED
  evidence:
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: places GIMAP5 upstream of GATA4, a transcription factor required for LSEC
      specification
    explanation: Identifies GATA4 and its role in specifying the affected cell type.
  downstream:
  - target: Sinusoidal Capillarization
    causal_link_type: DIRECT
    description: Without GATA4 the sinusoidal endothelium loses its specialized identity
      and takes on a continuous, capillary-like phenotype.
    evidence:
    - reference: PMID:33956074
      reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: its loss in both humans and mice results in capillarization of liver
        sinusoidal endothelial cells (LSECs)
      explanation: States the consequence in both species.
- name: Sinusoidal Capillarization
  biological_scale: TISSUE
  description: >-
    The specialized fenestrated sinusoidal endothelium is replaced by
    capillarized endothelium, and macrovascular hepatic endothelial cells are
    reduced. Critically this happens when GIMAP5 is deleted in endothelium
    alone, which is what establishes the lesion as endothelial-intrinsic rather
    than a consequence of the immune disease.
  locations:
  - preferred_term: hepatic sinusoid
    term:
      id: UBERON:0001281
      label: hepatic sinusoid
  cell_types:
  - preferred_term: liver sinusoidal endothelial cell
    term:
      id: CL:1000398
      label: endothelial cell of hepatic sinusoid
  evidence:
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: this effect is also seen when GIMAP5 is selectively deleted in endothelial
      cells
    explanation: The endothelial-specific deletion experiment establishing cell-intrinsic
      causation.
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: reveals replacement of LSECs with capillarized endothelial cells, a reduction
      of macrovascular hepatic endothelial cells
    explanation: Describes the cellular composition change by single-cell sequencing.
  downstream:
  - target: Increased Intrahepatic Vascular Resistance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Capillarized sinusoids, with nodular regenerative hyperplasia and
      obliterative portal venopathy, raise resistance to portal flow. The
      quantitative contribution of each histological change has not been
      partitioned.
    evidence:
    - reference: PMID:33956074
      reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: GIMAP5 is a critical regulator of liver endothelial cell homeostasis
        and, when absent, produces portal hypertension
      explanation: Links the endothelial lesion to the haemodynamic outcome without
        resolving the intervening steps.
- name: Increased Intrahepatic Vascular Resistance
  biological_scale: TISSUE
  description: >-
    Raised resistance to portal venous flow within a liver that is not
    cirrhotic. This is the defining haemodynamic abnormality, and the absence
    of cirrhosis, fibrosis and portal vein thrombosis is what makes the entity
    noncirrhotic portal hypertension rather than ordinary chronic liver
    disease.
  locations:
  - preferred_term: portal vein
    term:
      id: UBERON:0002017
      label: portal vein
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He was found to have an increased portal pressure of 14 mm Hg (normal
      portal venous pressure ranges between 5 and 10 mm Hg)
    explanation: The one directly measured portal pressure in the cohort, establishing
      the haemodynamic abnormality rather than inferring it.
  downstream:
  - target: Portal hypertension
    causal_link_type: DIRECT
    description: The raised resistance is the portal hypertension.
    evidence:
    - reference: PMID:33956074
      reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: GIMAP5 is a critical regulator of liver endothelial cell homeostasis
        and, when absent, produces portal hypertension
      explanation: States the causal endpoint directly.
  - target: Splenomegaly
    causal_link_type: DIRECT
    description: >-
      Portal congestion enlarges the spleen. The universal splenomegaly and the
      raised portal pressure are both reported, but no source states the causal
      step between them, so it is curated as an inference.
    evidence:
    - reference: PMID:33956074
      reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: All affected subjects have splenomegaly
      explanation: >-
        Establishes the splenomegaly alongside the portal hypertension in the same
        cohort. The step from raised portal pressure to splenic enlargement is
        standard portal-hypertension physiology and is the curator's inference, not
        a claim this paper makes.
  - target: Esophageal varix
    causal_link_type: DIRECT
    description: Portosystemic collaterals decompress the hypertensive portal system
      through the oesophageal veins.
    evidence:
    - reference: PMID:33956074
      reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Esophageal varices, a consequence of increased portal pressure, were
        confirmed in seven subjects by endoscopy
      explanation: States the causal relationship between raised portal pressure and
        varices, and confirms it endoscopically in seven patients.
  - target: Nodular regenerative hyperplasia of liver
    causal_link_type: DIRECT
    description: The characteristic hepatic histology of the disorder, found on biopsy
      in the absence of cirrhosis.
    evidence:
    - reference: PMID:42358996
      reference_title: "Unexpected genetically determined immune dysregulation with liver involvement: GIMAP5 therapeutic dilemmas between targeted therapy and HSCT."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: GIMAP5 deficiency drives a distinct vascular remodeling characterized
        by nodular regenerative hyperplasia (NRH) and porto-sinusoidal vascular disorder
        (PSVD), frequently progressing to non-cirrhotic portal hypertension
      explanation: Ties the histological lesion to the haemodynamic outcome in this
        disease.
- name: Lymphocyte Apoptosis and Impaired Proliferation
  biological_scale: CELLULAR
  description: >-
    Spontaneous T and NK cell apoptosis with impaired proliferation. GIMAP5 has
    long been recognized as an anti-apoptotic factor required for lymphocyte
    survival, and this arm of the disease was characterized in rodents well
    before the human portal hypertension phenotype was described.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  biological_processes:
  - preferred_term: negative regulation of apoptotic process
    term:
      id: GO:0043066
      label: negative regulation of apoptotic process
    modifier: DECREASED
  - preferred_term: T cell homeostasis
    term:
      id: GO:0043029
      label: T cell homeostasis
    modifier: DECREASED
  evidence:
  - reference: PMID:18796632
    reference_title: "Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking Gimap5."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: selective gene ablation of the mouse gimap5 gene impairs the final intrathymic
      maturation of CD8 and CD4 T cells and compromises the survival of postthymic
      CD4 and CD8 cells
    explanation: Establishes the survival defect in T cells on Gimap5 loss.
  - reference: PMID:29382851
    reference_title: "Gimap5-dependent inactivation of GSK3\u03b2 is required for CD4(+) T cell homeostasis and prevention of immune pathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a human patient with a GIMAP5 loss-of-function mutation has lymphopenia
      and impaired T cell proliferation in vitro that can be rescued with GSK3 inhibitors
    explanation: Confirms the proliferation defect in a human patient and identifies
      a pharmacological rescue.
  downstream:
  - target: Decreased total lymphocyte count
    causal_link_type: DIRECT
    description: Failure of lymphocyte survival and proliferation manifests as lymphopenia.
    evidence:
    - reference: PMID:38055739
      reference_title: "Essential role of MFSD1-GLMP-GIMAP5 in lymphocyte survival and liver homeostasis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Germline knockout alleles of Mfsd1, Glmp, and Gimap5 each caused lymphopenia,
        liver pathology, EMH, and lipid deposition in the bone marrow and liver
      explanation: Reports lymphopenia on Gimap5 loss alongside the liver pathology.
  - target: Recurrent infections
    causal_link_type: DIRECT
    description: Lymphopenia and T-cell exhaustion leave the patient susceptible to
      infection.
    evidence:
    - reference: PMID:42358996
      reference_title: "Unexpected genetically determined immune dysregulation with liver involvement: GIMAP5 therapeutic dilemmas between targeted therapy and HSCT."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: cause a severe syndrome characterized by altered immunity, lymphoproliferation,
        and progressive hepatopathy
      explanation: Names altered immunity as a defining component of the syndrome.
  - target: Autoimmune hemolytic anemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Immune dysregulation produces autoimmune cytopenias; how a survival defect
      in lymphocytes gives rise to autoimmunity rather than simple
      immunodeficiency is not resolved.
    evidence:
    - reference: PMID:42358996
      reference_title: "Unexpected genetically determined immune dysregulation with liver involvement: GIMAP5 therapeutic dilemmas between targeted therapy and HSCT."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: alongside an expanded atypical memory B-cell population and T-cell
        exhaustion
      explanation: Records the immune dysregulation accompanying the cytopenias
        without establishing how a lymphocyte survival defect produces
        autoimmunity.
phenotypes:
- name: Portal hypertension
  category: Gastrointestinal
  description: >-
    The defining feature, and noncirrhotic by definition: cirrhosis, fibrosis
    and portal or splanchnic vein thrombosis are explicitly excluded.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Portal hypertension
    term:
      id: HP:0001409
      label: Portal hypertension
  evidence:
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: four families with unexplained portal hypertension
    explanation: The presenting feature in every index family.
- name: Splenomegaly
  category: Hematologic
  description: Present in all affected subjects of the founding series, and the source
    of the hypersplenic thrombocytopenia.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All affected subjects have splenomegaly
    explanation: Gives both the finding and its frequency in the founding cohort of
      nine patients.
  - reference: PMID:38055739
    reference_title: "Essential role of MFSD1-GLMP-GIMAP5 in lymphocyte survival and liver homeostasis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: caused lymphopenia, splenomegaly, progressive liver pathology, and extramedullary
      hematopoiesis (EMH)
    explanation: The orthologous lesion reproduces the splenomegaly in the model
      system, corroborating the human finding rather than standing in for it.
- name: Thrombocytopenia
  category: Hematologic
  description: >-
    Near-universal, arising through hypersplenism and contributing to the
    bleeding tendency alongside the varices.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: thrombocytopenia, elevated transaminases, and esophageal varices were
      nearly universal (Table 1)
    explanation: Gives the near-universal frequency in the founding cohort, which is
      what the frequency grade rests on.
- name: Esophageal varix
  category: Gastrointestinal
  description: Portosystemic collaterals, endoscopically confirmed in the founding
    series and the main source of life-threatening bleeding.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Esophageal varix
    term:
      id: HP:0002040
      label: Esophageal varix
  evidence:
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: thrombocytopenia, elevated transaminases, and esophageal varices were
      nearly universal (Table 1)
    explanation: Gives the frequency directly in the founding cohort.
- name: Nodular regenerative hyperplasia of liver
  category: Gastrointestinal
  description: >-
    The characteristic biopsy finding, together with obliterative portal
    venopathy. It is what places the disorder within porto-sinusoidal vascular
    disorder rather than among the cirrhotic liver diseases.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Nodular regenerative hyperplasia of liver
    term:
      id: HP:0011954
      label: Nodular regenerative hyperplasia of liver
  evidence:
  - reference: PMID:42358996
    reference_title: "Unexpected genetically determined immune dysregulation with liver involvement: GIMAP5 therapeutic dilemmas between targeted therapy and HSCT."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: GIMAP5 deficiency drives a distinct vascular remodeling characterized
      by nodular regenerative hyperplasia (NRH) and porto-sinusoidal vascular disorder
      (PSVD), frequently progressing to non-cirrhotic portal hypertension
    explanation: States the histology and its progression to portal hypertension
      for this disease specifically.
- name: Elevated circulating hepatic transaminase concentration
  category: Laboratory
  description: Near-universal, though the liver injury is vascular rather than primarily
    hepatocellular.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: thrombocytopenia, elevated transaminases, and esophageal varices were
      nearly universal (Table 1)
    explanation: Gives the near-universal frequency in the founding cohort.
- name: Decreased total lymphocyte count
  category: Immunologic
  description: T and NK lymphopenia with T-cell exhaustion, the laboratory hallmark
    of the immune arm.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Decreased total lymphocyte count
    term:
      id: HP:0001888
      label: Decreased total lymphocyte count
  evidence:
  - reference: PMID:29382851
    reference_title: "Gimap5-dependent inactivation of GSK3\u03b2 is required for CD4(+) T cell homeostasis and prevention of immune pathology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a human patient with a GIMAP5 loss-of-function mutation has lymphopenia
      and impaired T cell proliferation in vitro
    explanation: Documents lymphopenia in a human patient.
- name: Recurrent infections
  category: Immunologic
  description: Consequence of the lymphopenia and T-cell exhaustion; severe viral infections
    are reported.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:42358996
    reference_title: "Unexpected genetically determined immune dysregulation with liver involvement: GIMAP5 therapeutic dilemmas between targeted therapy and HSCT."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: cause a severe syndrome characterized by altered immunity, lymphoproliferation,
      and progressive hepatopathy
    explanation: Establishes altered immunity as a core component.
- name: Autoimmune hemolytic anemia
  category: Immunologic
  description: >-
    One of the autoimmune cytopenias of the immune arm. Their occurrence
    alongside immunodeficiency is what makes this an inborn error of immunity
    rather than a simple immune deficiency.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Autoimmune hemolytic anemia
    term:
      id: HP:0001890
      label: Autoimmune hemolytic anemia
  evidence:
  - reference: PMID:42358996
    reference_title: "Unexpected genetically determined immune dysregulation with liver involvement: GIMAP5 therapeutic dilemmas between targeted therapy and HSCT."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The 11-year-old proband presented with autoimmune cytopenias, severe
      viral infections, and early biochemical liver anomalies
    explanation: Documents autoimmune cytopenias in a genetically confirmed
      patient.
- name: Hepatomegaly
  category: Gastrointestinal
  description: Common, reflecting the hepatic vascular and regenerative changes.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He was found to have hepatosplenomegaly at 2 yr of age
    explanation: Records hepatomegaly directly, in a genetically confirmed patient and
      at the age it was detected.
- name: Ascites
  category: Gastrointestinal
  description: A decompensating complication of the portal hypertension.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Ascites
    term:
      id: HP:0001541
      label: Ascites
  evidence:
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: from liver failure and portal hypertension complications, including
      hyperbilirubinemia, ascites, and encephalopathy
    explanation: Records ascites among the portal-hypertension complications in this
      cohort.
- name: Elevated gamma-glutamyltransferase level
  category: Laboratory
  description: Raised GGT alongside the transaminase elevation, reported in a genetically
    confirmed patient.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Elevated gamma-glutamyltransferase level
    term:
      id: HP:0030948
      label: Elevated gamma-glutamyltransferase level
  evidence:
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: His laboratory tests were remarkable for pancytopenia and elevation of
      liver transaminases and γ-glutamyl transferase
    explanation: Records the GGT elevation in a confirmed patient.
- name: Hepatocellular carcinoma
  category: Neoplastic
  description: >-
    A hepatic lesion radiologically suspicious for hepatocellular carcinoma was
    found in one patient. This is a single imaging finding described as
    suspicious rather than a histologically confirmed cancer, so it establishes
    a possible long-term risk and nothing stronger - but it is worth surfacing,
    because surveillance decisions in a young cohort with chronic liver disease
    turn on exactly this question.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Hepatocellular carcinoma
    term:
      id: HP:0001402
      label: Hepatocellular carcinoma
  evidence:
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: one 2-cm hepatic lesion with arterial enhancement and portal venous washout
      highly suspicious for hepatocellular carcinoma
    explanation: The finding as reported, with the source's own hedge that it is
      suspicious on imaging rather than confirmed.
progression:
- phase: Childhood presentation with portal hypertension
  age_range: Early childhood to adolescence
  notes: >-
    Presentation is typically in childhood, with splenomegaly, cytopenias and
    variceal bleeding. One patient was found to have hepatosplenomegaly at two
    years of age and another was first evaluated at thirteen for ecchymosis.
  evidence:
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He was found to have hepatosplenomegaly at 2 yr of age
    explanation: Gives the youngest documented age at detection in the founding
      cohort.
- phase: Progressive liver disease and death from portal-hypertension complications
  notes: >-
    The hepatic disease progresses. Three affected individuals in one kindred
    are deceased, two of them from complications of portal hypertension, and one
    patient developed direct hyperbilirubinemia and worsening coagulopathy after
    shunt surgery. This is what makes the disorder more than a haematological
    curiosity and is the reason transplantation is discussed at all.
  evidence:
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Notably, three affected individuals in kindred 2 are deceased; two of
      them died from complications of portal hypertension
    explanation: Establishes mortality from the hepatic arm of the disease.
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: His most recent blood work revealed direct hyperbilirubinemia and worsening
      coagulopathy consistent with progression of underlying liver disease
    explanation: Documents progression of the liver disease in an individual patient
      despite shunt surgery.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Roughly twenty to twenty-five patients have been reported. The largest
    single addition was four families in the gene-discovery study; a 2026 review
    collected twenty previously published patients alongside one new case. No
    population rate has been estimated.
  evidence:
  - reference: PMID:42358996
    reference_title: "Unexpected genetically determined immune dysregulation with liver involvement: GIMAP5 therapeutic dilemmas between targeted therapy and HSCT."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: reporting the first Italian pediatric case alongside his mono-allelic
      carrier twin, integrated with a review of twenty previously published patients
    explanation: Gives the published patient count at the time of the most recent
      review.
environmental: []
treatments:
- name: Variceal Prophylaxis with Nonselective Beta-Blockade
  description: >-
    Nonselective beta-blockade to lower portal pressure and reduce variceal
    bleeding risk, alongside endoscopic surveillance and band ligation. This is
    standard portal-hypertension care rather than anything specific to GIMAP5
    deficiency.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: propranolol
      term:
        id: CHEBI:8499
        label: propranolol
  target_mechanisms:
  - target: Increased Intrahepatic Vascular Resistance
    description: Beta-blockade reduces portal inflow and pressure; it does not act
      on the endothelial lesion.
    evidence:
    - reference: PMID:33956074
      reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: Esophageal varices, a consequence of increased portal pressure, were
        confirmed in seven subjects by endoscopy
      explanation: Establishes the raised portal pressure and the varices that
        prophylaxis targets. The efficacy of beta-blockade in this disorder
        specifically has not been studied.
  evidence:
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: Notably, three affected individuals in kindred 2 are deceased; two of
      them died from complications of portal hypertension
    explanation: Establishes that portal-hypertension complications are lethal in this
      disease, which is what motivates prophylaxis. No GIMAP5-specific trial evidence
      exists.
  notes: >-
    Extrapolated from general portal-hypertension practice. No study has tested
    beta-blockade in GIMAP5 deficiency specifically.
- name: Sirolimus for Autoimmune Cytopenias
  description: >-
    An mTOR inhibitor used for the immune arm, reported to achieve sustained
    remission of the autoimmune cytopenias in the most recently published case.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sirolimus
      term:
        id: CHEBI:9168
        label: sirolimus
  target_mechanisms:
  - target: Lymphocyte Apoptosis and Impaired Proliferation
    description: Acts on the immune arm of the disease and not on the hepatic vascular
      arm.
    evidence:
    - reference: PMID:42358996
      reference_title: "Unexpected genetically determined immune dysregulation with liver involvement: GIMAP5 therapeutic dilemmas between targeted therapy and HSCT."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Targeted therapies, particularly mTORC1 inhibitors like sirolimus,
        offer a compelling strategy to reverse the metabolic and senescent defects
        observed in patient lymphocytes
      explanation: States that the agent acts on the lymphocyte compartment, which
        is the arm this link targets.
  evidence:
  - reference: PMID:42358996
    reference_title: "Unexpected genetically determined immune dysregulation with liver involvement: GIMAP5 therapeutic dilemmas between targeted therapy and HSCT."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the proband achieved sustained clinical remission of cytopenias through
      immunomodulation with the mTOR inhibitor sirolimus
    explanation: Reports the observed response of the autoimmune cytopenias to
      sirolimus.
  notes: >-
    Single-patient experience. It addresses the immune arm only and is not
    expected to affect the portal hypertension.
- name: Liver Transplantation
  description: >-
    Considered for end-stage hepatic disease. It is mechanistically rational
    here in a way it is not for many multisystem disorders, because the causal
    lesion for the hepatic arm is intrinsic to the liver endothelium and would
    be replaced along with the organ.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Liver Transplantation
    term:
      id: NCIT:C15271
      label: Liver Transplantation
  target_mechanisms:
  - target: Sinusoidal Capillarization
    description: Replacing the liver replaces the capillarized endothelium that carries
      the lesion.
    evidence:
    - reference: PMID:33956074
      reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: this effect is also seen when GIMAP5 is selectively deleted in endothelial
        cells
      explanation: The endothelial-intrinsic nature of the lesion is what makes organ
        replacement a coherent strategy; no transplant outcome in this disease has
        been reported.
  evidence:
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: GIMAP5 is a critical regulator of liver endothelial cell homeostasis and,
      when absent, produces portal hypertension
    explanation: Establishes the hepatic-endothelial locus of disease that motivates
      transplantation.
  notes: >-
    No transplant outcome has been published for this disorder; the rationale is
    mechanistic rather than empirical.
- name: Hematopoietic Cell Transplantation
  description: >-
    Considered definitive for the immune and haematological disease. The
    important caveat is mechanistic: because the hepatic lesion is
    endothelial-intrinsic and lymphocyte-independent, transplanting the
    haematopoietic system is not expected to reverse established portal
    hypertension, so the risk-benefit calculation cannot treat it as a cure for
    the whole disease.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: Hematopoietic Cell Transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Lymphocyte Apoptosis and Impaired Proliferation
    description: Replaces the GIMAP5-deficient lymphoid compartment, addressing the
      immune arm alone.
    evidence:
    - reference: PMID:18796632
      reference_title: "Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking Gimap5."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Development of NK/NKT cells is restored on transfer of gimap5(-/-) bone
        marrow into a wild-type environment
      explanation: Shows the lymphoid defect is correctable by changing the haematopoietic
        environment, which is the principle transplantation relies on.
  evidence:
  - reference: PMID:18796632
    reference_title: "Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking Gimap5."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: This pathology persists in a Rag2-deficient background in the absence
      of mature B, T, or NK cells and cannot be adoptively transferred by transplanting
      gimap5(-/-) bone marrow into wild-type recipients
    explanation: >-
      Contradicts the expectation that haematopoietic transplantation addresses
      the liver disease. The hepatic pathology occurs without mature lymphocytes
      and is not transferable with marrow.
  notes: >-
    Curated with both sides deliberately. The transplantation is genuinely
    definitive for the immune arm and genuinely will not fix the liver, and the
    published discussion of this disease is framed as exactly that dilemma.
animal_models:
- name: Endothelial-specific Gimap5 knockout mouse
  species: Mouse
  genotype: Endothelial-cell-conditional Gimap5 deletion
  publication: PMID:33956074
  description: >-
    The model that isolates the hepatic vascular arm. Deleting Gimap5 in
    endothelium alone reproduces the sinusoidal capillarization, which is what
    establishes the lesion as cell-intrinsic to the endothelium.
  modeled_mechanisms:
  - target: Sinusoidal Capillarization
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Reproduces the defining endothelial phenotype without any
      haematopoietic manipulation, which is the cleanest available
      demonstration that the liver disease does not require the immune disease.
    limitations: >-
      A conditional deletion models the endothelial arm in isolation and
      therefore says nothing about the immune arm or about how the two interact
      in a patient carrying the variant in every cell.
    readouts:
    - name: Liver sinusoidal endothelial cell capillarization
      target: Sinusoidal Capillarization
      direction: INCREASED
      interpretation: The defining histological readout of this node.
      evidence:
      - reference: PMID:33956074
        reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: this effect is also seen when GIMAP5 is selectively deleted in endothelial
          cells
        explanation: Reports the capillarization in the endothelial-specific deletion.
    evidence:
    - reference: PMID:33956074
      reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Single-cell RNA-sequencing analysis in a GIMAP5-deficient mouse model
        reveals replacement of LSECs with capillarized endothelial cells
      explanation: The mouse measurement establishing that the model reproduces the
        endothelial phenotype under study.
- name: Germline Gimap5 knockout mouse
  species: Mouse
  genotype: Gimap5 germline knockout
  publication: PMID:18796632
  description: >-
    The whole-body null, which carries both arms of the disease and was
    characterized well before the human portal hypertension phenotype was
    described. Its most informative result for this entry is a negative one: the
    liver pathology persists when mature lymphocytes are absent.
  modeled_mechanisms:
  - target: Lymphocyte Apoptosis and Impaired Proliferation
    relationship: RECAPITULATES
    fidelity: HIGH
    description: Impaired intrathymic maturation and compromised survival of postthymic
      CD4 and CD8 cells, with a block in NK and NKT development.
    limitations: >-
      Median survival is about fifteen weeks, which is too short to model a
      chronic progressive disease, and the dominant hepatic phenotype in this
      model is hepatocyte apoptosis and liver failure rather than the
      capillarization and portal hypertension seen in patients.
    readouts:
    - name: Peripheral CD4 and CD8 T cell survival
      target: Lymphocyte Apoptosis and Impaired Proliferation
      direction: DECREASED
      interpretation: The lymphocyte survival defect that defines this node.
      evidence:
      - reference: PMID:18796632
        reference_title: "Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking Gimap5."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: compromises the survival of postthymic CD4 and CD8 cells, replicating
          findings in the BB rat model
        explanation: Reports the survival defect and its concordance with the rat
          model.
    evidence:
    - reference: PMID:18796632
      reference_title: "Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking Gimap5."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: selective gene ablation of the mouse gimap5 gene impairs the final intrathymic
        maturation of CD8 and CD4 T cells
      explanation: Establishes the model as informative for the lymphoid node.
  - target: Increased Intrahepatic Vascular Resistance
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The whole-body null develops liver failure through hepatocyte apoptosis
      and chronic hepatic haematopoiesis, not through the sinusoidal
      capillarization and portal hypertension that define the human disease.
    limitations: >-
      This model dies at a median of fifteen weeks from a hepatocellular rather
      than a vascular lesion, so it cannot be used to study portal hypertension
      even though it is the most complete genetic null available. The
      endothelial-specific deletion is the model for that arm.
    evidence:
    - reference: PMID:18796632
      reference_title: "Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking Gimap5."
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: in later stages show pronounced hepatocyte apoptosis, leading to liver
        failure
      explanation: The hepatic phenotype reported in this model is hepatocyte apoptosis
        and liver failure, which is not the noncirrhotic portal hypertension of the
        human disease.
    - reference: PMID:33956074
      reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: this effect is also seen when GIMAP5 is selectively deleted in endothelial
        cells
      explanation: The endothelial-specific model, not the germline null, is the one
        that reproduces the vascular mechanism.
histopathology:
- name: Sinusoidal CD34 positivity with nodular regenerative hyperplasia
  description: >-
    Liver biopsy shows nodular regenerative hyperplasia without cirrhosis, and
    CD34 immunostaining is positive in the sinusoidal endothelium. That CD34
    stain is the histological correlate of the capillarization node in this
    entry: normal sinusoidal endothelium does not express CD34, so its
    appearance marks the loss of sinusoidal identity directly.
  finding_term:
    preferred_term: sinusoidal capillarization with nodular regenerative hyperplasia
  evidence:
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: CD34 immunostaining showed increased staining in the sinusoidal endothelium
      suggesting capillarization of the sinusoids
    explanation: The histological demonstration of capillarization in patient liver
      tissue.
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The reticulin stain highlights the nodularity with zones of widened two-cell-thick
      plates bounded by a narrow, compressed cell plate consistent with nodular regenerative
      hyperplasia
    explanation: Documents the nodular regenerative hyperplasia on reticulin staining.
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: None had cirrhosis, splanchnic venous thrombosis, or other extrahepatic
      causes of portal hypertension
    explanation: The exclusion that makes the portal hypertension noncirrhotic, stated
      for the whole cohort.
diagnosis:
- name: Exome or genome sequencing for biallelic GIMAP5 variants
  description: >-
    The definitive diagnostic. The disorder was discovered by exome sequencing
    and there is no biochemical screening test, so molecular confirmation is how
    the diagnosis is made.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Seven affected individuals from these families were subjected to whole-exome
      sequencing to high depth of coverage across all coding bases and flanking intronic
      segments
    explanation: The method by which the diagnosis was established in the founding
      cohort.
- name: GIMAP5 protein expression by immunoblot
  description: >-
    A genuinely discriminating functional test, because every reported disease
    allele converges on the same consequence: loss of GIMAP5 protein. That makes
    absent protein on immunoblot informative for a variant of uncertain
    significance in a way a sequence result alone is not.
  diagnosis_term:
    preferred_term: protein expression analysis
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Notably, all four mutations (p.I47T, p.P109L, p.L204P, and p.L223F) lead
      to loss of GIMAP5 protein expression'
    explanation: The convergence of every reported allele on absent protein is what
      makes the immunoblot diagnostically useful.
  - reference: PMID:42358996
    reference_title: "Unexpected genetically determined immune dysregulation with liver involvement: GIMAP5 therapeutic dilemmas between targeted therapy and HSCT."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Genetic analysis identified compound heterozygous variants (p.Leu204Pro
      and p.Arg214Ter) in GIMAP5 gene resulting in absent protein expression'
    explanation: A later case in which the same absent-protein result was used
      alongside sequencing.
- name: Direct portal venography
  description: >-
    Measures the portal pressure itself. Performed in one patient of the founding
    cohort, and the only direct haemodynamic measurement reported in this
    disease.
  diagnosis_term:
    preferred_term: portal venography
    term:
      id: NCIT:C190556
      label: Angiography
  evidence:
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Subject P4-1 was the only individual in this cohort who underwent a direct
      portal venogram
    explanation: Records that the measurement was made, and in how many patients.
  notes: >-
    One patient only. The measured pressure was 14 mm Hg against a normal range
    of 5-10 mm Hg.
- name: Upper endoscopy for variceal surveillance
  description: >-
    Confirms and grades oesophageal varices, and is the surveillance test that
    drives prophylaxis decisions.
  diagnosis_term:
    preferred_term: upper gastrointestinal endoscopy
    term:
      id: NCIT:C16546
      label: Endoscopic Procedure
  evidence:
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Esophageal varices, a consequence of increased portal pressure, were confirmed
      in seven subjects by endoscopy
    explanation: Endoscopic confirmation in seven of nine patients.
differential_diagnoses:
- name: DGUOK-related noncirrhotic portal hypertension
  description: >-
    Noncirrhotic portal hypertension 1, caused by recessive DGUOK variants. It
    presents in the same way - portal hypertension of indeterminate cause
    beginning in infancy or childhood, without cirrhosis - and is separated only
    by sequencing.
  evidence:
  - reference: PMID:26874653
    reference_title: "Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Three subjects from two consanguineous families shared the identical rare
      homozygous p.N46S mutation in DGUOK, a deoxyguanosine kinase required for mitochondrial
      DNA replication
    explanation: Identifies the distinct gene and mechanism of the sibling entity.
  - reference: PMID:26874653
    reference_title: "Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All three affected subjects had stable portal hypertension with noncirrhotic
      liver disease for 6-16 years of follow-up
    explanation: Shows the clinical presentation is indistinguishable at the bedside.
- name: Other genetic causes of porto-sinusoidal vascular disorder
  description: >-
    A broad differential: more than thirty genes have been associated with
    porto-sinusoidal vascular disorder, some as part of syndromes and some as
    isolated disease. GIMAP5 sits among the isolated-PSVD genes, and the
    striking observation across the whole set is that these genes are
    predominantly expressed in immune cells.
  evidence:
  - reference: PMID:38900412
    reference_title: "Genetic predisposition to porto-sinusoidal vascular disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified 34 genes and 1 chromosomal abnormality associated with PSVD
      in the literature
    explanation: Gives the size of the genetic differential.
  - reference: PMID:38900412
    reference_title: "Genetic predisposition to porto-sinusoidal vascular disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we found that these genes are predominantly expressed in immune cells,
      suggesting that these cells may play a more important role in the development
      of PSVD than previously thought
    explanation: Places the GIMAP5 immune-endothelial duality within a broader pattern
      across PSVD genes.
- name: Drug-induced noncirrhotic portal hypertension
  description: >-
    Acquired phenocopies exist and must be excluded, notably didanosine
    exposure. The connection is not merely clinical: didanosine lowers
    deoxyguanosine kinase levels, which is the same protein whose loss causes
    the inherited NCPH1, so the acquired and inherited forms may converge
    mechanistically.
  evidence:
  - reference: PMID:26874653
    reference_title: "Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: treatment of patients with human immunodeficiency viral infection with
      the nucleoside analogue didanosine is known to cause portal hypertension in a
      subset of patients and lowers deoxyguanosine kinase levels in vitro
    explanation: Documents the acquired phenocopy and the shared molecular target.
discussions:
- discussion_id: hsct_will_not_reverse_portal_hypertension
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Does correcting the haematopoietic compartment alter the course of the
    hepatic vascular disease in GIMAP5 deficiency?
  attaches_to:
  - pathophysiology#Sinusoidal Capillarization
  - treatments#Hematopoietic Cell Transplantation
  rationale: >-
    The mouse evidence says the two arms are independent: endothelial-specific
    deletion reproduces the capillarization on its own, and the hepatic
    pathology persists in a Rag2-deficient background lacking mature B, T and NK
    cells, and cannot be adoptively transferred with marrow. The prediction is
    that haematopoietic transplantation will not reverse established portal
    hypertension. But this has not been tested in patients, and the untested
    question that matters is whether transplantation performed early, before
    capillarization is established, changes the hepatic trajectory. Because HSCT
    carries real mortality and is being weighed for the immune arm anyway, this
    gap sits directly on a clinical decision rather than beside one.
  evidence:
  - reference: PMID:18796632
    reference_title: "Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking Gimap5."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: This pathology persists in a Rag2-deficient background in the absence
      of mature B, T, or NK cells and cannot be adoptively transferred by transplanting
      gimap5(-/-) bone marrow into wild-type recipients
    explanation: The lymphocyte-independence result on which the prediction rests.
  - reference: PMID:33956074
    reference_title: "GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: this effect is also seen when GIMAP5 is selectively deleted in endothelial
      cells
    explanation: The complementary result showing the endothelium alone is sufficient.
- discussion_id: ceramide_pathway_to_endothelial_phenotype
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Does the CK2-ceramide senescence pathway account for the endothelial arm,
    or only the lymphocyte arm?
  attaches_to:
  - pathophysiology#Long-Chain Ceramide Accumulation
  - pathophysiology#Reduced GATA4 in Liver Sinusoidal Endothelial Cells
  rationale: >-
    The CK2-ceramide axis was demonstrated in T cells, where inhibiting CK2 or
    ceramide synthase rescues the cells. It is presented as a unifying mechanism
    for both arms of the disease, but the endothelial half of that claim is an
    extrapolation: no study has shown ceramide accumulation in liver sinusoidal
    endothelial cells, nor that CK2 or ceramide synthase inhibition prevents
    capillarization or reduces GATA4 loss. This matters because CK2 and
    ceramide-synthase inhibitors are the leading candidate targeted therapies,
    and whether they could address the portal hypertension or only the immune
    disease turns on exactly this question.
  proposed_experiments:
  - experiment_id: lsec_ceramide_and_ck2_rescue
    name: Ceramide profiling and CK2 inhibition in GIMAP5-deficient liver endothelium
    description: >-
      Measure long-chain ceramide species in liver sinusoidal endothelial cells
      isolated from endothelial-specific Gimap5 knockout mice against littermate
      controls, then test whether CK2 or ceramide-synthase inhibition prevents
      GATA4 loss and capillarization in the same model.
    readouts:
    - name: Long-chain ceramide abundance in isolated LSECs
      target: pathophysiology#Long-Chain Ceramide Accumulation
      direction: INCREASED
      interpretation: Accumulation in endothelium would extend the pathway beyond
        lymphocytes.
    - name: GATA4 expression after CK2 inhibition
      target: pathophysiology#Reduced GATA4 in Liver Sinusoidal Endothelial Cells
      direction: RESTORED
      interpretation: Restoration would place the ceramide pathway upstream of the
        endothelial transcriptional defect.
    would_support:
    - pathophysiology#Long-Chain Ceramide Accumulation
    supporting_outcome:
    - Ceramides accumulate in GIMAP5-deficient liver sinusoidal endothelial cells,
      and CK2 or ceramide-synthase inhibition preserves GATA4 expression and prevents
      capillarization.
    would_refute:
    - pathophysiology#Long-Chain Ceramide Accumulation
    refuting_outcome:
    - Ceramide levels are unchanged in GIMAP5-deficient liver endothelium, or
      inhibition rescues lymphocytes while leaving capillarization and GATA4 loss
      unaffected, showing the endothelial arm runs through a different pathway.
  evidence:
  - reference: PMID:38172257
    reference_title: "GIMAP5 deficiency reveals a mammalian ceramide-driven longevity assurance pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Inhibition of CK2 and CER synthase rescues GIMAP5-deficient T cells by
      preventing CER overaccumulation and cell deterioration
    explanation: The rescue is demonstrated in T cells; the endothelial equivalent
      is what is missing.
notes: >-
  Scope. This entry is GIMAP5 only. Noncirrhotic portal hypertension 1 is a
  distinct entity caused by DGUOK and is curated here as a differential rather
  than as content. The deep-research report is correct on this and states OMIM
  619463 for the phenotype; the preflight check flagged an OMIM mismatch only
  because it read the gene MIM 608086 and the NCPH1 MIM 617068 out of the text
  while missing the hash-prefixed 619463.

  Why the two arms are curated as independent branches. The hepatic and immune
  diseases share an upstream step but do not depend on one another, and the
  evidence for that is unusually clean in both directions: deleting Gimap5 in
  endothelium alone reproduces the sinusoidal capillarization, and the hepatic
  pathology persists in mice lacking mature B, T and NK cells and cannot be
  transferred with marrow. This is not a modelling nicety - it is why
  haematopoietic transplantation is not expected to reverse established portal
  hypertension, and the treatment entry for transplantation carries both a
  SUPPORT item for the immune arm and a REFUTE item for the hepatic one.

  What the shared upstream step does and does not cover. The CK2-ceramide
  senescence pathway is presented in the literature as unifying both arms, but
  it was demonstrated in T cells. No study has shown ceramide accumulation in
  liver sinusoidal endothelial cells, or that inhibiting CK2 or ceramide
  synthase prevents capillarization. That gap is recorded as an open discussion
  with a proposed experiment rather than smoothed over, because the leading
  candidate targeted therapies act on exactly that pathway.

  The germline null is curated as a partial failure. The whole-body Gimap5
  knockout mouse recapitulates the lymphocyte arm well but FAILS_TO_RECAPITULATE
  the portal hypertension: its hepatic phenotype is hepatocyte apoptosis and
  liver failure, and it dies at a median of fifteen weeks. Reporting it as
  simply "a mouse model of GIMAP5 deficiency" would obscure that the most
  complete genetic null available cannot be used to study the disease's defining
  feature.

  Report term corrections. CL:1000488, which the report offered for liver
  sinusoidal endothelial cell, is cholangiocyte; CL:1000398 endothelial cell of
  hepatic sinusoid is used instead. Two of the four NCIT treatment codes the
  report proposed are also wrong, and no report-side validation checks NCIT:
  C692, offered for propranolol, is Nimodipine, and C15356, offered for Liver
  Transplantation, is the Whipple Procedure. NCIT:C62073 and NCIT:C15271 are the
  correct terms; the report's C1212 for sirolimus and C15431 for haematopoietic
  cell transplantation are right. Every other identifier it suggested resolved
  correctly, which makes this a more reliable report than the FEPS3 one in the
  same batch.

  Deliberately not curated. No environmental entries: nothing environmental is
  required or established, and the acquired drug-induced phenocopies belong in
  differential diagnoses, where didanosine is recorded. Endoscopic variceal band
  ligation and transjugular intrahepatic portosystemic shunting are real
  management steps but no NCIT clinical-action term was found for variceal
  ligation, and the shunt outcome is a single-patient observation, so both are
  left out rather than bound to an approximate term. The GSK3 and
  CK2/ceramide-synthase inhibitors are in-vitro rescues, not treatments. The
  beta-blockade and transplantation entries carry notes recording that their
  rationale is extrapolated from general portal-hypertension practice or
  mechanistic reasoning rather than from evidence in this disease. One further reference, on
  NF-kappaB and MAPK activation in Gimap5-mutant rat T cells, was fetched by the
  research run, read and set aside: it concerns a signalling branch this entry
  does not model, and its cache is not shipped.

  Review round two, and the lesson in it. Six evidence items across this entry
  quoted one generic background sentence - that portal hypertension is a major
  contributor to decompensation and death from liver disease - as support for
  specific claims about this disease's varices, ascites, haemodynamics and
  treatment rationale. Every one of those snippets was a verbatim substring and
  passed every gate, and not one of them said what the claim above it said. The
  founding paper's full text was already cached in this branch and contains
  disease-specific, frequency-bearing sentences for all six. Passing the
  snippet verifier is not the same as having evidence, and that is the failure
  mode this correction is about.

  Consequences of that pass. Splenomegaly, a human phenotype graded
  VERY_FREQUENT, had been supported only by a mouse study, which the evidence
  policy forbids; it now leads with "All affected subjects have splenomegaly"
  from the human cohort, with the mouse result kept as corroboration rather than
  as the claim. Thrombocytopenia and elevated transaminases were graded
  VERY_FREQUENT on single-proband sentences and now rest on the cohort's
  "nearly universal" statement. The edge from raised portal pressure to
  splenomegaly quoted a paper that mentions neither; it now carries the human
  splenomegaly sentence with directness INDIRECT and an explanation that owns
  the inference as the curator's rather than the source's.

  Added in the same round: a diagnosis section (exome sequencing, GIMAP5
  immunoblot, direct portal venography, surveillance endoscopy), a
  histopathology record for the sinusoidal CD34 positivity that is the
  histological correlate of the capillarization node, three further variants
  bringing the spectrum to five, the convergence of every reported allele on
  absent protein, elevated GGT and a radiologically suspicious hepatocellular
  lesion as phenotypes, and a progression section recording that two patients in
  one kindred died of portal-hypertension complications.

  Not added. The BB-DP rat carries a spontaneous Gimap5 frameshift and is a
  genuine complementary model, but no cached source in this entry describes it;
  adding it would mean citing a paper I have not fetched. Its dominant phenotype
  is autoimmune diabetes rather than portal hypertension, so it is a weaker fit
  than the two mouse models already curated. Left out rather than cited from
  the research report's summary of it.
📚

References & Deep Research

Deep Research

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Evaluations and curation notes (2)

Record notes

Scope. This entry is GIMAP5 only. Noncirrhotic portal hypertension 1 is a distinct entity caused by DGUOK and is curated here as a differential rather than as content. The deep-research report is correct on this and states OMIM 619463 for the phenotype; the preflight check flagged an OMIM mismatch only because it read the gene MIM 608086 and the NCPH1 MIM 617068 out of the text while missing the hash-prefixed 619463. Why the two arms are curated as independent branches. The hepatic and immune diseases share an upstream step but do not depend on one another, and the evidence for that is unusually clean in both directions: deleting Gimap5 in endothelium alone reproduces the sinusoidal capillarization, and the hepatic pathology persists in mice lacking mature B, T and NK cells and cannot be transferred with marrow. This is not a modelling nicety - it is why haematopoietic transplantation is not expected to reverse established portal hypertension, and the treatment entry for transplantation carries both a SUPPORT item for the immune arm and a REFUTE item for the hepatic one. What the shared upstream step does and does not cover. The CK2-ceramide senescence pathway is presented in the literature as unifying both arms, but it was demonstrated in T cells. No study has shown ceramide accumulation in liver sinusoidal endothelial cells, or that inhibiting CK2 or ceramide synthase prevents capillarization. That gap is recorded as an open discussion with a proposed experiment rather than smoothed over, because the leading candidate targeted therapies act on exactly that pathway. The germline null is curated as a partial failure. The whole-body Gimap5 knockout mouse recapitulates the lymphocyte arm well but FAILS_TO_RECAPITULATE the portal hypertension: its hepatic phenotype is hepatocyte apoptosis and liver failure, and it dies at a median of fifteen weeks. Reporting it as simply "a mouse model of GIMAP5 deficiency" would obscure that the most complete genetic null available cannot be used to study the disease's defining feature. Report term corrections. CL:1000488, which the report offered for liver sinusoidal endothelial cell, is cholangiocyte; CL:1000398 endothelial cell of hepatic sinusoid is used instead. Two of the four NCIT treatment codes the report proposed are also wrong, and no report-side validation checks NCIT: C692, offered for propranolol, is Nimodipine, and C15356, offered for Liver Transplantation, is the Whipple Procedure. NCIT:C62073 and NCIT:C15271 are the correct terms; the report's C1212 for sirolimus and C15431 for haematopoietic cell transplantation are right. Every other identifier it suggested resolved correctly, which makes this a more reliable report than the FEPS3 one in the same batch. Deliberately not curated. No environmental entries: nothing environmental is required or established, and the acquired drug-induced phenocopies belong in differential diagnoses, where didanosine is recorded. Endoscopic variceal band ligation and transjugular intrahepatic portosystemic shunting are real management steps but no NCIT clinical-action term was found for variceal ligation, and the shunt outcome is a single-patient observation, so both are left out rather than bound to an approximate term. The GSK3 and CK2/ceramide-synthase inhibitors are in-vitro rescues, not treatments. The beta-blockade and transplantation entries carry notes recording that their rationale is extrapolated from general portal-hypertension practice or mechanistic reasoning rather than from evidence in this disease. One further reference, on NF-kappaB and MAPK activation in Gimap5-mutant rat T cells, was fetched by the research run, read and set aside: it concerns a signalling branch this entry does not model, and its cache is not shipped. Review round two, and the lesson in it. Six evidence items across this entry quoted one generic background sentence - that portal hypertension is a major contributor to decompensation and death from liver disease - as support for specific claims about this disease's varices, ascites, haemodynamics and treatment rationale. Every one of those snippets was a verbatim substring and passed every gate, and not one of them said what the claim above it said. The founding paper's full text was already cached in this branch and contains disease-specific, frequency-bearing sentences for all six. Passing the snippet verifier is not the same as having evidence, and that is the failure mode this correction is about. Consequences of that pass. Splenomegaly, a human phenotype graded VERY_FREQUENT, had been supported only by a mouse study, which the evidence policy forbids; it now leads with "All affected subjects have splenomegaly" from the human cohort, with the mouse result kept as corroboration rather than as the claim. Thrombocytopenia and elevated transaminases were graded VERY_FREQUENT on single-proband sentences and now rest on the cohort's "nearly universal" statement. The edge from raised portal pressure to splenomegaly quoted a paper that mentions neither; it now carries the human splenomegaly sentence with directness INDIRECT and an explanation that owns the inference as the curator's rather than the source's. Added in the same round: a diagnosis section (exome sequencing, GIMAP5 immunoblot, direct portal venography, surveillance endoscopy), a histopathology record for the sinusoidal CD34 positivity that is the histological correlate of the capillarization node, three further variants bringing the spectrum to five, the convergence of every reported allele on absent protein, elevated GGT and a radiologically suspicious hepatocellular lesion as phenotypes, and a progression section recording that two patients in one kindred died of portal-hypertension complications. Not added. The BB-DP rat carries a spontaneous Gimap5 frameshift and is a genuine complementary model, but no cached source in this entry describes it; adding it would mean citing a paper I have not fetched. Its dominant phenotype is autoimmune diabetes rather than portal hypertension, so it is a weaker fit than the two mouse models already curated. Left out rather than cited from the research report's summary of it.

Create: noncirrhotic portal hypertension 2 (GIMAP5) · 2026-09-02T00:25:05Z · View source

Curated NCPH2 / GIMAP5 deficiency from an OpenScientist deep-research report plus eight cited PubMed abstracts, one with full text. Nine-node pathograph from biallelic GIMAP5 loss of function through unrestrained CK2 activation of ceramide synthases, long-chain ceramide accumulation and cellular senescence, then dividing into a hepatic vascular arm (reduced GATA4 in liver sinusoidal endothelial cells, sinusoidal capillarization, increased intrahepatic vascular resistance, portal hypertension) and an immune arm (lymphocyte apoptosis and impaired proliferation, lymphopenia, recurrent infection, autoimmune cytopenias). The two arms are curated as independent branches because the evidence for their independence is unusually clean in both directions: endothelial-specific Gimap5 deletion reproduces the capillarization alone, and the hepatic pathology persists in mice lacking mature B, T and NK cells and cannot be transferred with marrow. That is not a modelling nicety, it is why haematopoietic transplantation is not expected to reverse established portal hypertension, so the transplantation treatment carries a SUPPORT item for the immune arm and a REFUTE item for the hepatic one, and an open discussion records the untested question of whether early transplantation changes the hepatic trajectory. The germline Gimap5 null mouse is curated with two links of opposite verdict: RECAPITULATES the lymphocyte node, FAILS_TO_RECAPITULATE the portal hypertension, because its hepatic phenotype is hepatocyte apoptosis and liver failure at a median survival of fifteen weeks rather than the vascular lesion of the human disease. A second discussion records that the CK2-ceramide pathway, presented as unifying both arms, was demonstrated only in T cells, with a proposed experiment to test whether it reaches the endothelium; this matters because CK2 and ceramide-synthase inhibitors are the leading candidate therapies. Scope is GIMAP5 only, with DGUOK-related NCPH1 as a differential; the preflight OMIM mismatch was a false alarm caused by the checker reading the gene MIM and the NCPH1 MIM while missing the hash-prefixed 619463 that the report states correctly. Report term corrections: CL:1000488, offered for liver sinusoidal endothelial cell, is cholangiocyte, so CL:1000398 is used; and two of four proposed NCIT treatment codes are wrong, with C692 for propranolol being Nimodipine and C15356 for Liver Transplantation being the Whipple Procedure, corrected to C62073 and C15271. Every other suggested identifier resolved correctly, making this report more reliable than the FEPS3 one in the same batch. During curation I attached a quote to the wrong PMID and reference validation caught it before commit; the sentence is from the case report rather than the PSVD genetics review. Nine snippets were upgraded to better quotes once full text proved available for the case report. Declined to curate endoscopic variceal ligation and portosystemic shunting for want of a suitable NCIT action term and single-patient evidence, and the GSK3 and CK2 inhibitors because they are in-vitro rescues rather than treatments. One uncited reference fetched by the research run was read, set aside and not shipped. Validation: schema, terms and references clean with 63/63 snippets verified; all offline gates green.

OpenScientist ▸
Portal Hypertension, Noncirrhotic, 2 (PHNC2 / NCPH2) — Comprehensive Disease Report
openscientist-autonomous 2026-09-02T00:06:12.121952

Portal Hypertension, Noncirrhotic, 2 (PHNC2 / NCPH2) — Comprehensive Disease Report

Disease: Portal Hypertension, Noncirrhotic, 2 MONDO: MONDO:0030397 · OMIM: #619463 · Causal gene: GIMAP5 (HGNC:18005) Evidence base: Aggregated disease-level resources (OMIM, MONDO, HPO, gnomAD, UniProt) plus individual-patient reports (~21 patients published to date). Fewer than ~25 molecularly confirmed patients worldwide; all conclusions rest on small case series, a landmark human+mouse mechanistic study, and rodent models.

Summary (Answer to the Research Question)

Portal Hypertension, Noncirrhotic, 2 (PHNC2) is a rare autosomal-recessive disorder caused by biallelic loss-of-function variants in GIMAP5, a small organellar GTPase of the immunity-associated protein (IAN) family expressed selectively in lymphocytes and endothelial cells. Loss of GIMAP5 produces a two-arm disease: (1) a hepatic vascular arm in which GIMAP5-deficient liver sinusoidal endothelial cells (LSECs) fail to maintain their identity (via reduced GATA4), undergo capillarization, and cause noncirrhotic (porto-sinusoidal) portal hypertension; and (2) an immune arm with lymphopenia, autoimmune cytopenias, and recurrent infections. A unifying biochemical lesion is pathological accumulation of long-chain ceramides (GIMAP5 normally restrains CK2-driven ceramide synthase activity), driving cellular senescence in both endothelium and lymphocytes. Presentation is typically in childhood with splenomegaly, thrombocytopenia, esophageal varices, and elevated transaminases, without cirrhosis.

1. Disease Information

Overview. PHNC2 is a Mendelian cause of idiopathic/noncirrhotic portal hypertension, now classified within the spectrum of porto-sinusoidal vascular disorder (PSVD). It is distinctive because portal hypertension arises from a primary endothelial defect rather than from hepatocellular injury or cirrhosis, and it co-occurs with an inborn error of immunity.

Key identifiers - MONDO: MONDO:0030397 ("portal hypertension, noncirrhotic, 2"; synonym NCPH2) - OMIM: #619463 (phenotype) - UMLS: C5561948 · MedGen: 1794158 - Gene: GIMAP5 — HGNC:18005; NCBI Gene 55340; Ensembl ENSG00000196329; UniProt Q96F15; gene MIM 608086; cytoband 7q36.1 - ICD-10: K76.6 (portal hypertension; no PHNC2-specific code) · ICD-11: DB98.5 region (non-cirrhotic portal hypertension/idiopathic; no specific code) - MeSH: most closely "Hypertension, Portal" (D006975); no PHNC2-specific MeSH - Orphanet: no PHNC2-specific ORPHA; overlaps "Idiopathic non-cirrhotic portal hypertension"/PSVD

Synonyms / alternative names: NCPH2; GIMAP5 deficiency; GIMAP5-related noncirrhotic portal hypertension; GIMAP5-related porto-sinusoidal vascular disorder; (historically discussed with "idiopathic noncirrhotic portal hypertension," INCPH). Note: PHNC1 (INCPH1, OMIM 617068) is a distinct entity caused by DGUOK (PMID 26874653).

Data provenance: Disease-level ontologies/aggregators + individual patient case reports/series (human clinical), complemented by mouse and rat model data and in-vitro mechanistic studies.

2. Etiology

Primary cause — genetic (monogenic). Biallelic (homozygous or compound-heterozygous) loss-of-function variants in GIMAP5. "we demonstrate homozygous damaging mutations in GIMAP5, a small organellar GTPase, in four families with unexplained portal hypertension" (Drzewiecki et al., PMID 33956074).

Genetic risk factors - Causal variants: recessive GIMAP5 alleles (see §4). Disease requires two damaged alleles. - Consanguinity is a major contributor: three of four index families were consanguineous (first-cousin unions) (PMID 33956074). - Founder/recurrent allele: p.Leu204Pro recurs across independent reports and is relatively common (gnomAD AF ≈2.1×10⁻³), so it is the most likely allele to appear in homozygous or compound-heterozygous state.

Environmental risk factors. None established. No toxin, infection, diet, or occupational exposure is required for disease; the phenotype is genetically determined. (Of note, acquired phenocopies of noncirrhotic portal hypertension exist — e.g., didanosine/thioguanine exposure, oxaliplatin — but these are not PHNC2.)

Protective factors. No genetic or environmental protective factors are defined. At the population level GIMAP5 is LOF-tolerant (gnomAD pLI = 0.003; observed/expected LOF = 8/9.9), so monoallelic carriers are generally healthy — heterozygosity is effectively "protective" relative to the biallelic state.

Gene–environment interactions. A 2026 report raised the hypothesis that partial (monoallelic) GIMAP5 deficiency might subtly predispose to localized vascular anomalies under specific environmental/epigenetic conditions via multi-hit mechanisms — the dizygotic twin carrying a single p.Leu204Pro allele showed a localized fibro-adipose vascular anomaly but no immune defect (PMID 42358996). This remains speculative.

3. Phenotypes (with HPO terms, type, and frequency)

Onset is typically in infancy/childhood; severity is variable; the hepatic disease is chronic and progressive.

Phenotype HPO Type Frequency / notes
Portal hypertension HP:0001409 Clinical sign Defining; universal
Splenomegaly HP:0001744 Physical sign All affected subjects (PMID 33956074)
Thrombocytopenia HP:0001873 Lab abnormality Near-universal (hypersplenism)
Elevated transaminases HP:0002910 Lab abnormality Near-universal
Esophageal varices HP:0002040 Clinical sign Near-universal; 7 subjects endoscopically confirmed
Nodular regenerative hyperplasia of liver HP:0011954 Pathology Present on biopsy
Hepatomegaly HP:0002240 Physical sign Common
Elevated GGT HP:0030948 Lab abnormality Reported
Ascites HP:0001541 Clinical sign Complication of portal hypertension
Ecchymosis / petechiae / epistaxis HP:0031364 / HP:0000967 / HP:0000421 Signs Bleeding from thrombocytopenia/varices
Hemoptysis HP:0002105 Sign Reported
Recurrent infections HP:0002719 Sign Immune arm
Autoimmune cytopenias (hemolytic anemia, immune thrombocytopenia) HP:0001890 / HP:0001873 Lab/clinical Immune dysregulation
Lymphopenia HP:0001888 Lab abnormality T (and NK) lymphopenia; T-cell exhaustion
Hepatocellular carcinoma HP:0001402 Neoplasm Listed as possible long-term risk
Fatigue HP:0012378 Symptom Nonspecific

Age of onset: neonatal–childhood (pediatric); portal hypertension complications and immune features generally manifest in the first two decades. Progression: progressive liver/vascular disease (one patient developed worsening coagulopathy and direct hyperbilirubinemia after shunt surgery) (PMID 33956074). Quality-of-life impact: substantial — recurrent variceal bleeding risk, transfusion-dependent cytopenias, infection susceptibility, growth/activity limitation, and the burden of surveillance endoscopy and possible transplantation. No formal EQ-5D/SF-36/PROMIS data exist for this ultra-rare disease.

4. Genetic / Molecular Information

Causal gene: GIMAP5 (GTPase, IMAP family member 5) — HGNC:18005; NCBI Gene 55340; Ensembl ENSG00000196329; UniProt Q96F15 (307 aa); gene MIM 608086; 7q36.1 (GRCh38 chr7:150,722,253–150,750,033, + strand). Part of the IAN GTPase cluster on 7q36.1; read-through transcript with upstream GIMAP1 exists. Aliases: IAN5, IAN4L1, IROD, NCPH2.

Protein architecture: GIMAP5 is a small AIG1-type guanine-nucleotide-binding (G) domain GTPase (InterPro IPR006703; Pfam PF04548 "AIG1 family"; PROSITE PS51720), belonging to the P-loop NTPase superfamily (IPR027417) and the GTPase GIMA/IAN/Toc family (IPR045058), with a C-terminal transmembrane anchor targeting it to lysosomal/endosomal membranes. The reported missense substitutions (I47T, P109L, L204P, L223P) map to/near this G-domain and are predicted to destabilize the fold and abolish GTPase function, consistent with the observed absent protein for null combinations.

Pathogenic variants (all germline, all loss-of-function / recessive):

Variant (protein) cDNA/type Zygosity Population frequency Source
p.Ile47Thr (I47T) missense homozygous (kindred 1) AF = 0 in gnomAD PMID 33956074
p.Pro109Leu (P109L) missense homozygous (kindred 3) ultra-rare (1/251,400 alleles) PMID 33956074
p.Leu204Pro (L204P) missense homozygous (kindred 4); also compound-het AF ≈2.1×10⁻³ (recurrent) PMID 33956074, 29382851, 42358996
p.Leu223Pro (L223P) missense homozygous (kindred 2) rare PMID 33956074
p.Arg214Ter (R214*) nonsense compound-het with L204P rare PMID 42358996
  • Variant classification (ACMG/AMP): the recurrent alleles are treated as pathogenic/likely pathogenic given segregation, absent/abolished protein, and functional data; many other GIMAP5 entries in ClinVar are VUS or large 7q copy-number changes not specific to PHNC2.
  • Variant types: predominantly missense; at least one nonsense (R214*). No pathogenic large structural rearrangement specific to PHNC2 is established (7q CNVs in ClinVar are contiguous-gene events, not PHNC2).
  • Functional consequence: loss of function — e.g., compound-het L204P/R214 yields absent GIMAP5 protein* on immunoblot (PMID 42358996). No gain-of-function or dominant-negative mechanism.
  • Somatic vs germline: exclusively germline.

Modifier genes. None formally proven. Mechanistically, GIMAP5 stability requires the lysosomal MFSD1–GLMP complex (PMID 38055739), so MFSD1/GLMP are candidate biological modifiers; downstream GATA4 and GSK3β/CK2/ceramide-synthase nodes modulate phenotype in models.

Epigenetic information / chromosomal abnormalities. No disease-specific DNA-methylation or histone signature reported. Contiguous 7q36 deletions/duplications affect GIMAP5 among many genes but are not the mechanism of PHNC2.

5. Environmental Information

  • Environmental factors / toxins: none required or established for PHNC2. (Toxic/drug-induced noncirrhotic portal hypertension — e.g., didanosine, thioguanine, arsenic, vinyl chloride, oxaliplatin — are separate acquired phenocopies to exclude.)
  • Lifestyle factors: not applicable to disease causation.
  • Infectious agents: not causal. However, because of the immune arm, patients suffer recurrent/severe viral infections as a consequence of the disease (e.g., severe viral infections in the proband, PMID 42358996). CHEBI/pathogen exposure is downstream, not upstream.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

  1. Biallelic loss-of-function variants in GIMAP5 lead to loss/instability of the GIMAP5 GTPase (compounded by loss of the stabilizing lysosomal MFSD1–GLMP–GIMAP5 complex). (demonstrated)
  2. GIMAP5 loss results in failure to restrain protein kinase CK2, which leads to over-activation of ceramide synthases and pathological accumulation of long-chain ceramides. (demonstrated in T cells; inferred in endothelium)
  3. Ceramide overaccumulation leads to cellular senescence / organelle (mitochondrial) dysfunction in GIMAP5-expressing cells — endothelial cells and lymphocytes. (demonstrated)

Branch A — hepatic vascular (portal hypertension): 4a. In liver sinusoidal endothelial cells (LSECs), GIMAP5 loss results in reduced GATA4 (the transcription factor required for LSEC specification). (demonstrated by scRNA-seq positioning GIMAP5 upstream of GATA4) 5a. Reduced GATA4 leads to loss of LSEC identity → capillarization (loss of fenestrae, acquisition of a basement membrane, CD34 positivity) and reduction of macrovascular hepatic endothelial cells. (demonstrated in humans and mice) 6a. Sinusoidal capillarization / porto-sinusoidal remodeling (with nodular regenerative hyperplasia and obliterative portal venopathy — venules absent in portal areas) increases intrahepatic vascular resistance. (demonstrated histologically) 7a. Increased resistance results in noncirrhotic portal hypertension → splenomegaly, esophageal varices, ascites, variceal bleeding; thrombocytopenia via hypersplenism. (clinical)

Branch B — immune (lymphopenia/autoimmunity): 4b. In lymphocytes, GIMAP5 loss (via ceramide, impaired mitochondrial/ER Ca²⁺ homeostasis, ER-stress/CHOP apoptosis, and constitutive GSK3β activity restricting c-Myc/NFATc1) leads to spontaneous T- and NK-cell apoptosis / impaired proliferation. (demonstrated in rat/mouse and patient cells) 5b. Lymphopenia and immune dysregulation result in recurrent infections, autoimmune cytopenias, T-cell exhaustion, and atypical memory B-cell expansion. (clinical)

Key point (branch independence): The hepatic vascular disease is cell-intrinsic to endothelium and lymphocyte-independent — endothelial-specific Gimap5 deletion reproduces capillarization, and Gimap5^sph/sph;Rag1⁻/⁻ mice (lacking T/B cells) still develop the liver phenotype (PMID 33956074). This predicts HSCT will not reverse established portal hypertension.

Category detail

  • Molecular pathways: CK2 → ceramide-synthase/sphingolipid pathway (GO:0006672 ceramide metabolic process); GATA4-dependent endothelial specification; GSK3β signaling (Wnt/insulin-adjacent) controlling c-Myc and NFATc1; NF-κB/MAPK dysregulation in Gimap5-mutant T cells (PMID 16584774).
  • Cellular processes: anti-apoptotic function (GO:0043066 negative regulation of apoptotic process); cellular senescence (GO:0090398); T-cell homeostasis (GO:0043029); endothelial cell differentiation (GO:0045446); autophagy/lysosomal biology.
  • Protein dysfunction: loss of a small AIG1-type G-domain GTPase (Pfam PF04548; InterPro IPR006703; GO:0003924 GTPase activity; GO:0005525 GTP binding); missense variants in/around the G-domain destabilize/abolish the protein (loss of function).
  • Metabolic/lipidomic changes: accumulation of long-chain ceramides (CHEBI:17761 ceramide) — a defining metabolic signature.
  • Immune involvement: combined features of immunodeficiency (lymphopenia, infection) and autoimmunity (cytopenias) — an inborn error of immunity.
  • Tissue-damage mechanism: endothelial capillarization/senescence → sinusoidal fibrosis-independent remodeling; progressive liver dysfunction.
  • Molecular profiling: single-cell RNA-seq of GIMAP5-deficient mouse liver documented replacement of LSECs by capillarized endothelial cells and placed GIMAP5 upstream of GATA4 (PMID 33956074); T-cell proteomics/lipidomics documented the CK2–ceramide axis (PMID 38172257).

GO / CL / CHEBI suggestions: GO:0003924, GO:0005525, GO:0043066, GO:0090398, GO:0006672, GO:0045446, GO:0043029; CL:1000488 (liver sinusoidal endothelial cell), CL:0000115 (endothelial cell), CL:0000084 (T cell), CL:0000623 (NK cell), CL:0000182 (hepatocyte); CHEBI:17761 (ceramide).

7. Anatomical Structures Affected

  • Organ level (primary): liver (UBERON:0002107) — specifically the hepatic sinusoid (UBERON:0001281) and portal venous system/portal vein (UBERON:0002017). Digestive/hepatobiliary and cardiovascular (portal venous) systems are primarily involved.
  • Secondary organ involvement: spleen (UBERON:0002106) — splenomegaly/hypersplenism; esophagus (UBERON:0001043) — varices; bone marrow (UBERON:0002371) and lymphoid organs — lymphopenia, extramedullary hematopoiesis (in models); gastrointestinal tract (variceal bleeding).
  • Tissue/cell level: vascular endothelium, chiefly liver sinusoidal endothelial cells (CL:1000488); T lymphocytes (CL:0000084) and NK cells (CL:0000623); hepatocytes secondarily; platelets (consumed peripherally).
  • Subcellular level: GIMAP5 localizes to the lysosomal membrane (GO:0005765) and multivesicular body/endosome membrane (GO:0032585) (UniProt Q96F15); older studies also implicated ER (GO:0005783) and mitochondria (GO:0005739) in T-cell survival/Ca²⁺ handling.
  • Localization / lateralization: intra-abdominal, bilateral/diffuse hepatic involvement; not lateralized.

8. Temporal Development

  • Onset: congenital-to-pediatric; portal hypertension and immune manifestations usually emerge in infancy through adolescence. Onset pattern is insidious/chronic (portal hypertension often detected via splenomegaly/thrombocytopenia or a variceal bleed).
  • Progression: chronic, progressive hepatic vascular disease; can advance to decompensation (coagulopathy, hyperbilirubinemia) despite shunting (PMID 33956074). Immune disease can be episodic (autoimmune cytopenia flares, intercurrent infections).
  • Disease course/duration: lifelong; no spontaneous remission of the vascular disease. Immune cytopenias can be treatment-induced remission (e.g., sirolimus) (PMID 42358996).
  • Critical periods / intervention windows: early molecular diagnosis enables variceal surveillance/prophylaxis, infection prophylaxis, and consideration of HSCT before irreversible organ damage; the endothelial disease may have an early window before established capillarization/portal hypertension (inferred).

9. Inheritance and Population

  • Inheritance: Autosomal recessive (HP:0000007). Recurrence risk 25% for siblings of an affected proband.
  • Penetrance: appears high/complete for biallelic LOF (all reported biallelic individuals affected), though phenotypic expressivity is variable (severity, relative weight of hepatic vs immune features).
  • Genetic anticipation / mosaicism: not applicable / not reported.
  • Consanguinity: a major factor — most index families are consanguineous (PMID 33956074).
  • Founder / recurrent allele: p.Leu204Pro (AF ≈2.1×10⁻³) recurs and drives a disproportionate share of cases; no formal founder haplotype study published.
  • Carrier frequency: GIMAP5 is LOF-tolerant (gnomAD pLI=0.003); heterozygous carriers are healthy. Aggregate carrier frequency is low but non-trivial where p.L204P is present.
  • Epidemiology: ultra-rare — on the order of ~20–25 molecularly confirmed patients reported worldwide (≥4 families in the founding study plus subsequent case reports/series, ~21 patients reviewed by 2026). No reliable prevalence/incidence estimate (well under 1/1,000,000). Reported patients are geographically diverse (Turkey, Europe, China, North America).
  • Sex ratio: no established skew (autosomal recessive). Age distribution: pediatric-predominant at diagnosis.

10. Diagnostics

Genetic testing (definitive): - Whole-exome sequencing (WES) or whole-genome sequencing (WGS) identifying biallelic GIMAP5 variants is the diagnostic gold standard (high-depth WES used in the founding study; PMID 33956074). GeneMatcher/trio exome aids ultra-rare gene discovery. - Single-gene / panel testing: GIMAP5 can be included on PSVD / noncirrhotic portal hypertension and inborn errors of immunity gene panels; targeted testing for the recurrent p.L204P is reasonable in consanguineous pedigrees. - CMA/karyotype/FISH: not primary; only relevant to exclude contiguous 7q36 CNVs. Mitochondrial/repeat-expansion testing not applicable. - Confirmatory functional test: GIMAP5 protein immunoblot (absent protein confirms LOF) and flow-cytometric immunophenotyping (T/NK lymphopenia, T-cell exhaustion, atypical memory B cells) (PMID 42358996).

Clinical/laboratory workup (supportive, to characterize the phenotype): - Labs: CBC (thrombocytopenia, cytopenias), transaminases (elevated), GGT (elevated), bilirubin/coagulation (with progression), lymphocyte subsets. LOINC-codable. - Liver histology (PSVD pattern): nodular regenerative hyperplasia, CD34-positive capillarized LSECs, obliterative portal venopathy (absent portal venules), no cirrhosis/significant fibrosis (PMID 33956074). SNOMED CT: nodular regenerative hyperplasia of liver. - Endoscopy: upper GI endoscopy for esophageal/gastric varices. - Imaging: ultrasound/Doppler, CT/MRI showing splenomegaly, portosystemic collaterals, patent portal vein (excluding portal/splanchnic vein thrombosis); transient elastography typically discordant with severe portal hypertension (low fibrosis vs high pressure).

Diagnostic criteria / differential. No PHNC2-specific criteria; diagnosis = PSVD/noncirrhotic portal hypertension features + biallelic GIMAP5. Differential diagnosis: cirrhosis of any cause; portal/splenic vein thrombosis (extrahepatic); congenital hepatic fibrosis; schistosomiasis; drug/toxin-induced NRH (didanosine, thioguanine, oxaliplatin); other genetic PSVD/INCPH genes — DGUOK (PHNC1/INCPH1), KCNN3, FCHSD1, FOPV, TRMT5, HRG, and syndromic causes (Adams–Oliver, telomere biology disorders, cystic fibrosis, Turner, Williams–Beuren) (review PMID 38900412). GIMAP5's accompanying immunodeficiency/autoimmunity is a key distinguishing clue.

Screening (asymptomatic): cascade/carrier testing of relatives; prenatal/preimplantation testing in known families (see §13).

11. Outcome / Prognosis

  • Survival/mortality: guarded in severe cases. In the founding cohort, three affected individuals in one kindred were deceased, two dying from complications of portal hypertension; one patient died at 17 with recurrent infections (PMID 33956074). No formal 5-/10-year survival statistics exist (too few patients).
  • Morbidity: recurrent variceal bleeding, refractory/transfusion-dependent cytopenias, infection susceptibility, progressive liver dysfunction (coagulopathy, hyperbilirubinemia), and risk of extramedullary hematopoiesis (models). Hepatocellular carcinoma (HP:0001402) is listed as a potential long-term risk.
  • Recovery potential: the vascular disease does not spontaneously remit; portosystemic shunting improves varices but does not halt underlying liver disease (PMID 33956074). Immune cytopenias can respond well to immunomodulation.
  • Prognostic factors: degree of portal hypertension/hepatic decompensation; severity of immunodeficiency and infection burden; genotype (null/absent protein alleles such as R214 may predict more complete deficiency). Prognostic biomarker candidate:* long-chain ceramide accumulation (mechanistic; not clinically validated).

12. Treatment

No disease-specific approved therapy exists; management is organ-directed and, increasingly, mechanism-informed.

A. Portal-hypertension / hepatic care (standard of care): - Endoscopic variceal band ligation and nonselective beta-blockers (e.g., propranolol/carvedilol) for variceal prophylaxis (NCIT: Propranolol C692; Endoscopic Variceal Ligation). - Portosystemic shunt surgery / TIPS — improved varices/collaterals in a reported patient (PMID 33956074) (NCIT: Transjugular Intrahepatic Portosystemic Shunt). - Ascites management (diuretics/sodium restriction); liver transplantation for end-stage disease (NCIT: Liver Transplantation C15356) — rational because the defect is intrahepatic-endothelial.

B. Immune-directed therapy: - Sirolimus (rapamycin; mTOR inhibitor) achieved sustained remission of autoimmune cytopenias (PMID 42358996) (NCIT: Sirolimus C1212). - Supportive: IVIG, targeted antimicrobial/antiviral prophylaxis, vaccination as tolerated (NCIT: Intravenous Immunoglobulin Therapy). - Allogeneic hematopoietic stem cell transplantation (HSCT) is considered definitive for the immune/hematologic disease (NCIT: Hematopoietic Stem Cell Transplantation C15431), but — because the liver disease is endothelial-intrinsic and lymphocyte-independent — HSCT is not expected to reverse established portal hypertension; the risk/benefit must be weighed carefully (PMID 42358996).

C. Experimental / mechanism-based (preclinical): - GSK3 inhibitors rescued patient T-cell proliferation in vitro (PMID 29382851). - CK2 inhibitors + ceramide-synthase inhibitors rescued GIMAP5-deficient T cells by preventing ceramide overaccumulation (PMID 38172257) — a candidate for future targeted therapy. - Gene/RNA therapy: none developed; conceptually attractive given recessive LOF and endothelial/lymphoid expression (not yet in trials). No NCT registrations identified.

Pharmacogenomics: none disease-specific. Personalized approach: genotype/phenotype-guided balancing of liver-directed vs immune-directed (sirolimus) vs HSCT strategies.

13. Prevention

  • Primary prevention: not possible for the genetic disease itself; preconception genetic counseling in consanguineous/known-carrier families, with carrier testing, prenatal diagnosis, and preimplantation genetic testing (PGT-M) to prevent affected births (autosomal recessive, 25% recurrence).
  • Secondary prevention (early detection): molecular diagnosis enables variceal surveillance endoscopy, monitoring of platelet counts/liver tests, and early immune monitoring; cascade genetic screening of at-risk relatives.
  • Tertiary prevention (complication avoidance): beta-blockers/band ligation to prevent variceal hemorrhage; infection prophylaxis and vaccination; timely immunomodulation for cytopenias; transplant planning.
  • Immunization/public-health/environmental measures: standard immunizations (with attention to live-vaccine caution in immunodeficiency); no vector/sanitation measures apply (non-infectious etiology).
  • Counseling: genetic counseling is central given recessive inheritance and consanguinity.

14. Other Species / Natural Disease

  • Taxonomy of affected/model species: human Homo sapiens (NCBI:txid9606); Mus musculus (NCBI:txid10090); Rattus norvegicus (NCBI:txid10116). GIMAP5 orthologs are also studied in chicken (Gallus gallus, NCBI:txid9031; PMIDs 31579581, 32147998).
  • Orthologous genes: mouse Gimap5 (NCBI Gene 14468; MGI), rat Gimap5 (RGD). Mechanisms (anti-apoptotic GTPase, lymphocyte survival) are evolutionarily conserved across rodents and birds.
  • Natural (spontaneous) animal disease: the BioBreeding diabetes-prone (BB-DP) rat carries a spontaneous Gimap5 frameshift (lyp) allele causing T-cell lymphopenia and autoimmune type 1 diabetes (PMIDs 17655828, 19007993) — a naturally occurring model of GIMAP5 deficiency, though its hallmark is autoimmune diabetes rather than portal hypertension. No specific companion-animal PHNC2 (no OMIA entry for GIMAP5 portal hypertension identified).
  • Comparative pathology: rodents recapitulate lymphopenia and liver pathology; the portal-hypertension/LSEC-capillarization phenotype is specifically demonstrated in mouse (endothelial-intrinsic).
  • Zoonotic potential: none (genetic, non-transmissible).

15. Model Organisms

Mouse (Mus musculus; MGI) — primary PHNC2 model: - Germline Gimap5 knockout / sph (sphinx) ENU allele: impaired peripheral T-cell survival, disrupted NK/NKT development, chronic hepatic hematopoiesis, hepatocyte apoptosis and liver failure, median survival ~15 weeks (PMID 18796632). - Endothelial-cell-conditional Gimap5 deletion: reproduces LSEC capillarization — the most faithful model of the human portal-hypertension mechanism (PMID 33956074). - Epistasis models: Gimap5^sph/sph;Rag1⁻/⁻ mice (no T/B cells) still develop liver disease → portal hypertension is lymphocyte-independent (PMID 33956074). - Complex/humanized biology: Mfsd1, Glmp, and Gimap5 germline knockouts each cause lymphopenia, liver pathology, and extramedullary hematopoiesis, defining the stabilizing MFSD1–GLMP–GIMAP5 complex (PMID 38055739). - Mechanistic mouse models: GSK3β-axis studies (PMID 29382851); ceramide/CK2 senescence pathway (PMID 38172257).

Rat (Rattus norvegicus; RGD): BB-DP (lyp/lyp) and congenic lines — spontaneous Gimap5 frameshift; robust model of T-cell lymphopenia, ER-stress/CHOP apoptosis, mitochondrial Ca²⁺ dysregulation, and autoimmune diabetes (PMIDs 17655828, 19424493, 19007993, 21502331).

In vitro / cellular: patient T cells (proliferation defect rescued by GSK3 inhibitors), Jurkat/HEK overexpression studies, and primary LSEC analyses.

Phenotype recapitulation & limitations: rodents faithfully model the immune arm (lymphopenia, autoimmunity) and, in mouse endothelial-specific/whole-body models, the hepatic vascular arm (capillarization, portal hypertension). Limitations: the BB-DP rat's dominant phenotype is autoimmune diabetes (not seen as a core human PHNC2 feature); mouse whole-body nulls have very short lifespans complicating chronic-disease study; hepatocellular carcinoma risk and human-specific variant effects are not fully captured. Resources: MGI (mouse Gimap5), RGD (rat Gimap5, BB rat), IMPC/IMSR for alleles.

Supported vs. Refuted Hypotheses

Supported: - PHNC2 is caused by biallelic LOF GIMAP5 variants, autosomal recessive (PMID 33956074). - Portal hypertension arises from GATA4-dependent LSEC capillarization, an endothelial-intrinsic, lymphocyte-independent mechanism (PMID 33956074). - A unifying CK2–ceramide senescence pathway links hepatic and immune disease (PMID 38172257). - Disease is multisystem (portal hypertension + immunodeficiency/autoimmunity) with childhood onset (PMIDs 33956074, 42358996).

Refuted / not supported: - PHNC2 is not due to cirrhosis, fibrosis, or portal/splanchnic vein thrombosis (explicitly excluded; PMID 33956074). - Not caused by DGUOK (that is the distinct PHNC1/INCPH1, PMID 26874653). - No environmental/infectious cause is required; heterozygous carriers are unaffected.

Limitations and Future Directions

  • Very small N (~20–25 patients) limits penetrance, expressivity, natural-history, prognosis, and QoL precision.
  • Genotype–phenotype relationships (e.g., missense vs null alleles; the recurrent p.L204P; possible monoallelic vascular predisposition) need larger cohorts.
  • Therapeutic priorities: validate CK2/ceramide-synthase and GSK3 inhibition clinically; define whether early HSCT alters liver outcomes; assess liver transplantation outcomes; explore endothelial-directed or gene-based therapy.
  • Registry/omics: a dedicated PSVD-genetics registry and hepatic single-cell/lipidomic profiling in patients would refine mechanism and biomarkers.

Key References (PMID)

  • 33956074 Drzewiecki et al., J Exp Med 2021 — GIMAP5 maintains liver endothelial cell homeostasis and prevents portal hypertension (disease-defining).
  • 38172257 Park et al., Nat Immunol 2024 — GIMAP5 deficiency reveals a ceramide-driven longevity/senescence pathway.
  • 38055739 Zhong et al., PNAS 2023 — MFSD1–GLMP–GIMAP5 complex in lymphocyte survival and liver homeostasis.
  • 42358996 Moratti et al., Front Immunol 2026 — clinical spectrum, sirolimus, HSCT dilemmas (compound-het L204P/R214*).
  • 29382851 Patterson et al., Nat Commun 2018 — Gimap5–GSK3β; first human LOF patient.
  • 18796632 Schulteis et al., Blood 2008 — Gimap5-KO mouse liver failure/lymphopenia.
  • 38900412 Ciriaci et al., Hepatology 2026 — genetic predisposition to PSVD (differential/gene list).
  • 26874653 Vilarinho et al., 2016 — DGUOK in INCPH1 (distinct PHNC1).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 9
Resolved 9
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 9
On topic 5
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 44
Resolved 43
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 30
Terms named correctly 19
Terms named as a different term 3
Terms whose name is worth a second look 8

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • CL:1000488 (2 mentions) - the report calls it "liver sinusoidal endothelial cell"; CL calls it cholangiocyte
  • UBERON:0002106 (1 mention) - the report calls it "spleen", "Secondary organ involvement: spleen"; UBERON calls it spleen
  • GO:0005765 (1 mention) - the report calls it "Subcellular level: GIMAP5 localizes to the lysosomal membrane"; GO calls it lysosomal membrane

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • MONDO:0030397 (2 mentions) - the report calls it "portal hypertension, noncirrhotic, 2"; synonym NCPH2"; MONDO calls it portal hypertension, noncirrhotic, 2**
  • HP:0002910 (1 mention) - the report calls it "Elevated transaminases"; HP calls it Elevated circulating hepatic transaminase concentration, and lists "Elevated transaminases" among its other names
  • HP:0002040 (1 mention) - the report calls it "Esophageal varices"; HP calls it Esophageal varix, and lists "Esophageal varices" among its other names
  • HP:0030948 (1 mention) - the report calls it "Elevated GGT"; HP calls it Elevated gamma-glutamyltransferase level, and lists "Elevated serum GGT" among its other names
  • HP:0001888 (1 mention) - the report calls it "Lymphopenia"; HP calls it Decreased total lymphocyte count, and lists "Lymphopenia" among its other names
  • CL:0000623 (2 mentions) - the report calls it "NK cell"; CL calls it natural killer cell, and lists "NK cell" among its other names
  • UBERON:0002017 (1 mention) - the report calls it "portal venous system/portal vein"; UBERON calls it portal vein, and lists "portal venous tree organ part" among its other names
  • HP:0000007 (1 mention) - the report calls it "Autosomal recessive", "Inheritance: Autosomal recessive"; HP calls it Autosomal recessive inheritance, and lists "Autosomal recessive" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • UBERON:0002106 - called "spleen", "Secondary organ involvement: spleen"
  • HP:0000007 - called "Autosomal recessive", "Inheritance: Autosomal recessive"