Genetic predisposition to porto-sinusoidal vascular disorder: a functional genomic-based, multi-generational family study.

BACKGROUND AND AIMS

Porto-sinusoidal vascular disorder (PSVD) is a group of liver vascular diseases featuring lesions encompassing the portal venules and sinusoids unaccompanied by cirrhosis, irrespective of the presence/absence of portal hypertension. It can occur secondary to coagulation disorders or insult by toxic agents. However, the cause of PSVD remains unknown in most cases. Hereditary cases of PSVD are exceptionally rare, but they are of particular interest and may unveil genetic alterations and molecular mechanisms associated with the disease.

APPROACH AND RESULTS

We performed genome sequencing of four patients and two healthy individuals of a large multi-generational Lebanese family with PSVD and identified a heterozygous deleterious variant (c.547C>T, p.R183W) of FCHSD1, an uncharacterised gene, in patients. This variant segregated with the disease, and its pattern of inheritance was suggestive of autosomal dominant with variable expressivity. RNA structural modelling of human FCHSD1 suggests that the C-to-T substitution at position 547, corresponding to FCHSD1R183W , may increase both mRNA and protein stability and its interaction with mLST8, a key protein of the mTOR pathway. These predictions were substantiated by biochemical analyses, which showed that FCHSD1R183W induced high FCHSD1 mRNA stability, overexpression of FCHSD1 protein, and an increase in mTORC1 activation. This human FCHSD1 variant was introduced into mice through CRISPR/Cas9 genome editing. Nine out of the fifteen mice carrying the human FCHSD1R183W variant mimicked the phenotype of human PSVD, including splenomegaly and enlarged portal vein.

CONCLUSIONS

Aberrant FCHSD1 structure and function leads to mTOR pathway overactivation and may cause PSVD.