Genetic linkage analysis of a large family identifies FIGN as a candidate modulator of reduced penetrance in heritable pulmonary arterial hypertension

Abstract

BackgroundMapping the genetic component of molecular mechanisms responsible for the reduced penetrance (RP) of rare disorders constitutes one of the most challenging problems in human genetics. Heritable pulmonary arterial hypertension (PAH) is one such disorder characterised by rare mutations mostly occurring in the bone morphogenetic protein receptor type 2 (BMPR2) gene and a wide heterogeneity of penetrance modifier mechanisms. Here, we analyse 32 genotyped individuals from a large Iberian family of 65 members, including 22 carriers of the pathogenic BMPR2 mutation c.1472G>A (p.Arg491Gln), 8 of them diagnosed with PAH by right-heart catheterisation, leading to an RP rate of 36.4%.MethodsWe performed a linkage analysis on the genotyping data to search for genetic modifiers of penetrance. Using functional genomics data, we characterised the candidate region identified by linkage analysis. We also predicted the haplotype segregation within the family.ResultsWe identified a candidate chromosome region in 2q24.3, 38 Mb upstream from BMPR2, with significant linkage (LOD=4.09) under a PAH susceptibility model. This region contains common variants associated with vascular aetiology and shows functional evidence that the putative genetic modifier is located in the upstream distal promoter of the fidgetin (FIGN) gene.ConclusionOur results suggest that the genetic modifier acts through FIGN transcriptional regulation, whose expression variability would contribute to modulating heritable PAH. This finding may help to advance our understanding of RP in PAH across families sharing the p.Arg491Gln pathogenic mutation in BMPR2.

Extracorporeal membrane oxygenation support for balloon atrial septostomy in a BMPR2 variant‐associated pulmonary arterial hypertension

“…2 The current patient had previously reported pathogenic variant in BMPR2: c.1472 G > A (p.Arg491Gln) located in a kinase domain. 3 The missense heterozygous variant is predicted to be disruptive based on the alteration and interaction of protein structure, although the functional mechanism has yet to be clarified. 4 The epigenetic mechanism may also contribute to the genetic bases for the etiopathogenesis of PAH, because the COVID-19 pandemic is known to be associated with PAH.…”

Landscape of Genome-Wide DNA Methylation of Colorectal Cancer Metastasis

“…Two of these genes, HTRA3 and STAC2 , were found as the top five hypermethylated CGIs in primary tumour and LNM, respectively. FIGN (fidgetin) is a gene coding for a microtubule severing enzyme as well as a depolymerase, predominantly involved in mitosis but also contributing to cell migration and neuronal development [ 46 ]. Studies have shown that FIGN is overexpressed in human hepatocellular carcinomas promoting hepatocyte invasion [ 47 ] HTRA3 (high temperature requirement A3) is a member of the HtrA family and is a proapoptotic protease shown to promote drug-induced cytotoxicity and proposed to have an antitumour effect [ 48 ].…”

The fidgetin family: Shaking things up among the microtubule‐severing enzymes

“…Fidgetin may play a cardioprotective role through a non‐severing function according to recent evidence. Multiple human single nucleotide polymorphisms (SNPs) associated with cardiorespiratory phenotypes and with heritable pulmonary arterial hypertension have been identified in the distal promoter region of the fidgetin gene, leading to less penetrance of the gene mutation responsible for heritable pulmonary arterial hypertension (Puigdevall et al, 2019). Studies with Han Chinese populations indicated three isoforms of fidgetin, one of which—X3—was associated with lower risk of congenital heart defects when it contained a +94762G>C SNP (D. Wang, Chu, et al, 2017).…”