A W148R mutation in the human FOXD4 gene segregating with dilated cardiomyopathy, obsessive-compulsive disorder, and suicidality

Abstract

Abstract. The forkhead/winged helix box (FOX) gene family comprises at least 43 different genes encoding transcriptional factors with a highly conserved DNA-binding domain. To date, mutations in members of the FOX gene family have been causally linked to a variety of different human diseases. We describe a three-generation Albanian pedigree in which a complex phenotype consisting of dilated cardiomyopathy, obsessive-compulsive disorder, and suicidality is segregated with a missense mutation (W148R) in the human FOXD4 gene. This mutation disrupts an extremely highly conserved tryptophan residue in the forkhead domain of FOXD4, possibly resulting in reduced DNA binding capacity and altered transcriptional activity. Our present findings widen the spectrum of diseases associated with genetic aberrations in the forkhead gene family.

Genetic basis of dilated cardiomyopathy

“…Finally one missense pathogenic variant has been reported but associated with a complex phenotype consisting of familial DCM, obsessive-compulsive disorder, and suicidality (CM073074) [53].…”

The transcription factor unc-130/FOXD3/4 contributes to the biphasic calcium response required to optimize avoidance behavior

“…Future unc-130 studies may lead to universal molecular insights into primary neurogenesis. In addition, whole-human genome analysis has implied that FOXD4 is a risk factor for suicide and obsessive–compulsive disorder 67 . Such outcomes may be attributable to vulnerability to stress.…”

FOXD4 induces tumor progression in colorectal cancer by regulation of the SNAI3/CDH1 axis

“…7,8 FOXD4 is a transcription factor (TF) that belongs to the forkhead/winged helix-box (FOX) famil. 9 FOX transcription factors participate in several key processes, such as metabolism, cell proliferation, and metastasi. 10,11 It is reported that mutations in FOXD4 transcription are related to multiple phenotypes including dilated cardiomyopathy, obsessive-compulsive disorders, and suicidalit.…”

“…10,11 It is reported that mutations in FOXD4 transcription are related to multiple phenotypes including dilated cardiomyopathy, obsessive-compulsive disorders, and suicidalit. 9 Previous studies have revealed that epithelial-mesenchymal transition (EMT) is an important process preceding tumor metastasi. 12,13 EMT is an evolutionarily conserved developmental process characterized by the conversion of polarized immotile epithelial cells to motile mesenchymal cell.…”