Hypo- and hypermorphic FOXC1 mutations in dominant glaucoma: transactivation and phenotypic variability

PloS One
Cristina Medina-TrilloJulio Escribano

Abstract

Dominant glaucoma, a heterogeneous, infrequent and irreversible optic neuropathy, is often associated with elevated intraocular pressure and early-onset. The role of FOXC1 in this type of glaucoma was investigated in twelve Spanish probands via nucleotide variation screening of its proximal promoter and unique exon. Functional evaluations of the identified variants included analyses of the transcriptional activity, protein stability, DNA binding ability and subcellular localization. Four different mutations that were identified in four probands (33.3%) were associated with remarkable phenotypic variability and were functionally classified as either hypermorphic (p.Y47X, p.Q106X and p.G447_G448insDG) or hypomorphic (p.I126S) alleles. To the best of our knowledge, three of the variants are novel (p.Y47X, p.I126S and p.G447_G448insDG) and, in addition, hypermorphic FOXC1 mutations are reported herein for the first time. The presence of an intact N-terminal activation domain in the truncated proteins p.Y47X and p.Q106X may underlie their associated transactivation hyperactivity by a gain-of-function mechanism involving dysregulated protein-protein interactions. Similarly, altered molecular interactions may also lead to increased p....Continue Reading

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Citations

Jul 30, 2015·European Journal of Human Genetics : EJHG·Cristina Medina-TrilloJulio Escribano
Apr 23, 2017·American Journal of Medical Genetics. Part a·Susana CarmonaConceição Egas
May 18, 2017·European Journal of Human Genetics : EJHG·Emmanuelle SouzeauJamie E Craig
Mar 1, 2018·Oncotarget·Fahed A ElianMichael A Walter
Sep 23, 2016·Nature Reviews. Disease Primers·Robert N WeinrebKeith R Martin
Jul 29, 2020·Human Molecular Genetics·Jesús-José Ferre-FernándezElena V Semina
Aug 25, 2020·Translational Vision Science & Technology·Elena LangChristina Gerth-Kahlert

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electrophoresis
dot blot
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Software Mentioned

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SIFT
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