title: Hypo- and hypermorphic FOXC1 mutations in dominant glaucoma: transactivation and phenotypic variability.
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.G447_G448insDG activity. In contrast, the partial loss-of-function associated with p.I126S was due to impaired protein stability, DNA binding, protein phosphorylation and subcellular distribution. These results support that moderate and variable FOXC1 transactivation changes are associated with moderate goniodysgenesis, dominant glaucoma and remarkable phenotypic variability.
authors.affiliation: Área de Genética, Facultad de Medicina, Universidad de Castilla-La Mancha, Albacete, Spain; Instituto de Investigación en Discapacidades Neurológicas (IDINE), Universidad de Castilla-La Mancha, Albacete, Spain; Cooperative Research Network on Age-Related Ocular Pathology, Visual and Life Quality, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Medina-Trillo
authors.affiliation: Área de Genética, Facultad de Medicina, Universidad de Castilla-La Mancha, Albacete, Spain; Instituto de Investigación en Discapacidades Neurológicas (IDINE), Universidad de Castilla-La Mancha, Albacete, Spain; Cooperative Research Network on Age-Related Ocular Pathology, Visual and Life Quality, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Sánchez-Sánchez
authors.affiliation: Área de Genética, Facultad de Medicina, Universidad de Castilla-La Mancha, Albacete, Spain; Instituto de Investigación en Discapacidades Neurológicas (IDINE), Universidad de Castilla-La Mancha, Albacete, Spain; Cooperative Research Network on Age-Related Ocular Pathology, Visual and Life Quality, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: José-Daniel
authors.initials: JD
authors.lastname: Aroca-Aguilar
authors.affiliation: Área de Genética, Facultad de Medicina, Universidad de Castilla-La Mancha, Albacete, Spain; Instituto de Investigación en Discapacidades Neurológicas (IDINE), Universidad de Castilla-La Mancha, Albacete, Spain.
authors.forename: Jesús-José
authors.initials: JJ
authors.lastname: Ferre-Fernández
authors.affiliation: Servicio de Oftalmología, Hospital Clínico San Carlos, Madrid, Spain; Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Morales
authors.affiliation: Servicio de Oftalmología, Hospital Clínico San Carlos, Madrid, Spain; Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: Carmen-Dora
authors.initials: CD
authors.lastname: Méndez-Hernández
authors.affiliation: Servicio de Genética, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Fiona
authors.initials: F
authors.lastname: Blanco-Kelly
authors.affiliation: Servicio de Genética, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Ayuso
authors.affiliation: Servicio de Oftalmología, Hospital Clínico San Carlos, Madrid, Spain; Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: Julián
authors.initials: J
authors.lastname: García-Feijoo
authors.affiliation: Área de Genética, Facultad de Medicina, Universidad de Castilla-La Mancha, Albacete, Spain; Instituto de Investigación en Discapacidades Neurológicas (IDINE), Universidad de Castilla-La Mancha, Albacete, Spain; Cooperative Research Network on Age-Related Ocular Pathology, Visual and Life Quality, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Escribano
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D002648:Child; D002675:Child, Preschool; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005901:Glaucoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D015533:Transcriptional Activation
chemical_list: C112743:FOXC1 protein, human; D051858:Forkhead Transcription Factors