title: Digenic inheritance of mutations in FOXC1 and PITX2 : correlating transcription factor function and Axenfeld-Rieger disease severity.
abstract: Disease-causing mutations affecting either one of the transcription factor genes, PITX2 or FOXC1, have been previously identified in patients with Axenfeld-Rieger syndrome (AR). We identified a family who segregate novel mutations in both PITX2 (p.Ser233Leu) and FOXC1 (c.609delC). The most severely affected individual, who presented with an atypical phenotype of corneal opacification, lens extrusion, persistent hyperplastic primary vitreous (PHPV), and subsequent bilateral retinal detachment, inherited mutations in both genes, whereas the single heterozygous mutations caused mild AR phenotypes. This is the first report of such digenic inheritance. By analyzing cognate targets of each gene, we showed that FOXC1 and PITX2 can independently regulate their own and each other's target gene promoters and do not show synergistic action in vitro. Mutation in either gene caused reduced transcriptional activation to different extents on the FOXO1 and PLOD1 promoters, whereas both mutations in combination showed the lowest level of activation. These data show how the compensatory activity of one factor, when the other is impaired, may lessen the phenotypic impact of developmental anomalies, yet reduced activity of both transcription factors increased disease severity. This suggests an under-reported mechanism for phenotypic variability whereby single mutations cause mild AR phenotypes, whereas digenic inheritance increases phenotypic severity.
authors.affiliation: Ulverscroft Vision Research Group, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kelberman
authors.forename: Lily
authors.initials: L
authors.lastname: Islam
authors.forename: Susan E
authors.initials: SE
authors.lastname: Holder
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Jacques
authors.forename: Patrick
authors.initials: P
authors.lastname: Calvas
authors.forename: Raoul C
authors.initials: RC
authors.lastname: Hennekam
authors.forename: Ken K
authors.initials: KK
authors.lastname: Nischal
authors.forename: Jane C
authors.initials: JC
authors.lastname: Sowden
mesh_terms: D000328:Adult; D000869:Anterior Eye Segment / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005123:Eye / Q000473:pathology; D005124:Eye Abnormalities / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015785:Eye Diseases, Hereditary; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010641:Phenotype; D012720:Severity of Illness Index; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation; D000097577:Homeobox Protein PITX2
chemical_list: D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C112743:FOXC1 protein, human