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 AxenfeldRieger 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

Rare FOXC1 variants in congenital glaucoma: identification of translation regulatory sequences

“…4 FOXC1/PITX2 glaucoma transmission has also been described in ARS. 20 As noted above, our data also indicate a role for the moderately hypermorphic p.(G456dup) variant as a possible modifying factor. Interestingly, this variant was present in two patients who also had two other hypermorphic variants (c.-429C4G and p.(G380Rfs*144) in families PCG-96 and PCG-54, respectively) (Figure 1b and d), contributing to the overall increase in FOXC1 activity associated with these genotypes.…”

The 6p25 deletion syndrome: An update on a rare neurocristopathy

“…3,4 The FOXC1 gene (MIM #601090) encodes a transcription factor with the same name that regulates proliferation, differentiation, migration and regression of NC (derived) cells during embryonic development. 2,3,8,12 Interestingly, there is considerable overlap in clinical features between ARS and the chromosome 6pter-p24 deletion syndrome (MIM #612582, in this paper referred to as the 6p25 deletion syndrome) with heterozygous loss of FOXC1.…”

“…These malformations are present bilaterally at birth, not necessarily symmetrically, and predispose for glaucoma. [1][2][3][4][5][7][8][9] ARS is associated with a wide spectrum of additional ocular and extraocular malformations. Key clinical features comprise facial dysmorphism including mid-face and dental hypoplasia, hearing loss, short stature, skeletal abnormalities, cardiac anomalies and involuted periumbilical skin.…”

“…Key clinical features comprise facial dysmorphism including mid-face and dental hypoplasia, hearing loss, short stature, skeletal abnormalities, cardiac anomalies and involuted periumbilical skin. 1,[3][4][5]8,9 ARS can occur sporadically or as familial autosomal dominant (AD) disorder without sex predominance with full penetrance but highly variable expressivity. 5,9,10 Familial ARS accounts for 70% of cases.…”

“…The raised IOP is typically difficult to control and over 50% of patients eventually develop glaucoma, which usually presents during childhood or adolescence. [1][2][3][4][5][6]8,9,17 The typical facial dysmorphisms in ARS are caused by the involvement of NC cells in the formation of craniofacial bones, cartilages and connective tissue, and dental papillae. 1,9,16 NC cells additionally contribute to development of the forebrain, cerebral and spinal ganglia, peripheral neurons, glia and Schwann cells, and the leptomeninges.…”