FOXC1 gene

Overview

Gene (OMIM No.)
Function of gene/protein
  • Protein: Forkhead box C1
  • Transcription factor regulating the activity of other genes
  • Interacts with the PITX2 protein in influencing migration and differentiation of neural crest cells into distinct anterior segment structures
  • Also involved in the normal development of other parts of the body, including the heart, kidneys, and brain
Clinical phenotype
(OMIM phenotype no.)
  • Anterior segment dysgenesis 3, multiple subtypes (#601631)
  • Axenfeld-Rieger syndrome, type 3 (#602482)
Inheritance
Ocular features
  • High clinical variability between and within families
  • Some patients present with striking ocular features in infancy or early childhood while others are more subtle
  • Glaucoma is the main associated ocular co-morbidity
  • Axenfeld-Reiger anomaly (posterior embryotoxon, iris hypoplasia, polycoria, corectopia)
  • Primary congenital glaucoma
  • Peters anomaly
  • Strabismus (due to sensory deprivation amblyopia)
  • Reduced vision
  • Incidentally identified ocular hypertension and glaucomatous cupping in later life
Systemic featuresAxenfeld-Rieger syndrome:
  • Distinctive facial features (hypertelorism, broad, flat nasal bridge and a prominent forehead)
  • Dental abnormalities (micro-, hypo-, oligo-, and/or anodontia, taurodontism, enamel hypoplasia, shortened roots, delayed eruption and cone-shaped teeth)
  • Redundant periumbilical skin
  • Cardiovascular defects (patent ductus arteriosus, atrial/ventricular septal defect)
  • Brain maldevelopment (hydrocephalus, hypoplasia of the cerebellum, brainstem, and corpus callosum)
  • Sensorineural hearing loss
  • Genitourinary anomalies (hypospadias, ureteral stenosis)
  • Skeletal anomalies (clinodactyly)
  • Developmental delay
Key investigations
  • Orthoptic assessment and refraction
  • Ultrasound biomicroscopy and B-scan ultrasound: to assess the anterior and posterior segments in the presence of corneal clouding, corneal diameter and axial length measurements
  • Anterior segment OCT also allows visualisation of anterior segment structures if corneal oedema is present
  • Glaucoma assessment (IOP measurement, gonioscopy if tolerated or EUA, disc imaging and perimetry)
  • Electrophysiology: assess a child’s level of vision
  • Systemic screening by a paediatrician for any extraocular involvement
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (ASD)
  • Whole exome sequencing
  • Whole genome sequencing
ManagementOcularSystemic
  • Multidisciplinary approach
Therapies under research
  • None at present
Further information

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References

  1.  Carlsson P, Mahlapuu M. Forkhead transcription factors: key players in development and metabolism. Dev Biol. 2002;250(1):1-23
  2.  Smith RS, Zabaleta A, Kume T, et al. Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development. Hum Mol Genet. 2000;9(7):1021-1032
  3.  Erickson RP. Forkhead genes and human disease. J Appl Genet. 2001;42(2):211-221
  4.  Lehmann OJ, Sowden JC, Carlsson P, Jordan T, Bhattacharya SS. Fox’s in development and disease. Trends Genet. 2003;19(6):339-344
  5.  Berry FB, Lines MA, Oas JM, et al. Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis. Hum Mol Genet. 2006;15(6):905-919
  6.  Lines MA, Kozlowski K, Water MA. Molecular genetics of Axenfeld-Rieger malformations. Hum Mol Genet. 2002;11:1177-1184
  7.  Seo S, Kume T. Forkhead transcription factors, Foxc1 and Foxc2, are required for the morphogenesis of the cardiac outflow tract. Dev Biol. 2006;296(2):421-436
  8.  Aldinger KA, Lehmann OJ, Hudgins L, et al. FOXC1 is required for normal cerebellar development and is a major contributor to chromosome 6p25.3 Dandy-Walker malformation. Nat Genet. 2009;41(9):1037-1042
  9.  Gould DB, Mears AJ, Pearce WG, Walter MA. Autosomal dominant Axenfeld-Rieger anomaly maps to 6p25. Am J Hum Genet. 1997;61(3):765-768
  10.  Nishimura DY, Swiderski RE, Alward WL, et al. The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25. Nat Genet. 1998;19(2):140-147
  11.  Gould D, John S. Anterior segment dysgenesis and the developmental glaucomas are complex traits. Hum Mol Genet. 2002;11(10):1185-1193
  12.  Mears AJ, Jordan T, Mirzayans F, et al. Mutations of the forkhead/winged-helix gene, FKHL7, in patients with Axenfeld-Rieger anomaly. Am J Hum Genet. 1998;63(5):1316-1328
  13.  Weisschuh N, Wolf C, Wissinger B, Gramer E. A novel mutation in the FOXC1 gene in a family with Axenfeld-Rieger syndrome and Peters’ anomaly. Clin Genet. 2008;74(5):476-480
  14.  Maclean K, Smith J, St Heaps L, et al. Axenfeld-Rieger malformation and distinctive facial features: Clues to a recognizable 6p25 microdeletion syndrome. Am J Med Genet A. 2005;132A(4):381-385
  15.  Lehmann OJ, Ebenezer ND, Ekong R, et al. Ocular developmental abnormalities and glaucoma associated with interstitial 6p25 duplications and deletions. Invest Ophthalmol Vis Sci. 2002;43(6):1843-1849
  16.  Cunningham ET, Eliott D, Miller NR, et al. Familial Axenfeld-Rieger Anomaly, Atrial Septal Defect, and Sensorineural Hearing Loss: A Possible New Genetic Syndrome. Arch Ophthalmol. 1998;116(1):78–82
  17.  O’Dwyer EM, Jones DC. Dental anomalies in Axenfeld-Rieger syndrome. Int J Paediatr Dent. 2005;15(6):459-463

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Updated on November 30, 2020
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