A Spectrum of FOXC1 Mutations Suggests Gene Dosage As a Mechanism for Developmental Defects of the Anterior Chamber of the Eye

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2001 Feb 15

PMID 11170889

Citations 77

Authors

D Y Nishimura

C C Searby

W L Alward

D Walton

J E Craig

D A Mackey

K Kawase

A B Kanis

S R Patil

E M Stone

V C Sheffield

Affiliations

Soon will be listed here.

Abstract

Mutations in the forkhead transcription-factor gene (FOXC1), have been shown to cause defects of the anterior chamber of the eye that are associated with developmental forms of glaucoma. Discovery of these mutations was greatly facilitated by the cloning and characterization of the 6p25 breakpoint in a patient with both congenital glaucoma and a balanced-translocation event involving chromosomes 6 and 13. Here we describe the identification of novel mutations in the FOXC1 gene in patients with anterior-chamber defects of the eye. We have detected nine new mutations (eight of which are novel) in the FOXC1 gene in patients with anterior-chamber eye defects. Of these mutations, five frameshift mutations predict loss of the forkhead domain, as a result of premature termination of translation. Of particular interest is the fact that two families have a duplication of 6p25, involving the FOXC1 gene. These data suggest that both FOXC1 haploinsufficiency and increased gene dosage can cause anterior-chamber defects of the eye.

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References

Mirzayans F, Gould D, Heon E, Billingsley G, Cheung J, Mears A . Axenfeld-Rieger syndrome resulting from mutation of the FKHL7 gene on chromosome 6p25. Eur J Hum Genet. 2000; 8(1):71-4. DOI: 10.1038/sj.ejhg.5200354. View

Swiderski R, Reiter R, Nishimura D, Alward W, Kalenak J, Searby C . Expression of the Mf1 gene in developing mouse hearts: implication in the development of human congenital heart defects. Dev Dyn. 1999; 216(1):16-27. DOI: 10.1002/(SICI)1097-0177(199909)216:1<16::AID-DVDY4>3.0.CO;2-1. View

Alward W . The genetics of open-angle glaucoma: the story of GLC1A and myocilin. Eye (Lond). 2000; 14 ( Pt 3B):429-36. DOI: 10.1038/eye.2000.127. View

Lehmann O, Ebenezer N, Jordan T, Fox M, Ocaka L, Payne A . Chromosomal duplication involving the forkhead transcription factor gene FOXC1 causes iris hypoplasia and glaucoma. Am J Hum Genet. 2000; 67(5):1129-35. PMC: 1288555. DOI: 10.1016/S0002-9297(07)62943-7. View

Glaser T, Jepeal L, Edwards J, Young S, Favor J, Maas R . PAX6 gene dosage effect in a family with congenital cataracts, aniridia, anophthalmia and central nervous system defects. Nat Genet. 1994; 7(4):463-71. DOI: 10.1038/ng0894-463. View

Quigley H . Number of people with glaucoma worldwide. Br J Ophthalmol. 1996; 80(5):389-93. PMC: 505485. DOI: 10.1136/bjo.80.5.389. View

Schedl A, Ross A, Lee M, Engelkamp D, Rashbass P, Van Heyningen V . Influence of PAX6 gene dosage on development: overexpression causes severe eye abnormalities. Cell. 1996; 86(1):71-82. DOI: 10.1016/s0092-8674(00)80078-1. View

Phillips J, Del Bono E, Haines J, Pralea A, Cohen J, Greff L . A second locus for Rieger syndrome maps to chromosome 13q14. Am J Hum Genet. 1996; 59(3):613-9. PMC: 1914897. View

Mears A, Mirzayans F, Gould D, PEARCE W, Walter M . Autosomal dominant iridogoniodysgenesis anomaly maps to 6p25. Am J Hum Genet. 1996; 59(6):1321-7. PMC: 1914875. View

10.

Semina E, Reiter R, Leysens N, Alward W, Small K, Datson N . Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet. 1996; 14(4):392-9. DOI: 10.1038/ng1296-392. View

11.

Stone E, Fingert J, Alward W, Nguyen T, Polansky J, Sunden S . Identification of a gene that causes primary open angle glaucoma. Science. 1997; 275(5300):668-70. DOI: 10.1126/science.275.5300.668. View

12.

Stoilov I, Akarsu A, Sarfarazi M . Identification of three different truncating mutations in cytochrome P4501B1 (CYP1B1) as the principal cause of primary congenital glaucoma (Buphthalmos) in families linked to the GLC3A locus on chromosome 2p21. Hum Mol Genet. 1997; 6(4):641-7. DOI: 10.1093/hmg/6.4.641. View

13.

Gould D, Mears A, PEARCE W, Walter M . Autosomal dominant Axenfeld-Rieger anomaly maps to 6p25. Am J Hum Genet. 1997; 61(3):765-8. PMC: 1715932. View

14.

Jordan T, Ebenezer N, Manners R, McGill J, Bhattacharya S . Familial glaucoma iridogoniodysplasia maps to a 6p25 region implicated in primary congenital glaucoma and iridogoniodysgenesis anomaly. Am J Hum Genet. 1997; 61(4):882-8. PMC: 1715988. DOI: 10.1086/514874. View

15.

Graff C, Jerndal T, Wadelius C . Fine mapping of the gene for autosomal dominant juvenile-onset glaucoma with iridogoniodysgenesis in 6p25-tel. Hum Genet. 1997; 101(2):130-4. DOI: 10.1007/s004390050601. View

16.

Aalfs C, Fantes J, Wenniger-Prick L, Sluijter S, Hennekam R, Van Heyningen V . Tandem duplication of 11p12-p13 in a child with borderline development delay and eye abnormalities: dose effect of the PAX6 gene product?. Am J Med Genet. 1998; 73(3):267-71. DOI: 10.1002/(sici)1096-8628(19971219)73:3<267::aid-ajmg7>3.0.co;2-p. View

17.

Nishimura D, Swiderski R, Alward W, Searby C, Patil S, Bennet S . The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25. Nat Genet. 1998; 19(2):140-7. DOI: 10.1038/493. View

18.

Mears A, Jordan T, Mirzayans F, Dubois S, Kume T, Parlee M . Mutations of the forkhead/winged-helix gene, FKHL7, in patients with Axenfeld-Rieger anomaly. Am J Hum Genet. 1998; 63(5):1316-28. PMC: 1377542. DOI: 10.1086/302109. View

19.

Blixt A, Mahlapuu M, Bjursell C, Darnfors C, Johannesson T, Enerback S . The two-exon gene of the human forkhead transcription factor FREAC-2 (FKHL6) is located at 6p25.3. Genomics. 1998; 53(3):387-90. DOI: 10.1006/geno.1998.5451. View

20.

Fingert J, Heon E, Liebmann J, Yamamoto T, Craig J, Rait J . Analysis of myocilin mutations in 1703 glaucoma patients from five different populations. Hum Mol Genet. 1999; 8(5):899-905. DOI: 10.1093/hmg/8.5.899. View