Tags

Type your tag names separated by a space and hit enter

Severe molecular defects of a novel FOXC1 W152G mutation result in aniridia.
Invest Ophthalmol Vis Sci. 2009 Aug; 50(8):3573-9.IO

Abstract

PURPOSE

FOXC1 mutations result in Axenfeld-Rieger syndrome, a disorder characterized by a broad spectrum of malformations of the anterior segment of the eye and an elevated risk for glaucoma. A novel FOXC1 W152G mutation was identified in a patient with aniridia. Molecular analysis was conducted to determine the functional consequences of the FOXC1 W152G mutation.

METHODS

Site-directed mutagenesis was used to introduce the W152G mutation into the FOXC1 complementary DNA. The levels of W152G protein expression and the functional abilities of the mutant protein were determined.

RESULTS

After screening for mutations in PAX6, CYP1B1, and FOXC1, a novel FOXC1 W152G mutation was identified in a newborn boy with aniridia and congenital glaucoma. Molecular analysis of the W152G mutation revealed that the mutant protein has severe molecular consequences in FOXC1, including defects in phosphorylation, protein folding, DNA-binding ability, inability to transactivate a reporter gene, and nuclear localization. Although W152G has molecular defects similar to those of the previously studied FOXC1 L130F mutation, W152G causes a more severe phenotype than L130F. Both the W152G and the L130F mutations result in the formation of protein aggregates in the cytoplasm. However, unlike the L130F aggregates, the W152G aggregates do not form microtubule-dependent inclusion bodies, known as aggresomes.

CONCLUSIONS

Severe molecular consequences, including the inability of the W152G protein aggregates to form protective aggresomes, may underlie the aniridia phenotype that results from the FOXC1 W152G mutation.

Authors+Show Affiliations

Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19279310

Citation

Ito, Yoko A., et al. "Severe Molecular Defects of a Novel FOXC1 W152G Mutation Result in Aniridia." Investigative Ophthalmology & Visual Science, vol. 50, no. 8, 2009, pp. 3573-9.
Ito YA, Footz TK, Berry FB, et al. Severe molecular defects of a novel FOXC1 W152G mutation result in aniridia. Invest Ophthalmol Vis Sci. 2009;50(8):3573-9.
Ito, Y. A., Footz, T. K., Berry, F. B., Mirzayans, F., Yu, M., Khan, A. O., & Walter, M. A. (2009). Severe molecular defects of a novel FOXC1 W152G mutation result in aniridia. Investigative Ophthalmology & Visual Science, 50(8), 3573-9. https://doi.org/10.1167/iovs.08-3032
Ito YA, et al. Severe Molecular Defects of a Novel FOXC1 W152G Mutation Result in Aniridia. Invest Ophthalmol Vis Sci. 2009;50(8):3573-9. PubMed PMID: 19279310.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Severe molecular defects of a novel FOXC1 W152G mutation result in aniridia. AU - Ito,Yoko A, AU - Footz,Tim K, AU - Berry,Fred B, AU - Mirzayans,Farideh, AU - Yu,May, AU - Khan,Arif O, AU - Walter,Michael A, Y1 - 2009/03/11/ PY - 2009/3/13/entrez PY - 2009/3/13/pubmed PY - 2009/8/12/medline SP - 3573 EP - 9 JF - Investigative ophthalmology & visual science JO - Invest Ophthalmol Vis Sci VL - 50 IS - 8 N2 - PURPOSE: FOXC1 mutations result in Axenfeld-Rieger syndrome, a disorder characterized by a broad spectrum of malformations of the anterior segment of the eye and an elevated risk for glaucoma. A novel FOXC1 W152G mutation was identified in a patient with aniridia. Molecular analysis was conducted to determine the functional consequences of the FOXC1 W152G mutation. METHODS: Site-directed mutagenesis was used to introduce the W152G mutation into the FOXC1 complementary DNA. The levels of W152G protein expression and the functional abilities of the mutant protein were determined. RESULTS: After screening for mutations in PAX6, CYP1B1, and FOXC1, a novel FOXC1 W152G mutation was identified in a newborn boy with aniridia and congenital glaucoma. Molecular analysis of the W152G mutation revealed that the mutant protein has severe molecular consequences in FOXC1, including defects in phosphorylation, protein folding, DNA-binding ability, inability to transactivate a reporter gene, and nuclear localization. Although W152G has molecular defects similar to those of the previously studied FOXC1 L130F mutation, W152G causes a more severe phenotype than L130F. Both the W152G and the L130F mutations result in the formation of protein aggregates in the cytoplasm. However, unlike the L130F aggregates, the W152G aggregates do not form microtubule-dependent inclusion bodies, known as aggresomes. CONCLUSIONS: Severe molecular consequences, including the inability of the W152G protein aggregates to form protective aggresomes, may underlie the aniridia phenotype that results from the FOXC1 W152G mutation. SN - 1552-5783 UR - https://www.unboundmedicine.com/medline/citation/19279310/Severe_molecular_defects_of_a_novel_FOXC1_W152G_mutation_result_in_aniridia_ L2 - https://iovs.arvojournals.org/article.aspx?doi=10.1167/iovs.08-3032 DB - PRIME DP - Unbound Medicine ER -