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Human Molecular Genetics, 2001, Vol. 10, No. 16 1631-1638
© 2001 Oxford University Press

Functional analyses of two newly identified PITX2 mutants reveal a novel molecular mechanism for Axenfeld–Rieger syndrome

Megan Priston1, Kathy Kozlowski2, Dan Gill1, Ken Letwin1, Yvonne Buys1, Alex V. Levin3, Mike A. Walter2 and Elise Héon1,3,+

1Department of Ophthalmology and The Vision Science Research Program, University Health Network, The Toronto Western Hospital, Toronto, Ontario M5T 2S8, Canada, 2Departments of Ophthalmology and Medical Genetics, University of Alberta, Edmonton, Canada and 3Department of Ophthalmology, The Hospital for Sick Children, Toronto, Ontario, Canada

The specific role of PITX2 in the pathogenesis of anterior segment dysgenesis has yet to be clearly defined. We provide here new insight into PITX2 pathogenesis through mutational and functional analyses. Three PITX2 mutations were found in a screen of 38 unrelated individuals affected with anterior segment anomalies (8%). All three mutations were found among the 21 individuals affected with Axenfeld–Rieger syndrome (ARS). We have identified two novel mutations, a valine->leucine (V45L) missense mutation at position 45 within the PITX2 homeodomain, and a seven amino acid duplication (7aaDup) of residues 6–12 of the homeodomain. DNA-binding studies of the two mutant PITX2 proteins demonstrated a <10-fold reduction in the DNA-binding activity of the V45L mutant, and a >100-fold reduction in activity of the 7aaDup mutant. Luciferase reporter assays showed a >200% increase in PITX2 transactivation activity of the V45L mutant, while the 7aaDup mutant was unable to transactivate at detectable levels. Our analyses of the V45L PITX2 mutant reveal that the DNA-binding domain of PITX2 can influence transactivation activity independently of DNA binding. Furthermore, our findings expand the hypothesis that the amount of residual PITX2 activity underlies the variable severity of ocular phenotypes that result from PITX2 mutation. For the first time, we present evidence that increased PITX2 activity may underlie the severe ARS ocular phenotype. We conclude that increased activity of one PITX2 allele may be as physiologically disruptive as a mutation that nullifies a PITX2 allele, with either condition resulting in ARS.

+ To whom correspondence should be addressed at: Toronto Western Hospital, 399 Bathurst Street, Room 6-412, Toronto, Ontario M5T 2S8, Canada. Tel: +1 416 603 5418; Fax: +1 416 603 5126; Email: eheon@uhnres.utoronto.ca The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors


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