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A novel PITX2 mutation and a polymorphism in a 5-generation family with Axenfeld-Rieger anomaly and coexisting Fuchs' endothelial dystrophy


Kniestedt, Christoph; Taralczak, Malgorzata; Thiel, Michael A; Stuermer, Joerg; Baumer Wolz, Alessandra; Gloor, Balder P (2006). A novel PITX2 mutation and a polymorphism in a 5-generation family with Axenfeld-Rieger anomaly and coexisting Fuchs' endothelial dystrophy. Ophthalmology, 113(10):1791.e1-1797.e2.

Abstract

PURPOSE

To investigate the clinical and genetic appearance of Axenfeld-Rieger anomaly or syndrome (ARAS) and Fuchs' endothelial dystrophy (FED) in a 5-generation pedigree coexpressing both pathologic features in a large number of family members.

DESIGN

Observational case-control and DNA linkage and screening study.

PARTICIPANTS

Of 114 family members, 50 underwent clinical investigation and DNA analysis between July 2001 and March 2004.

METHODS

Linkage at the PITX2 locus was demonstrated using a number of microsatellites mapping to the critical region 4q25 to 4q26. The PITX2 gene was subsequently screened for mutations in all investigated family members.

MAIN OUTCOME MEASURE

Linkage of the ARAS and FED phenotype and mutation detection in the PITX2 gene.

RESULTS

Twenty-seven patients were identified as being affected by ARAS. Fuchs' endothelial dystrophy was found in 19 patients. Fifteen patients presented both kinds of anomaly. Deoxyribonucleic acid sequencing revealed 2 heteroallelic DNA variants that segregated together (on the same allele) and were present in all severely affected ARAS individuals. The first variant, g.20913G>T, assumed to be the causative mutation for ARAS, causes amino acid substitution at codon 137 (G137V). A statistically significant 2-point logarithm of the odds score of 4.06 was obtained with marker D4S406. The second variant is likely a polymorphism in the intron between exons 2 and 3 (IVS2+8delCinsGTT) and was detected in heterozygous form in 20% of control individuals.

CONCLUSION

This gene analysis revealed a novel PITX2 mutation and a polymorphism in a family with ARAS. Whether FED, also manifested in the severely affected individuals, is due to a different but cosegregating gene is to be determined.

Abstract

PURPOSE

To investigate the clinical and genetic appearance of Axenfeld-Rieger anomaly or syndrome (ARAS) and Fuchs' endothelial dystrophy (FED) in a 5-generation pedigree coexpressing both pathologic features in a large number of family members.

DESIGN

Observational case-control and DNA linkage and screening study.

PARTICIPANTS

Of 114 family members, 50 underwent clinical investigation and DNA analysis between July 2001 and March 2004.

METHODS

Linkage at the PITX2 locus was demonstrated using a number of microsatellites mapping to the critical region 4q25 to 4q26. The PITX2 gene was subsequently screened for mutations in all investigated family members.

MAIN OUTCOME MEASURE

Linkage of the ARAS and FED phenotype and mutation detection in the PITX2 gene.

RESULTS

Twenty-seven patients were identified as being affected by ARAS. Fuchs' endothelial dystrophy was found in 19 patients. Fifteen patients presented both kinds of anomaly. Deoxyribonucleic acid sequencing revealed 2 heteroallelic DNA variants that segregated together (on the same allele) and were present in all severely affected ARAS individuals. The first variant, g.20913G>T, assumed to be the causative mutation for ARAS, causes amino acid substitution at codon 137 (G137V). A statistically significant 2-point logarithm of the odds score of 4.06 was obtained with marker D4S406. The second variant is likely a polymorphism in the intron between exons 2 and 3 (IVS2+8delCinsGTT) and was detected in heterozygous form in 20% of control individuals.

CONCLUSION

This gene analysis revealed a novel PITX2 mutation and a polymorphism in a family with ARAS. Whether FED, also manifested in the severely affected individuals, is due to a different but cosegregating gene is to be determined.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Genetics
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Health Sciences > Ophthalmology
Language:English
Date:October 2006
Deposited On:26 May 2021 14:35
Last Modified:25 Apr 2024 01:37
Publisher:Elsevier
ISSN:0161-6420
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.ophtha.2006.05.017
Official URL:https://www.sciencedirect.com/science/article/pii/S0161642006006804
PubMed ID:16876867