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


METHODS
Observational case-control and DNA linkage and screening study.


METHODS
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.


METHODS
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.


CONCLUSIONS
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.
Kniestedt
Christoph
C
Department of Ophthalmology, Cantonal Hospital Winterthur, Winterthur, Switzerland. research@kniestedt.ch
Taralczak
Malgorzata
M
Thiel
Michael A
MA
Stuermer
Joerg
J
Baumer
Alessandra
A
Gloor
Balder P
BP
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002452:Cell Count; D002648:Child; D002675:Child, Preschool; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D003315:Cornea / Q000002:abnormalities* / Q000000981:diagnostic imaging / Q000473:pathology; D004252:DNA Mutational Analysis; D005124:Eye Abnormalities / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D005260:Female; D005642:Fuchs' Endothelial Dystrophy / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D008040:Genetic Linkage; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007498:Iris / Q000002:abnormalities* / Q000000981:diagnostic imaging / Q000473:pathology; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D011110:Polymorphism, Genetic; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*; D014463:Ultrasonography; D000097577:Homeobox Protein PITX2
D018398:Homeodomain Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2