Replication and refinement of linkage of posterior polymorphous corneal dystrophy to the posterior polymorphous corneal dystrophy 1 locus on chromosome 20.
OBJECTIVE
The study purpose was to identify the genetic basis of posterior polymorphous corneal dystrophy, an autosomal dominant disorder of the corneal endothelium that is associated with the development of corneal edema, necessitating corneal transplantation for visual rehabilitation. Glaucoma also develops in up to 40% of patients with posterior polymorphous corneal dystrophy.


METHODS
Linkage analysis, using microsatellite markers previously used to demonstrate linkage of posterior polymorphous corneal dystrophy to the chromosome 20 candidate region known as posterior polymorphous corneal dystrophy 1, was performed in 29 members of a family with posterior polymorphous corneal dystrophy. Thirty-four microsatellite markers were used to refine the posterior polymorphous corneal dystrophy 1 interval. TCF8, located on chromosome 10, was screened in an affected family member to exclude posterior polymorphous corneal dystrophy 3.


RESULTS
Significant evidence of linkage to the posterior polymorphous corneal dystrophy 1 interval was obtained with both single-point and multipoint analyses. The largest single-point log odds ratio score obtained was 4.38 (theta=0) at marker D20S471; within 4.7 Mbp (7.2 cM) of D20S471 eight markers provided single-point log odds ratio scores of greater than 3.00 and three markers provided single-point log odds ratio scores greater than 4.00. The largest multipoint log odds ratio score obtained was 4.83, found across the adjacent markers D20S844, D20S191, D20S484, and D20S111. The support interval for posterior polymorphous corneal dystrophy 1 in the family we report is approximately 13.5 Mbp (10 cM) long and lies between the markers D20S182 and D20S195. Eleven markers have multipoint log odds ratio scores greater than 4.0 within this region. No coding region mutations were identified in TCF8 in an affected member of the family, effectively excluding posterior polymorphous corneal dystrophy 3.


CONCLUSIONS
The originally described 19.8 cM posterior polymorphous corneal dystrophy 1 candidate disease interval has been refined to a 10 cM interval between markers D20S182 and D20S195. A portion of this refined interval overlaps a more recently reported posterior polymorphous corneal dystrophy 1 interval, with only 20 known and predicted genes mapped to the 2.4 cM common interval.
Yellore
Vivek S
VS
Cornea Service, The Jules Stein Eye Institute, Department of Human Genetics, and Retinal Biochemistry Laboratory, David Geffen School of Medicine at University of California Los Angeles, California 90095, USA.
Papp
Jeanette C
JC
Sobel
Eric
E
Khan
M Ali
MA
Rayner
Sylvia A
SA
Farber
Debora B
DB
Aldave
Anthony J
AJ
D002874:Chromosome Mapping; D002890:Chromosomes, Human, Pair 20; D003317:Corneal Dystrophies, Hereditary / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D004728:Endothelium, Corneal / Q000473:pathology; D008040:Genetic Linkage; D005820:Genetic Testing; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008126:Lod Score; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
D018398:Homeodomain Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1