Linkage of posterior amorphous corneal dystrophy to chromosome 12q21.33 and exclusion of coding region mutations in KERA, LUM, DCN, and EPYC.
OBJECTIVE
To identify the genetic basis of posterior amorphous corneal dystrophy (PACD) segregating in a large pedigree.


METHODS
The authors performed clinical evaluation of a previously unreported pedigree with PACD, light and electron microscopic examination of an excised corneal button, genomewide linkage analysis, fine mapping linkage and haplotype analysis, and screening of four candidate genes (KERA, LUM, DCN, and EPYC).


RESULTS
Twenty-one participants were determined to be affected based on the presence of characteristic clinical features of PACD; 15 affected and 39 unaffected individuals from a single pedigree enrolled in the study and provided DNA for analysis. Histopathologic examination of an excised corneal specimen from an affected individual demonstrated disorganized stromal lamellae and stromal staining with colloidal iron. Genomewide analysis demonstrated significant evidence of linkage to chromosome region 12q21.33 and evidence suggestive of linkage to chromosome region 8q22.3. Fine mapping of the chromosome 12 locus confirmed significant linkage; the largest multipoint log odds ratio score was 5.6 at D12S351. The linkage support interval was approximately 3.5 Mb (3.5 cM) in length between flanking markers D12S1812 and D12S95, roughly the entire chromosome band 12q21.33. No coding region mutations were identified in four candidate genes-KERA, LUM, DCN, EPYC-located in the chromosome 12 linkage support interval.


CONCLUSIONS
Linkage and haplotype analyses identified 12q21.33 as a locus for PACD. However, no mutations were identified in the candidate genes (KERA, LUM, DCN, EPYC) within this region.
Aldave
Anthony J
AJ
Jules Stein Eye Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA. aldave@jsei.ucla.edu
Rosenwasser
George O D
GO
Yellore
Vivek S
VS
Papp
Jeanette C
JC
Sobel
Eric M
EM
Pham
Michele N
MN
Chen
Michael C
MC
Dandekar
Sugandha
S
Sripracha
Ram
R
Rayner
Sylvia A
SA
Sassani
Joseph W
JW
Gorin
Michael B
MB
D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D003317:Corneal Dystrophies, Hereditary / Q000235:genetics*; D058575:Decorin; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007632:Keratan Sulfate / Q000235:genetics*; D000071234:Lumican; D008297:Male; D009154:Mutation; D016366:Open Reading Frames; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011509:Proteoglycans / Q000235:genetics*; D000071232:Small Leucine-Rich Proteoglycans
D011508:Chondroitin Sulfate Proteoglycans; C546878:DCN protein, human; D058575:Decorin; C119499:EPYC protein, human; D016326:Extracellular Matrix Proteins; C490948:KERA protein, human; C000604306:LUM protein, human; D000071234:Lumican; D011509:Proteoglycans; D000071232:Small Leucine-Rich Proteoglycans; D007632:Keratan Sulfate