A genome-wide scan maps a novel juvenile-onset primary open angle glaucoma locus to chromosome 5q.
OBJECTIVE
To map the disease-associated locus of a family with autosomal dominant juvenile-onset primary open angle glaucoma (JOAG) and to screen the novel glaucoma gene WD repeat domain 36 (WDR36).


METHODS
Complete ophthalmic examination and genomic DNA were obtained from 27 family members, in which nine were confirmed JOAG patients. Myocilin (MYOC), optineurin (OPTN), and WDR36 were screened for mutations by polymerase chain reaction and direct sequencing. Genome-wide scanning was carried out using the ABI PRISM Linkage Mapping Set MD-10. Two-point and multipoint linkage analyses were performed with the MLINK, ILINK, and LINKMAP programs. For fine mapping, additional markers flanking the most promising region on chromosome 5q were also analyzed. The significance of LOD scores was tested with simulation analyses using FASTLINK. Haplotypes were constructed using Simwalk2.


RESULTS
MYOC or OPTN mutations were excluded in all family members. A maximum LOD score value of 4.82 at theta=0.00 was obtained for the marker D5S2011. Markers D5S2065, D5S1384, D5S471, D5S503, D5S2098, and D5S638 had LOD score values over 4.0 at theta=0.00. Haplotype analysis and recombination mapping further confined this region to 5q22.1-q32 within a region of 36 Mb flanked by D5S2051 and D5S2090. Screening of the novel WDR36 glaucoma-associated gene, which lies centromeric to the disease interval, revealed no mutations within any of the 23 coding exons or splicing junctions.


CONCLUSIONS
Our results provided the mapping of a novel locus for JOAG at 5q and excluded coding or splicing junctions mutations within the WDR36 gene.
Pang
Chi Pui
CP
Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China. cppang@cuhk.edu.hk
Fan
Bao Jian
BJ
Canlas
Oscar
O
Wang
Dan Yi
DY
Dubois
Stephane
S
Tam
Pancy Oi Sin
PO
Lam
Dennis Shun Chiu
DS
Raymond
Vincent
V
Ritch
Robert
R
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5; D004252:DNA Mutational Analysis; D005136:Eye Proteins / Q000235:genetics*; D005799:Genes, Dominant; D015894:Genome, Human; D005902:Glaucoma, Open-Angle / Q000453:epidemiology / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008126:Lod Score; D008297:Male; D010375:Pedigree; D011995:Recombination, Genetic
D005136:Eye Proteins; C502341:WDR36 protein, human