A genome-wide scan maps a novel juvenile-onset primary open-angle glaucoma locus to 15q.
OBJECTIVE
To map the disease-associated locus of a family with autosomal dominant juvenile-onset primary open-angle glaucoma (JOAG).


METHODS
A complete ophthalmic examination was conducted, and genomic DNA was obtained from 25 members of a Chinese family, of which eight were confirmed as having JOAG. Myocilin (MYOC), optineurin (OPTN), and WD repeat-domain 36 (WDR36) were screened for sequence alterations, by PCR and direct sequencing. Subsequently, a genome-wide scan was performed (Prism Linkage Mapping Set MD-10; Applied Biosystems, Inc., Foster City, CA). 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 15q were analyzed. The significance of the lod score was tested with simulation analyses by using FASTLINK. Haplotypes were constructed with Simwalk2. Three candidate genes, NR2E3, SMAD6, and CLN6, located within the critical region, were screened for mutations.


RESULTS
MYOC, OPTN, and WDR36 mutations were excluded in all family members. A maximum two-point lod score of 3.31 at theta = 0.0 was obtained for the marker D15S125. Four adjacent markers, rs2030040, rs169169963, D15S153, and D15S131, gave two-point lod scores of 2.41, 2.90, 3.02, and 2.68, respectively, at theta = 0.0. Haplotype analysis and recombination mapping further confined this region to 15q22-q24 within a genetic distance of 16.6 Mb flanked by D15S1036 and rs922693. No mutations were found in the coding exons and splicing junctions of NR2E3, SMAD6, and CLN6.


CONCLUSIONS
The results provide evidence for the mapping of a novel locus for JOAG at 15q22-q24. A further search for the disease-causing gene in this new JOAG locus is in progress.
Wang
Dan Yi
DY
Department of Ophthalmology and Visual Sciences, Chinese University of Hong Kong, Hong Kong, China.
Fan
Bao Jian
BJ
Chua
John K H
JK
Tam
Pancy O S
PO
Leung
Christopher K S
CK
Lam
Dennis S C
DS
Pang
Chi Pui
CP
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D018797:Cell Cycle Proteins; D002648:Child; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D005902:Glaucoma, Open-Angle / Q000235:genetics*; D006023:Glycoproteins / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008126:Lod Score; D008297:Male; D026901:Membrane Transport Proteins; D010375:Pedigree; D035582:Transcription Factor TFIIIA / Q000235:genetics; D000099179:Myocilin
D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D006023:Glycoproteins; D026901:Membrane Transport Proteins; D035582:Transcription Factor TFIIIA; D000099179:Myocilin; C409460:OPTN protein, human; C502341:WDR36 protein, human