The Role of the WDR36 Gene on Chromosome 5q22.1 in a Large Family With Primary Open-Angle Glaucoma Mapped to This Region

Abstract

To determine whether mutations in the WD40-repeat 36 (WDR36) gene are responsible for primary open-angle glaucoma (POAG) that maps to the GLC1G locus in a family with 16 affected family members. Methods: Ninety-two family members underwent clinical evaluation for POAG on the basis of intraocular pressures, cupping of discs, and visual fields after informed consent was obtained. All 23 exons of WDR36 were sequenced in DNA from 5 affected and 2 unaffected family members. Results: Sixteen family members showed evidence of POAG. A number of sequence variations were identified in family members; most of the variations were previously described single-nucleotide polymorphisms also

Copy Number Variation at Chromosome 5q21.2 Is Associated With Intraocular Pressure

“…These studies, however, failed to unequivocally identify the causal gene at this locus; candidate gene sequencing of the GLC1G linkage locus by Monemi et al 33 suggested that a mutation in the WDR36 gene segregates with the phenotype, but subsequent independent studies failed to replicate their finding or identify any other causal variants in this region. 34,36,38 While linkage and CNV findings in this region so far have implicated large regions encompassing many genes, our study implicates a much smaller region overlapping the gene RAB9BP1. Moreover, given that the RAB9BP1 CNV locus (5q21.2) is very near the centromeric end of the GLC1G locus (5q21.3), it is also worth investigating whether RAB9BP1 copy number change explains any part of the GLC1G linkage signal.…”

“…Several studies have reported linkage loci (GLC1G and GLC1M) for glaucoma and IOP encompassing the region 5q21-32. [33][34][35][36][37] Davis et al 27 demonstrated that two POAG patients carried large CNVs within the GLC1G/GLC1M linkage locus (involving the genes DMXL1 and DTWD2) while none of the controls in their study had CNVs at that locus, thus suggesting that rare CNVs contained in this region might cause POAG. These studies, however, failed to unequivocally identify the causal gene at this locus; candidate gene sequencing of the GLC1G linkage locus by Monemi et al 33 suggested that a mutation in the WDR36 gene segregates with the phenotype, but subsequent independent studies failed to replicate their finding or identify any other causal variants in this region.…”

Copy Number Variation at Chromosome 5q21.2 Is Associated With Intraocular Pressure

“…These studies, however, failed to unequivocally identify the causal gene at this locus; candidate gene sequencing of the GLC1G linkage locus by Monemi et al 33 suggested that a mutation in the WDR36 gene segregates with the phenotype, but subsequent independent studies failed to replicate their finding or identify any other causal variants in this region. 34,36,38 While linkage and CNV findings in this region so far have implicated large regions encompassing many genes, our study implicates a much smaller region overlapping the gene RAB9BP1. Moreover, given that the RAB9BP1 CNV locus (5q21.2) is very near the centromeric end of the GLC1G locus (5q21.3), it is also worth investigating whether RAB9BP1 copy number change explains any part of the GLC1G linkage signal.…”

“…Several studies have reported linkage loci (GLC1G and GLC1M) for glaucoma and IOP encompassing the region 5q21-32. [33][34][35][36][37] Davis et al 27 demonstrated that two POAG patients carried large CNVs within the GLC1G/GLC1M linkage locus (involving the genes DMXL1 and DTWD2) while none of the controls in their study had CNVs at that locus, thus suggesting that rare CNVs contained in this region might cause POAG. These studies, however, failed to unequivocally identify the causal gene at this locus; candidate gene sequencing of the GLC1G linkage locus by Monemi et al 33 suggested that a mutation in the WDR36 gene segregates with the phenotype, but subsequent independent studies failed to replicate their finding or identify any other causal variants in this region.…”

Replication of a Glaucoma Candidate Gene on 5q22.1 for Intraocular Pressure in Mongolian Populations: The GENDISCAN Project

“…10 Several variants of WDR36 have been associated with POAG. 35,36 In a recent study, alterations in WDR36 in Japanese patients with POAG were not associated with normotensive POAG, whereas one variant of WDR36 was significantly associated with hightension POAG. 37 Our findings not only replicate those of previous studies but further suggest the possibility that normal variation in IOP, elevated IOP, and POAG may be regulated by common genetic factors.…”

Comparison of MicroRNA Expression in Aqueous Humor of Normal and Primary Open-Angle Glaucoma Patients Using PCR Arrays: A Pilot Study

“…20 The miR-143 gene is located on the long arm of chromosome 5 (gene ID: 406935; Chr 5q32: 149,428,918-149,429,023). Two linkage loci associated with glaucoma and IOP ( GLC1G , GLC1M ) involving the region 5q21-32 have been extensively described by several groups, 21–23 with a recent study reporting an association between IOP and copy number variation at this locus. 24 The gene encoding miR-518d is located on the long arm of chromosome 19 (gene ID: 574489; Chr 19q13.42: 53,734,877-53,734,963).…”

Copy Number Variation at Chromosome 5q21.2 Is Associated With Intraocular Pressure

“…These studies, however, failed to unequivocally identify the causal gene at this locus; candidate gene sequencing of the GLC1G linkage locus by Monemi et al 33 suggested that a mutation in the WDR36 gene segregates with the phenotype, but subsequent independent studies failed to replicate their finding or identify any other causal variants in this region. 34,36,38 While linkage and CNV findings in this region so far have implicated large regions encompassing many genes, our study implicates a much smaller region overlapping the gene RAB9BP1. Moreover, given that the RAB9BP1 CNV locus (5q21.2) is very near the centromeric end of the GLC1G locus (5q21.3), it is also worth investigating whether RAB9BP1 copy number change explains any part of the GLC1G linkage signal.…”

“…Several studies have reported linkage loci (GLC1G and GLC1M) for glaucoma and IOP encompassing the region 5q21-32. [33][34][35][36][37] Davis et al 27 demonstrated that two POAG patients carried large CNVs within the GLC1G/GLC1M linkage locus (involving the genes DMXL1 and DTWD2) while none of the controls in their study had CNVs at that locus, thus suggesting that rare CNVs contained in this region might cause POAG. These studies, however, failed to unequivocally identify the causal gene at this locus; candidate gene sequencing of the GLC1G linkage locus by Monemi et al 33 suggested that a mutation in the WDR36 gene segregates with the phenotype, but subsequent independent studies failed to replicate their finding or identify any other causal variants in this region.…”

Replication of a Glaucoma Candidate Gene on 5q22.1 for Intraocular Pressure in Mongolian Populations: The GENDISCAN Project

“…10 Several variants of WDR36 have been associated with POAG. 35,36 In a recent study, alterations in WDR36 in Japanese patients with POAG were not associated with normotensive POAG, whereas one variant of WDR36 was significantly associated with hightension POAG. 37 Our findings not only replicate those of previous studies but further suggest the possibility that normal variation in IOP, elevated IOP, and POAG may be regulated by common genetic factors.…”

Comparison of MicroRNA Expression in Aqueous Humor of Normal and Primary Open-Angle Glaucoma Patients Using PCR Arrays: A Pilot Study

“…20 The miR-143 gene is located on the long arm of chromosome 5 (gene ID: 406935; Chr 5q32: 149,428,918-149,429,023). Two linkage loci associated with glaucoma and IOP ( GLC1G , GLC1M ) involving the region 5q21-32 have been extensively described by several groups, 21–23 with a recent study reporting an association between IOP and copy number variation at this locus. 24 The gene encoding miR-518d is located on the long arm of chromosome 19 (gene ID: 574489; Chr 19q13.42: 53,734,877-53,734,963).…”

Copy Number Variation at Chromosome 5q21.2 Is Associated With Intraocular Pressure

“…These studies, however, failed to unequivocally identify the causal gene at this locus; candidate gene sequencing of the GLC1G linkage locus by Monemi et al 33 suggested that a mutation in the WDR36 gene segregates with the phenotype, but subsequent independent studies failed to replicate their finding or identify any other causal variants in this region. 34,36,38 While linkage and CNV findings in this region so far have implicated large regions encompassing many genes, our study implicates a much smaller region overlapping the gene RAB9BP1. Moreover, given that the RAB9BP1 CNV locus (5q21.2) is very near the centromeric end of the GLC1G locus (5q21.3), it is also worth investigating whether RAB9BP1 copy number change explains any part of the GLC1G linkage signal.…”

“…Several studies have reported linkage loci (GLC1G and GLC1M) for glaucoma and IOP encompassing the region 5q21-32. [33][34][35][36][37] Davis et al 27 demonstrated that two POAG patients carried large CNVs within the GLC1G/GLC1M linkage locus (involving the genes DMXL1 and DTWD2) while none of the controls in their study had CNVs at that locus, thus suggesting that rare CNVs contained in this region might cause POAG. These studies, however, failed to unequivocally identify the causal gene at this locus; candidate gene sequencing of the GLC1G linkage locus by Monemi et al 33 suggested that a mutation in the WDR36 gene segregates with the phenotype, but subsequent independent studies failed to replicate their finding or identify any other causal variants in this region.…”

Replication of a Glaucoma Candidate Gene on 5q22.1 for Intraocular Pressure in Mongolian Populations: The GENDISCAN Project

“…10 Several variants of WDR36 have been associated with POAG. 35,36 In a recent study, alterations in WDR36 in Japanese patients with POAG were not associated with normotensive POAG, whereas one variant of WDR36 was significantly associated with hightension POAG. 37 Our findings not only replicate those of previous studies but further suggest the possibility that normal variation in IOP, elevated IOP, and POAG may be regulated by common genetic factors.…”

Comparison of MicroRNA Expression in Aqueous Humor of Normal and Primary Open-Angle Glaucoma Patients Using PCR Arrays: A Pilot Study

“…20 The miR-143 gene is located on the long arm of chromosome 5 (gene ID: 406935; Chr 5q32: 149,428,918-149,429,023). Two linkage loci associated with glaucoma and IOP ( GLC1G , GLC1M ) involving the region 5q21-32 have been extensively described by several groups, 21–23 with a recent study reporting an association between IOP and copy number variation at this locus. 24 The gene encoding miR-518d is located on the long arm of chromosome 19 (gene ID: 574489; Chr 19q13.42: 53,734,877-53,734,963).…”