Fine mapping of new glaucoma locus GLC1M and exclusion ofneuregulin 2 as the causative gene

[摘要] Purpose: We recently identified a novel glaucoma locus on5q22.1-q32, designated as GLC1M, in a family from the Philippineswith autosomal dominant juvenile-onset primary open angle glaucoma(JOAG). No mutations in myocilin (MYOC), optineurin(OPTN), and WD-repeat protein 36 (WDR36) were found.Neuregulin 2 (NRG2) is an excellent potential functional as wellas positional candidate at GLC1M. The goal of the present study wasto evaluate the role of the NRG2 gene in this JOAG family andunrelated JOAG patients and to refine the critical interval forGLC1M.Methods: Genomic DNA was obtained from 27 family members. All codingexons and splicing sites of NRG2 were screened for sequencealterations by polymerase chain reaction (PCR) and DNA sequencing. Acohort of 92 unrelated JOAG patients and 92 control subjects weregenotyped for the three single nucleotide polymorphisms (SNPs) ofNRG2 by PCR and DNA sequencing. Haplotype and segregation analyseswere performed in the family. Fisher's exact test was used to comparethe frequencies of the NRG2 polymorphisms between affected andunaffected subjects in the family and between unrelated JOAG patientsand control subjects.Results: Three SNPs were identified: c.98G>A (S33N), IVS3+13A>G (rs889022), and c.1976A>G (G659G). None of them segregated with theJOAG phenotype in this family. No association was found between NRG2and JOAG in the case-control study (p>0.12). However, furtherinspection of the haplotypes in the family localized the NRG2 genetelomeric to the disease locus. The critical interval of GLC1M wastherefore refined to a region of 28 Mb between D5S2051 and NRG2.Conclusions: The linkage interval for GLC1M was refined to asmaller region. The NRG2 gene was excluded as the causative gene forJOAG.

[学科分类] 生物化学/生物物理