Abstract
Purpose: :
Genetic bases for comitant strabismus remain unknown notwithstanding the well-known heritability of strabismus. To identify chromosomal susceptibility loci for comitant strabismus, we previously reported a genome-wide linkage analysis among 30 Japanese families (Acta Med Okayama 2003;57:109-16). In this on-going study, we presented the results of linkage analysis among 58 families.
Methods: :
Recruited in this study were 58 families in which two or more family members have been diagnosed as either comitant esotropia or exotropia. Genomic DNA was isolated from the peripheral blood, and 400 microsatellite regions with about 10 cM resolution were amplified by PCR. DNA fragments were analyzed by ABI PRISM 310 Genetic Analyzer. Using GENEHUNTER software, NPL (nonparametric linkage) scores and P values were calculated. In addition, we stratified the families according to the phenotype, either esotropia or exotropia, to investigate whether the results would remain consistent between both groups. To replicate the result reported by Parikh et al (PNAS 2003;100:12283-8), suggesting a susceptibility locus on 7p22.1 region, NPL scores were calculated in the subgroup of only the families showing >1.0 NPL scores on that region.
Results: :
Among the 58 families, regions with the highest peaks, suggestive of linkage (NPL scores>2.5, P<0.0017), were found at D2S337 (NPL=2.65, P=0.0015), at D6S262 (NPL=2.85, P =0.0006), at D7S515 (NPL=2.82, P=0.0007), and at D19S420 (NPL=2.76, P=0.0010). After stratifying the families to an esotropia group and an exotropia group, the NPL scores dropped to <2.0 at D2S337 in both groups, at D6S262 in the esotropia group, and at D19S420 in the exotropia group. NPL scores dropped but remained to be >2.0 at D6S262 in the exotropia group, at D7S515 in both groups, and at D19S420 in the esotropia group. Three new loci, suggestive of linkage, emerged in the esotropia group at D6S281 (NPL=2.51, P=0.0010), at D10S1652 (NPL=2.8, P=0.0004), and at D17S799 (NPL=2.7, P=0.0006). Replicating the result of Parikh et al, NPL scores on 7p22.1 failed to reach a level suggestive of linkage among the 58 families. When a subgroup of only the families showing NPL>1.0 on 7p22.1 was analyzed, the NPL score reached a significant level of 4.27 (P=5.06 x 10-6) at D7S507.
Conclusions: :
Our results suggest several susceptibility loci for comitant strabismus. The inconsistency of the results between the groups, stratified according to the phenotype, suggests a different genetic base between esotropia and exotropia.
Keywords: strabismus • linkage analysis • gene mapping