The ldis1 lens mutation in RIIIS/J mice maps to chromosome 8near cadherin 1

[摘要] Purpose: We have discovered a spontaneous and severe mutation thatleads to partial or complete disruption of the lens and cataract in theRIIIS/J inbred strain of mice. The purpose of this study was todetermine the mode of inheritance, specificity, and range of phenotypesusing histological, ophthalmic, quantitative electron microscopic, andmicroarray-based methods. We also have fine-mapped the mutation,ldis1 (lens disrupter 1), and have evaluated positional candidategenes.Methods: Eyes from mutant RIIIS/J animals and from an F2 intercrossbetween RIIIS/J and DBA/2J were examined and scored to map the ldis1mutation. Axons in the optic nerve were counted. Messenger RNA frommutant eyes was hybridized to Affymetrix short oligomer microarrays andcompared to five control strains. Expression differences were used toevaluate molecular sequellae of the mutation.Results: Mice that are homozygous for ldis1 have small eyes.Lenses are without exception opaque, deformed, dislocated, fragmented,and small. In contrast, retinal architecture and ganglion cell numbersare within normal range. We have not detected any otherldis1-associated ocular or systemic abnormalities. ldis1 isrecessive and maps to chromosome 8 at about 106.5 Mb betweenD8Mit242 and D8Mit199 with a peak LOD score near cadherin 1.The homologous human chromosomal interval is 16q22.1. The expression ofseveral downstream crystallin transcripts are severely affected in themutant, as are the expression levels of multiple members of thetransforming growth factor superfamily and the glutathioneS-transferases.Conclusions: We have discovered and mapped a recessive mutation tomouse chromosome 8 between 105 and 109 Mb. Homozygous mutant mice have aselective and severe effect on lens integrity. On the basis of thephenotype and the locus position, several candidate genes have beenidentified.

[学科分类] 生物化学/生物物理