IOVS Antimicrobial Agents and Chemotherapy
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(Investigative Ophthalmology and Visual Science. 2007;48:3905-3913.)
© 2007 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.06-1464
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Analysis of Ocular Hypopigmentation in Rab38cht/cht Mice

Brian P. Brooks,1,2,3 Denise M. Larson,2,3 Chi-Chao Chan,1 Sten Kjellstrom,4 Richard S. Smith,5,6 Mary A. Crawford,1 Lynn Lamoreux,7 Marjan Huizing,3 Richard Hess,3 Xiaodong Jiao,1 J. Fielding Hejtmancik,1 Arvydas Maminishkis,1 Simon W. M. John,5,6 Ronald Bush,4 and William J. Pavan3

1From the National Eye Institute, the 3National Human Genome Research Institute, and the 4National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland; 5Howard Hughes Medical Institute, Bar Harbor, Maine; 6The Jackson Laboratory, Bar Harbor, Maine; and the 7Comparative Genetics Program, Texas A & M University, College Station, Texas.

PURPOSE. To characterize the ocular phenotype resulting from mutation of Rab38, a candidate gene for Hermansky-Pudlak syndrome.

METHODS. Chocolate mice (cht, Rab38cht/cht) and control heterozygous (Rab38cht/+) and wild-type mice were examined clinically, histologically, ultrastructurally, and electrophysiologically. Mice homozygous for both the Rab38cht and the Tyrp1b alleles were similarly examined.

RESULTS. Rab38cht/cht mice showed variable peripheral iris transillumination defects at 2 months of age. Patches of RPE hypopigmentation were noted clinically in 57% of Rab38cht/cht eyes and 6% of Rab38cht/+ eyes. Rab38cht/cht mice exhibited thinning of the iris and RPE and larger b-wave amplitudes in the scotopic range when compared with the control animals. Compared with wild-type mice, Rab38cht/cht melanosomes were smaller and there were fewer in neuroectodermally derived retinal pigment epithelium; in neural crest-derived choroid melanocytes, they were smaller in size only. Mutation of both Rab38 and Tyrp1 produced mice with ocular and coat color pigment dilution greater than that seen with either mutation alone. Comprehensive clinical and pathologic analyses showed no other organ system or blood defects in Rab38cht/cht mice.

CONCLUSIONS. Rab38cht/cht mice show ocular characteristics reminiscent of human oculocutaneous albinism, as well as iris and RPE thinning. The synergistic effects of the Rab38cht and Tyrp1b alleles suggest that TYRP1 is not the only target of RAB38 trafficking. This mouse line provides a useful model for studying melanosome biology and its role in human ocular diseases.






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Copyright © 2007 by the Association for Research in Vision and Ophthalmology