1. Department of Dermatology, Veterans Affairs Medical Center, University of California, San Francisco, CA, U.S.A.
2. ^*Jackson Laboratory, Bar Harbor, ME, U.S.A.
3. ^†Department of Molecular and Cellular Biology, Roswell Park Cancer Center, Buffalo, NY, U.S.A.

Correspondence: Dr Maria L. Wei, Dermatology Service (190), Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121, U.S.A. Email: mlwei@orca.ucsf.edu

Received 18 August 2002; Revised 6 September 2002; Accepted 12 September 2002.

Abstract

Hermansky–Pudlak syndrome is an autosomal recessive disease characterized by pigment dilution and prolonged bleeding time. At least 15 mutant mouse strains have been classified as models of Hermansky–Pudlak syndrome. Some of the genes are implicated in intracellular vesicle trafficking: budding, targeting, and secretion. Many of the Hermansky–Pudlak syndrome genes remain uncharacterized and their functions are unknown. Clues to the functions of these genes can be found by analyzing the physiologic and cellular phenotypes. Here we have examined the morphology of the melanosomes in the skin of 10 of the mutant mouse Hermansky–Pudlak syndrome strains by transmission electron microscopy. We demonstrate that the morphologies reflect inhibition of organelle maturation or transfer. The Hermansky–Pudlak syndrome strains are classified into morphologic groups characterized by the step at which melanosome biogenesis or transfer to keratinocytes is inhibited, with the cappuccino strain observed to be blocked at the earliest step and gunmetal blocked at the latest step. We show that all Hermansky–Pudlak syndrome mutant strains except gunmetal have an increase in unpigmented or hypopigmented immature melanosomal forms, leading to the hypopigmented coat colors seen in these strains. In contrast, the hypopigmentation seen in the gunmetal strain is due to the retention of melanosomes in melanocytes, and inefficient transfer into keratinocytes.