Cross-linking defects in hair cuticle have been observed in certain rare human disorders (trichothiodystrophy, transglutaminase-deficient lamellar ichthyosis). The hypothesis being investigated is that defective cross-linking in the cuticle or other parts of the fiber is a feature of some mouse mutants in which the hair is sparse or appears structurally unsound. Pelage hair samples from 13 mouse mutants displaying defective hair were extracted with sodium dodecyl sulfate and dithiothreitol at neutral pH and examined by transmission electron microscopy. All samples were indistinguishable after extraction from normal hair fibers in appearance of the medulla and cortex. In the cortex, keratins were completely extractable, but material remaining at the cell boundaries was clearly evident. Cells of the medulla were largely unextracted, containing distinct nuclei and amorphous material in the cytoplasm. In two samples (from mice with the matted/flaky tail and naked mutations) cells of the cuticle, which readily detached from the fiber when incubated at 100 degrees C, were more extensively extracted than normal. Defective cross-linking is thus observable in a minority of mouse hair mutants. The observed perturbation of cross-linking in the cuticle was not accompanied by visible perturbation in the cortex or medulla, indicating that different proteins participate in cross-linking in the different cell types.