ISOLATION OF ANIMAL-CELL MUTANTS DEFECTIVE IN LONG-CHAIN FATTY ALDEHYDE DEHYDROGENASE - SENSITIVITY TO FATTY ALDEHYDES AND SCHIFFS BASE MODIFICATION OF PHOSPHOLIPIDS - IMPLICATIONS FOR SJOGREN-LARSSON-SYNDROME

Using tritium suicide, we have isolated a variant of the Chinese hamst er ovary cell line, CHO-K1, that is deficient in long-chain fatty alco hol:NAD(+) oxidoreductase (FAO; FC 1.1.1.192), Specifically, it was th e fatty aldehyde dehydrogenase component that was affected, The enzyma tic deficiency found in this mutant strain, designated FAA.K1A, was si milar to that displayed by fibroblasts from patients with Sjogren-Lars son syndrome (SLS), an inheritable neurocutaneaus disorder. Complement ation analyses suggested that the deficiency in fatty alcohol oxidatio n in the FAA.K1A cells and the SLS fibroblasts is a result of lesions in homologous genes, The FAA.K1A cells were usable to convert long cha in fatty aldehydes to the corresponding fatty acids, This resulted in a hypersensitivity of the FAA.K1A cells to the cytotoxic effects of lo ng chain fatty aldehydes. The difference between the mutant and wild-t ype cans was most obvious when using fatty aldehydes between 14 and 20 carbons, with the greatest difference between wild-type and mutant ce lls found when using octadecanal, Fibroblasts from a patient with SLS also displayed the hypersensitivity phenotype when compared with FA1dD H(+) human fibroblasts. In both CHO and human FA1dDH(-) cell lines, ad dition of long chain fatty aldehydes to the medium caused a dramatic i ncrease in aldehyde-modified phosphatidylethanolamine, presumably thro ugh Schiffs base addition to the primary amine of the ethanolamine hea d group, When 25 mu M hexadecanal was added to the growth medium, appr oximately 10% of the phosphatidylethanolamine was found in the fatty a ldehyde-modified form in FAA.K1A, although this was not observed in wi ld-type cells, Modified phosphatidylethanolamine could be detected in FA1dDH(-) cells even when exogenous fatty aldehydes were not added to the medium, We propose a possible role for fatty aldehydes, or other a ldehydic species, in mediating some of the symptoms associated with Sj ogren-Larsson syndrome.