Human acid ceramidase gene: Novel mutations in Farber disease

Farber disease is an autosomal recessive disorder caused by lysosomal acid ceramidase (AC) deficiency, It commonly manifests during the first few mont hs after birth with a unique triad of painful and progressive deformed join ts, subcutaneous nodules, and progressive hoarseness, In order to understan d the molecular mechanism(s) of pathogenesis of Farber disease, we isolated and characterized a full-length human AC gene, mapped its chromosomal loca tion, determined the tissue-specific expression, and analyzed mutations in Farber disease patients. We also studied the AC-mRNA expression in gastroin testinal tumors and adjoining normal tissues. In addition, we determined th e pattern of tissue-specific AC-mRNA expression in the adult mouse and duri ng fetal development. Our results show that human AC gene consists of 14 ex ons and 13 introns spanning approximately 26.5 kb of genomic DNA. It is map ped to human chromosome 8p22-21.2, a region often disrupted in several canc ers. The AC-mRNA is expressed in the mouse fetus from the seventh day of ge station. Interestingly, while the AC-mRNA is expressed in all segments of t he normal gastrointestinal tract, none of the gastrointestinal tumor tissue s had any AC-mRNA expression. We also uncovered four novel mutations in Far ber disease patients that were not previously reported. Taken together, our results not only attest to the physiological importance of AC but also unc over several new mutations in Farber disease that may advance our knowledge towards establishing a genotype-phenotype correlation in this disease. (C) 2000 Academic Press.