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© 1993 Oxford University Press

RESEARCH-ARTICLE

Cloning and expression cDNA encoding human galactocerebrosidase, the enzyme deficient in globoid cell leukodystrophy

Yue Qun Chen, Mohammad A. Rafi, Gregory de Gala and David A. Wenger*

Departments of Medicine (Medical Genetics) and Biochemistry and Molecular Biology, Thomas JHefferson University, Jefferson Medical College 1100 Walnut Street, Philadelphia, PA 19107, USA

*To whom correspondence should be addressed

Received July 20, 1993; Revised August 18, 1993; Accepted August 18, 1993

Globold cell leukodystrophy (Krabbe disease) is an autosomal recessive disorder resulting from the deficiency of galactocerebrosidase (GALC) activity. GALC is responsible for the lysosomal catabollsm of galactosytceramide, a major llpid In myelln, kidney and epithelial cells of small intestine and colon. We describe the molecular cloning of human GALC cDNA and its expression in COS-1 cells. Degenerate PCR primers, derived from N-terminal amino acid sequence from the 51 KDa band from human brain, were used to amplify cat testes RNA, and the resulting product was used to screen human testes and brain libraries. Two overlapping clones contained the total protein coding region, while additional clones and PCR amplification were needed to obtain the complete 3' end of the cDNA. The 3795 bp obtained Include 47 bp 5' to the initiation start site, 2007 bp of open reading frame (coding for 669 amino acids), and 1741 bp of 3' untranslated sequence. Modification of the sequence surrounding the initiation codon to one more favorable for expression, resulted in a 6-fold increase in GALC activity in transfected COS-1 cells. The isolation of this clone will permit investigations into the causes for GALC deficiency in humans and available animal models, development of more accurate tests for patient and carrier identification, and evaluation of methods for effectively treating GALC deficiency, initially using the animal models.


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