Mutational hotspot in the human biotinidase gene causes profound biotinidase deficiency

Biotlnidase deficiency is an autosomal recessive inherited disorder that is characterized by neurological and cutaneous symptoms1–3. Biotinidase-deficient children cannot recycle endogenous biotin, an essential water-soluble B vitamin. Biotin is covalently attached to ɛ-amino groups of lysyl residues of four carboxylases. These carboxylases are subsequently degraded to biocytin (biotin-ɛ-lysine)4,5. Biotinidase cleaves biocytin to biotin and lysine, thereby completing the biotin cycle5,6. The symptoms of biotinidase deficiency can be resolved or prevented by treatment with biotin5. Therefore, it is important that biotinidase deficiency is diagnosed early so that permanent neurological damage can be prevented. Many states and countries currently perform newborn screening for biotinidase deficiency7. We have recently isolated and characterized the cDNA for normal human biotinidase8 and localized the gene to chromosome 3p25 (ref. 9). We have now identified the first mutation that causes profound biotinidase deficiency. It occurs in a distinct region of the gene that encodes the putative signal peptide. Fifty percent of symptomatic children studied have a 7-bp deletion coupled with a 3-bp insertion in at least one of their alleles of the biotinidase gene. This mutation appears to be a common cause of biotinidase deficiency in symptomatic children.