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 symptoms^1–3. 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 cycle^{5, 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.