Mutations in BTD causing biotinidase deficiency

Hum Mutat. 2001 Nov;18(5):375-81. doi: 10.1002/humu.1208.


Biotinidase (BTD) is the only enzyme that can cleave biocytin, a product of the proteolytic digestion of holocarboxylases. Profound BTD deficiency (less than 10% mean normal activity in serum) is an autosomal recessive disorder that can result in neurological and cutaneous abnormalities. Both the cDNA and the genomic DNA of normal BTD gene have been isolated and characterized. The BTD gene is localized to chromosome 3p25. Thus far 61 mutations in three of the four exons of the BTD and one mutation in an intron gene that cause profound BTD deficiency have been reported. Mutations occur at different frequencies in symptomatic children than they do in children ascertained by newborn screening. Two mutations, 98-104del7ins3 and R538C, were present in 52% or 31 of 60 alleles found in symptomatic patients. Three other mutations, A755G, Q456H, and 511 G>A; 1330G>C (double mutation), accounted for 52% of the alleles detected by newborn screening in the United States. Two asymptomatic adults, parents of children with profound BTD deficiency detected by newborn screening, have been described. Additional different mutations have been found in Turkish, Saudi Arabian, and Japanese children with profound BTD deficiency. Partial BTD deficiency (10-30% of mean normal serum activity) is predominantly caused by the single 1330G>C mutation that results in D444H on one allele in combination with one of the mutations causing profound deficiency on the other allele. Four intragenic polymorphisms, three neutral and one amino acid change, have also been found. Although a preponderance of mutations causing the production of truncated BTD protein occurs in symptomatic children with profound deficiency, preliminary studies fail to demonstrate clear genotype-phenotype correlations.

Publication types

  • Review

MeSH terms

  • Alleles
  • Amidohydrolases / deficiency*
  • Amidohydrolases / genetics*
  • Biotinidase
  • Chromosomes, Human, Pair 3 / genetics
  • Exons / genetics
  • Gene Frequency / genetics
  • Genetic Testing
  • Humans
  • Introns / genetics
  • Mutation / genetics*
  • Polymorphism, Genetic / genetics


  • Amidohydrolases
  • Biotinidase