Analysis of mutations causing biotinidase deficiencya

Abstract

Biotinidase deficiency is an inherited disorder in which the vitamin, biotin, is not recycled. Individuals with biotinidase deficiency can develop neurological and cutaneous symptoms if they are not treated with biotin. Biotinidase deficiency screening has been incorporated into essentially all newborn screening programs in the United States and in many countries. We now report 140 known mutations in the biotinidase gene (BTD) that cause biotinidase deficiency. All types of mutations have been found to cause biotinidase deficiency. Variants have been identified throughout the coding sequence. Essentially all the variants result in enzymatic activities with less than 10% of mean normal enzyme activity (profound biotinidase deficiency) with the exception of the c.1330G>C (p.D444H) mutation, which results in an enzyme having 50% of mean normal serum activity. The putative three-dimensional structure of biotinidase has been predicted by homology to that of nitrilases/ amidases. The effect of the various missense mutations can be predicted to affect various important sites within the structure of the enzyme. This compilation of variants causing biotinidase deficiency will be useful to clinical laboratories that are performing mutation analysis for confirmational testing when the enzymatic results are equivocal for children identified through newborn screening. Hum Mutat 31:983-991,

Biotinidase deficiency: “if you have to have an inherited metabolic disease, this is the one to have”

“…68 Mutations are continually updated in a database on the following Internet site: (http://www.arup.utah.edu/database/BTD/BTD_ welcome.php). 77 …”

“…[65][66][67][68] These mutations include missense, nonsense, deletion, insertions, double-allelic, and splice-junction mutations. Mutations have been found throughout the gene, with some clustering at the carboxy-terminus.…”

“…Mutations have been found throughout the gene, with some clustering at the carboxy-terminus. 68 Many of the missense mutations occur within conserved regions of the enzyme 69 and/or the tertiary structure of the enzyme. 17 Six different mutation combinations account for about 60% of the mutations causing profound and partial biotinidase deficiency ( Table 1).…”

“…In addition to the one double mutation causing profound biotinidase deficiency cited above (p.(Ala171Thr;Asp444His)), this laboratory also tests for two other mutations that in combination with the Asp444His mutation, p.(Phe403vVal;Asp444His) and p.(Arg157His;Asp444His), cause profound biotinidase deficiency. 68 The latter targeted mutation panel allows more definitive differentiation of individuals having the Asp444His mutation causing partial biotinidase deficiency from those having profound biotinidase deficiency.…”

Clinical utility gene card for: Biotinidase deficiency

“…All types of alterations have been observed: missense, nonsense, splice-site, and frameshift mutations. 2 However, no large deletion has been identified to date. No hotspot mutation region has been observed and alterations have occurred throughout the coding sequence, except in exon 1 that may not contain the true initiation ATG codon.…”