Novel mutations causing biotinidase deficiency in individuals identified by newborn screening in Michigan including an unique intronic mutation that alters mRNA expression of the biotinidase gene.

Abstract

Biotinidase deficiency (BD) is an autosomal recessive disorder resulting in the inability to recycle the vitamin biotin. Individuals with biotinidase deficiency can develop neurological and cutaneous symptoms if they are not treated with biotin. To date, more than 165 mutations in the biotinidase gene (BTD) have been reported. Essentially all the mutations result in enzymatic activities with less than 10% of mean normal serum 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 and causes partial biotinidase deficiency (10-30% of mean normal serum biotinidase activity) if there is a mutation for profound biotinidase deficiency on the second allele. We now reported eight novel mutations in ten children identified by newborn screening in Michigan from 1988 to the end of 2012. Interestingly, one intronic mutation, c.310-15delT, results in an approximately two-fold down-regulation of BTD mRNA expression by Quantitative real-time reverse-transcription PCR (qRT-PCR). This is the first report of an intronic mutation in the BTD gene with demonstration of its effect on enzymatic activity by altering mRNA expression. This study identified three other mutations likely to cause partial biotinidase deficiency. These results emphasize the importance of full gene sequencing of BTD on patients with biotinidase deficiency to better understand the genotype and phenotype correlation in the future.

• Authors: H Li, L Spencer, F Nahhas, J Miller, A Fribley, G Feldman, R Conway, B Wolf
• Journal: Molecular genetics and metabolism (Mol Genet Metab) Vol. 112 Issue 3 Pg. 242-6 (Jul 2014) ISSN: 1096-7206 [Electronic] United States
• PMID: 24797656 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• RNA, Messenger
• Biotinidase

Topics

• Biotinidase (genetics, metabolism)
• Biotinidase Deficiency (diagnosis, genetics)
• DNA Mutational Analysis
• Enzyme Activation
• Gene Expression Regulation
• Gene Order
• Genetic Loci
• Humans
• Infant, Newborn
• Introns
• Michigan
• Mutation
• Neonatal Screening
• RNA, Messenger (genetics)