title: 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.affiliation: Carmen and Ann Adams Department of Pediatrics, Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI 48201, USA; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.affiliation: Carmen and Ann Adams Department of Pediatrics, Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI 48201, USA; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA.
authors.forename: L
authors.initials: L
authors.lastname: Spencer
authors.affiliation: Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48201, USA; Molecular Genetics Laboratory, Detroit Medical Center University Laboratories, Detroit, MI 48201, USA.
authors.forename: F
authors.initials: F
authors.lastname: Nahhas
authors.affiliation: Carmen and Ann Adams Department of Pediatrics, Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI 48201, USA; The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA.
authors.forename: J
authors.initials: J
authors.lastname: Miller
authors.affiliation: Carmen and Ann Adams Department of Pediatrics, Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI 48201, USA; The Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI 48201, USA.
authors.forename: A
authors.initials: A
authors.lastname: Fribley
authors.affiliation: Carmen and Ann Adams Department of Pediatrics, Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI 48201, USA; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA.
authors.forename: G
authors.initials: G
authors.lastname: Feldman
authors.affiliation: Carmen and Ann Adams Department of Pediatrics, Children's Hospital of Michigan, Wayne State University School of Medicine, Detroit, MI 48201, USA; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA.
authors.forename: R
authors.initials: R
authors.lastname: Conway
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA; Genetics Research Laboratory of the Department of Research Administration, Henry Ford Hospital, Detroit, MI 48202, USA. Electronic address: bwolf1@hfhs.org.
authors.forename: B
authors.initials: B
authors.lastname: Wolf
mesh_terms: D043523:Biotinidase / Q000235:genetics* / Q000378:metabolism; D028921:Biotinidase Deficiency / Q000175:diagnosis* / Q000235:genetics*; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D023061:Gene Order; D056426:Genetic Loci; D006801:Humans; D007231:Infant, Newborn; D007438:Introns; D008824:Michigan; D009154:Mutation; D015997:Neonatal Screening; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D043523:Biotinidase
keywords: Biotinidase deficiency; Intronic; Mutation; Newborn screening; Transcription