title: Differential gene expression during early development in brains of wildtype and biotinidase-deficient mice.
abstract: Biotinidase deficiency is an autosomal recessively inherited disorder characterized by neurological and cutaneous abnormalities. Untreated individuals with biotinidase deficiency cannot recycle biotin from biocytin (N-biotinyl-ϵ-lysine), the proteolytic digestion product of protein-bound biotin. Biotin therapy can markedly resolve symptoms, or can prevent the development of symptoms if initiated early. To understand better the pathogenesis of the neurological problems in the disorder in humans, we have compared gene transcription changes during the first week post-birth in the brains of biotinidase-deficient, transgenic, knock-out mice at days 1 and 8 and compared to changes in wildtype mice at the same times. The knockout pups that were not supplemented with unconjugated biotin became symptomatic by day 8 and exhibiting failure to thrive. Wildtype pups remained asymptomatic under the same experimental conditions. We compared all four possible combinations and noted the most significant up- and down-regulated genes in the knockout animals at Day 8 compared to those at Day 1, reflecting the changes in gene expression over the first week of development. These alterations involved neurological development and immunological function pathways and provide some clues to avenues for further research. At this time, these preliminary analyses provide us with limited, but new information. However, with the development of new algorithms and programs examining various mechanisms and pathways in the central nervous system, these analyses may help us to understand better the role of biotinidase and the pathogenesis of biotinidase deficiency.
authors.affiliation: Department of Research Administration, Henry Ford Health System, Detroit, MI 48202, United States.
authors.forename: Christian
authors.initials: C
authors.lastname: Brigolin
authors.affiliation: Department of Research Administration, Henry Ford Health System, Detroit, MI 48202, United States.
authors.forename: Nathan
authors.initials: N
authors.lastname: McKenty
authors.affiliation: Department of Research Administration, Henry Ford Health System, Detroit, MI 48202, United States; Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, United States.
authors.forename: Kirit
authors.initials: K
authors.lastname: Pindolia
authors.affiliation: Department of Research Administration, Henry Ford Health System, Detroit, MI 48202, United States; Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, United States.
authors.forename: Barry
authors.initials: B
authors.lastname: Wolf
keywords: Biotinidase deficiency; Gene expression; Gene transcription; Knock-out mouse; Mouse; Neurological abnormalities; Transgenic mouse