Stuttering has long been known to have a genetic component. We have recently identified mutations in the GNPTAB gene that occur in individuals who stutter but do not occur in normal controls. Based on these results, we went on to identify mutations in two genes that function in the same biochemical pathway, GNPTG and NAGPA. Together these results indicate that stuttering can be associated deficits in the lysosomal targeting pathway. A goal of our current research is to identify how the subtle metabolic defects caused by mutations in these three genes lead to stuttering without any other discernible symptoms. In initial studies designed to localize the site of the pathology involved, we are measuring the level of expression of these three genes in 56 different regions of the human brain. We are also working to develop a mouse model of human stuttering. This is being done by creating so-called knock-in strains of mice that carry the mutations identified in humans who stutter. These experiments require a detailed acoustical analysis of mouse vocalization, which is largely ultrasonic in nature. In these experiments, we are working with Drs. Terra Barnes and Tim Holy at Washington University in St. Louis, who are leaders in the study of mouse vocalization. In a parallel line of inquiry, we are working with Dr. Stuart Kornfeld, also at Washington University in St. Louis. Dr. Kornfeld is a world leader in the study of the enzymes encoded by the GNPTAB, GNPTG, and NAGPA genes. The goal of these studies is to better understand the effects of the mutations observed in human stutterers on the function of these enzymes at the molecular and cellular level. Initial results in our analysis of mutations of the NAGPA gene found in stuttering indicate that these mutations reduce the activity of this enzyme by about half, and cause it to be mis-localized and/or more rapidly degraded than the normal version of this enzyme. In the past year we have performed additional family ascertainment and recruitment in Pakistan. This has resulted in the enrollment of six new consanguineous families, all characterized by a high density of individuals with persistent stuttering. Linkage analysis in these families has been completed, and we have discovered that variant genes located on chromosomes 3 and16 are the cause of stuttering in some of these families. We are currently working to identify the causative gene at these loci. We have also continued our studies in a group of families in Cameroon, West Africa, in which stuttering occurs consistent with a simple inherited trait. We had previously obtained evidence that a gene on chromosome 1 is responsible in the largest of these families, but follow-up studies, including a subsequent new genome-wide linkage analysis failed to confirm this linkage. It is now clear that more than one causative gene (at more than one location) is at work in this large family, and we have identified significant linkage on chromosomes 2, 3, 14, and 15. We are working to refine these linkage locations and to identify candidate genes in these regions. Our studies of deficits in the sense of taste currently focus on sweet taste. During the past year, we have evaluated variation in other genes that encode known components of the mammalian taste transduction system. Variation in most of the candidate genes we've evaluated shows no evidence of association with variation in sweet taste perception in our subject population. However, we've obtained strong evidence that genetic variation in the G-alpha gustducin gene exerts a major effect on sweet perception, and further experiments to confirm this association, and to understand thee mechanism by which this variation exerts its effect, are underway.

Project Start
Project End
Budget Start
Budget End
Support Year
15
Fiscal Year
2012
Total Cost
$2,246,231
Indirect Cost
Name
National Institute on Deafness and Other Communication Disorders
Department
Type
DUNS #
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Zip Code
Risso, Davide S; Mezzavilla, Massimo; Pagani, Luca et al. (2016) Corrigendum: Global diversity in the TAS2R38 bitter taste receptor: revisiting a classic evolutionary PROPosal. Sci Rep 6:28406
Barnes, Terra D; Wozniak, David F; Gutierrez, Joanne et al. (2016) A Mutation Associated with Stuttering Alters Mouse Pup Ultrasonic Vocalizations. Curr Biol :
Roudnitzky, Natacha; Risso, Davide; Drayna, Dennis et al. (2016) Copy Number Variation in TAS2R Bitter Taste Receptor Genes: Structure, Origin, and Population Genetics. Chem Senses :
Brewer, Carmen C; Zalewski, Christopher K; King, Kelly A et al. (2016) Heritability of non-speech auditory processing skills. Eur J Hum Genet 24:1137-44
Risso, Davide S; Mezzavilla, Massimo; Pagani, Luca et al. (2016) Global diversity in the TAS2R38 bitter taste receptor: revisiting a classic evolutionary PROPosal. Sci Rep 6:25506
Raza, M Hashim; Domingues, Carlos E F; Webster, Ronald et al. (2015) Mucolipidosis types II and III and non-syndromic stuttering are associated with different variants in the same genes. Eur J Hum Genet :
Raza, M Hashim; Mattera, Rafael; Morell, Robert et al. (2015) Association between Rare Variants in AP4E1, a Component of Intracellular Trafficking, and Persistent Stuttering. Am J Hum Genet 97:715-25
Risso, Davide S; Howard, Louisa; VanWaes, Carter et al. (2015) A potential trigger for pine mouth: a case of a homozygous phenylthiocarbamide taster. Nutr Res 35:1122-5
Domingues, C E F; Olivera, C M C; Oliveira, B V et al. (2014) A genetic linkage study in Brazil identifies a new locus for persistent developmental stuttering on chromosome 10. Genet Mol Res 13:2094-101
Campbell, Michael C; Ranciaro, Alessia; Zinshteyn, Daniel et al. (2014) Limited evidence for adaptive evolution and functional effect of allelic variation at rs702424 in the promoter of the TAS2R16 bitter taste receptor gene in Africa. J Hum Genet 59:349-52

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