A recent study of the genetic basis of persistent stuttering identified 10 mutations in the three genes that encode the two enzymes that add a Mannose 6-phosphate tag onto newly synthesized lysosomal acid hydrolases. This tag serves to direct ("target") the acid hydrolases to lysosomes. The objective of this research is to determine the effect of the mutations found in the stuttering population on the acid hydrolase targeting pathway. The hypothesis is that these mutations impair lysosomal function in neurons that are involved in stuttering, thereby damaging these critical cells. Patient fibroblasts will be used for these studies as surrogates for the neurons and the synthesis of the Man-6-P tag will be studied in a variety of ways. In addition, cells will be transfected with cDNAs encoding the mutant forms of the enzymes to follow potential effects on protein folding, trafficking, localization and half-life. The overall goal is to obtain an understanding of the cellular abnormalities that lead to stuttering.

Public Health Relevance

This research is directly relevant to the molecular understanding of how mutations in the genes that encode proteins involved in the biogenesis of lysosomes lead to familial stuttering, a relatively common condition the impairs communication and has life altering effects.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DC011332-02
Application #
8306145
Study Section
Therapeutic Approaches to Genetic Diseases (TAG)
Program Officer
Shekim, Lana O
Project Start
2011-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$190,000
Indirect Cost
$65,000
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Das, Debanu; Lee, Wang-Sik; Grant, Joanna C et al. (2013) Structure and function of the DUF2233 domain in bacteria and in the human mannose 6-phosphate uncovering enzyme. J Biol Chem 288:16789-99