MOLECULAR BASIS OF FAMILIAL STUTTERING

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DESCRIPTION (provided by applicant): 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.