MOLECULAR BASIS OF FAMILIAL STUTTERING

描述（由申请人提供）：最近一项关于持续性口吃遗传基础的研究发现，编码两种酶的基因中有10个突变，这两种酶将甘露糖6-磷酸标签添加到新合成的溶酶体酸水解酶上。这个标签用于指导（“目标”）酸水解酶到溶酶体。本研究的目的是确定在口吃人群中发现的突变对酸水解酶靶向途径的影响。假设是这些突变损害了与口吃有关的神经元中溶酶体的功能，从而损害了这些关键细胞。这些研究将使用患者成纤维细胞作为神经元的替代物，并且将以多种方式研究Man-6-P标签的合成。此外，细胞将被转染编码酶突变形式的cdna，以跟踪对蛋白质折叠、运输、定位和半衰期的潜在影响。总的目标是了解导致口吃的细胞异常。

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. 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.