Analysis of the mouse p(100H) mutation. Implications for two disease related genes: P and Sox6.

摘要

My dissertation is focused on the genetics analyses of a mouse mutation, p100H. This mutation is caused by a radiation-induced chromosomal inversion that disrupts both the p gene and Sox6. The human counterparts of these two murine genes are either known to cause human disease (human P gene) or have potential implications in developing a new strategy to treat human disease (SOX6).; In the first part of my dissertation (Chapter One, Part I) on the human P gene, I found that all Navajos with albinism carry a homozygous deletion of 122.5 kb of genomic DNA, including exons 10--20 of the P gene, indicating that albinism among the Navajos is OCA2. This deletion of P gene is Navajo-specific, since I did not find this deletion allele in 34 other individuals with albinism who list various other Native American origins. The Navajo-specific P gene deletion came from a founder mutation. The estimated age of the deletion is 400--1,000 years. In addition, as part of my dissertation (Chapter one, Part II), I found that many patients with Hermansky-Pudlak syndrome-like clinical presentations actually carry P gene mutation. This highlights the importance of molecular analysis in clinical diagnosis.; In the second part of my dissertation (Chapter Two), I characterized a novel function of the transcription factor Sox6 in red cell development and in the silencing of epsilon globin, an embryonic globin gene. This finding bears significance in the field of globin gene regulation and has an important potential in the development of new therapeutic strategies for treating sickle cell anemia and beta thalassemia.