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Characterization of the protein encoded by KIAA0319 - a dyslexia candidate gene. / CUHK electronic theses & dissertations collection

Developmental Dyslexia (DD) refers to a reading disorder affecting individuals that possess otherwise normal intelligence. Having demonstrated by familial and twin studies, genetic factors are found to be of major significance to DD development. A strong dyslexia susceptibility gene KIAA0319 (K), of which crucial role in DD had been revealed by various linkage and association studies, was found to have 40% reduction in expression in the DD risk haplotype. Besides, both up- and down-regulation of K would result in impaired neuronal migration in rat. Despite the undoubtedly strong linkage of K to DD, biological and molecular knowledge of K is still lacking. Consequently, how K plays its role in DD remains unclear. To address this question, investigations of human K protein and its interactions in molecular level were performed. K protein is a large transmembrane protein which consists of four main parts, including the N-terminus of K which has a MANSC domain downstream of the signal peptide, a large cluster of five PKD domains in the middle of the protein sequence, a Cysteine -rich C6 region together with a transmembrane domain which had been demonstrated to be critical for forming K protein homodimer, and the only cytoplasmic C-terminus of K. Having shown that no gross effect on gene expression at both mRNA and protein level was found with overexpressing K by DNA microarray and two-dimensional gel electrophoresis, protein interactions involving K were targeted for investigation. Towards this goal, a monoclonal antibody against K was raised, which is capable for recognizing native full-length K proteins in immunoblotting, indirect immunofluorescence staining, as well as in immunoprecipitation. A novel K interaction partner protein KIAA0319-Like (KL), which is a homologous protein of K with high sequence similarity (59%), has been found and confirmed by co-immunoprecipitation. No interaction was shown for truncation mutants of Cysteine-rich C6 region in either K or KL proteins, cuing that the interaction of K and KL at C6 region is a mimic of K homodimer, and led to a hypothesis that the function of K is regulated by KL, which serves as a molecular control of neuronal migration by regulating the formation of K dimer. Another known interaction partner of K protein, the mu---subunit of Adaptor protein 2 complex (AP2M1) which binds to cytoplasmic C-terminus of K (55% similarity to that of KL), was found to have similar binding behaviour towards K as well as KL by co-immunoprecipitation and molecular docking. In addition to AP2M1, two adaptor proteins FEM and SH2 were also confirmed to be interacting with cytoplasmic C-terminus of K, suggested that cytoplasmic region of K is responsible for interactions of downstream cellular pathways. Interaction of K with adaptor proteins also suggested that K might be a membrane receptor that mediates signalling via various adapter proteins. The N-terminus of K protein which has the least sequence similarity to KL (31%) is hence thought to confer to the specificity of the receptor and is critical to the function of K in DD. / Chan, Hoi Ling. / Adviser: Mary M. Y. Waye. / Source: Dissertation Abstracts International, Volume: 72-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 164-170). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Identiferoai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_344549
Date January 2010
ContributorsChan, Hoi Ling., Chinese University of Hong Kong Graduate School. Division of Life Sciences.
Source SetsThe Chinese University of Hong Kong
LanguageEnglish, Chinese
Detected LanguageEnglish
TypeText, theses
Formatelectronic resource, microform, microfiche, 1 online resource (xv, 188 leaves : ill.)
RightsUse of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/)

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