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Title: A clinical and molecular genetic study of the skeletal dysplasia dyggve melchior clausen syndrome
Authors: Kinning, Esther
Award date: 2008
Presented at: University of Leicester
Abstract: Dyggve Melchior Clausen (DMC) syndrome is an autosomal recessive skeletal dysplasia caused by mutations in the Dymeclin (DYM ) gene on chromosome 18q12-21. Affected individuals have multiple bony abnormalities and mental retardation.;The aim of this work was to elucidate the function of the DYM gene product (DYM) and determine the mechanisms by which mutation of the disease gene lead to cellular and clinical phenotype. Ten affected individuals from eight families were recruited to the study and five DYM mutations identified. These included two novel and complex genomic duplication/repetition events each predicted to result in a truncated transcript.;In-silico analyses of DYM suggest it encodes a transmembrane protein involved in protein sorting and targeting within the cell. The DYM transcript was shown by in-situ hybridization to be expressed at high levels in cartilage and brain, particularly in resting and hypertrophic chondrocytes. Sub-cellular localisation demonstrated the DYM gene product to be located within the endoplasmic reticulum.;Yeast two-hybrid analysis performed to detect DYM interacting proteins identified EGF-containing fibulin-like extracellular matrix protein (EFEMP1) and vacuolar protein sorting protein 25 (VPS25, human homologue known as EAP20). EFEMP1 is an extracellular matrix (ECM) protein and EAP20 a component of the endosomal sorting complex required for transport which acts in transport of transmembrane proteins for export and recycling.;Taken together, these findings indicate that DYM is an endoplasmic reticulum transmembrane protein required for cargo transport through the endosomal compartment. Abnormal chondrocyte differentiation and brain function occur in the absence of adequate functional DYM. Given that cartilage and brain both have substantial requirements for extracellular matrix, it is suggested that DYM contributes to the transport of components of the ECM.
Type: Thesis
Level: Doctoral
Qualification: PhD
Rights: Copyright © the author. All rights reserved.
Appears in Collections:Theses, Dept. of Genetics
Leicester Theses

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