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Title: The genes involved in hearing and endocrine disorders
Author: Jenkinson, Emma Mary
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2012
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In recent years, there has been a great deal of interest in rare autosomal recessive disorders. This project entitled ‘The Genes Involved in Hearing and Endocrine Disorders’ focuses on a group of autosomal recessive phenotypes which include symptoms such as sensorineural hearing loss, ovarian dysgenesis, hypogonadotropic hypogonadism, short stature and developmental delay. The aim of the project is to give insight into the molecular pathology of two disorders; Perrault syndrome (PS) and an unclassified Hypogonadotropic Hypogonadism (HH) disorder, through the identification of causative genes. Perrault syndrome is defined as the association of sensorineural hearing loss and primary ovarian failure/ovarian dysgenesis. The phenotypic spectrum of PS is broad with the most common additional features being neurological, including ataxia. The HH disorder presented in this thesis is novel, where affected family members present with a complex combination of features including hearing loss, hypogonadism, facial dysmorphism, microcephaly and learning disability. I undertook a combination of genetic techniques including autozygosity mapping and next generation sequencing to define the causative genes. In one consanguineous PS family I identified a locus at 19p13 and subsequent sequence analysis determined three novel missense changes in PCP2, CLPP and GTF2F1 which may be pathogenic. In the HH family autozygosity mapping defined a locus at chromosome 3p21 and a novel missense variant in BSN was identified. Subsequent developmental biology techniques were used to define the pathogenicity of these variants. In conclusion, the data presented in this thesis has contributed to current understanding of hearing and endocrine disorders in humans. Novel mutations have been identified in genes which have not previously been linked to hearing or sexual development. Future work will be aimed at determining the specific roles of these genes in disease pathogenesis and providing accurate risk estimation for the families who have taken part in this study. An additional aim will be to increase the understanding of the pathogenesis of more common disorders of hearing loss and infertility in the hope of developing novel therapeutics.
Supervisor: Davis, Julian; Newman, William Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available