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Identification of disease mutations in early-onset neuropathies by whole exome sequencing

Show simple item record 2013-05-20T12:00:10Z 2015-07-29T08:20:44Z 2013-05-20T12:00:10Z 2015-07-29T08:20:44Z 2013-05-20
dc.title Identification of disease mutations in early-onset neuropathies by whole exome sequencing en
ethesis.discipline Translational Medicine en
ethesis.department Biomedicinska institutionen sv
ethesis.department Institute of Biomedicine en
ethesis.department Biolääketieteen laitos fi
ethesis.faculty Faculty of Medicine en
ethesis.faculty Medicinska fakulteten sv
ethesis.faculty Lääketieteellinen tiedekunta fi
ethesis.faculty.URI Helsingfors universitet sv University of Helsinki en Helsingin yliopisto fi
dct.creator Pöyhönen, Julia Rosanna Hellin
dct.issued 2013
dct.language.ISO639-2 eng
dct.abstract Charcot-Marie-Tooth (CMT) neuropathy is phenotypically and genetically a very heterogeneous disease. It can be inherited as an autosomal recessive, dominant or X-linked trait. CMT is characterized by distal muscle weakness, atrophy and deformity of the feet as well as clumsiness of gait. The onset of CMT varies and also the symptoms of the disease can vary even among the members of a single family. So far more than 40 genes have been identified for CMT and the list is estimated to grow by 30-50 genes. Whole exome sequencing (WES) is a new next generation sequencing technique, which targets the protein-coding area of the genome. Through WES analysis it is possible to search for disease causing mutations with all kinds of inheritance patterns. Patients suffering from CMT are good candidates for WES analysis because of the genetic heterogeneity of their disease. WES can be used for diagnosing Mendelian disorders with atypical symptoms as well as diseases, which are difficult to confirm using clinical criteria alone and which require costly evaluation, e.g. CMT. In this master study new disease causing mutations for early-onset neuropathies are identified by whole exome sequencing (WES). The aims of this study include using WES for the molecular diagnosis of four patients suffering from early-onset axonal neuropathies, the functional analysis of possible causative variants and improving and developing the process of analyzing variants from whole exome sequencing data, especially the analyzing steps of insertion and deletion variants. Finding causative variants among the insertion and deletion variants has previously been often left out from the WES analysis because of the lack of systematic analysis technique. As a result of the WES data analysis a new candidate disease gene, tripartite motif containing 2 (TRIM2) was identified. A missense mutation c.761T>A (p.E254V) and a deletion c.1779delA (p.K594Rfs7X) were found in patient 2, who suffers from severe CMT type 2. The carrier frequency was analysed to see whether the variants are present in the general population or not. The functional analysis of TRIM2 was started by preparing constructs carrying the missense mutation and the deletion and by setting up conditions for western blotting. en
dct.subject Charcot-Marie-Tooth neuropathy en
dct.subject whole exome sequencing en
dct.subject disease gene en
dct.subject molecular diagnosis en
dct.subject functional analysis en
dct.language en
ethesis.language English en
ethesis.language englanti fi
ethesis.language engelska sv
ethesis.supervisor Tyynismaa, Henna
ethesis.thesistype pro gradu-avhandlingar sv
ethesis.thesistype pro gradu -tutkielmat fi
ethesis.thesistype master's thesis en
dct.identifier.urn URN:NBN:fi:hulib-201507282456
dc.type.dcmitype Text Translational Medicine en
ethesis-internal.updated TRUE2

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