Browsing by Subject "Disease gene identification"

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Open Access
Identification and characterization of exonic variants related with familial essential tremor
(2017-07) Tuncay, İslam Oğuz
Essential tremor (ET) is the most common movement disorder in humans. Despite its high heritability and frequency, the genetic basis and pathophysiology of ET is not well understood. In this study, whole exome sequencing and pedigree analyses were performed in unrelated ET families from Anatolia. Whole exome sequencing analysis of family members resulted in the identification of MMP19 p.R456Q in families ET-5 and ET-49. Expression analysis in mice showed a possible developmental pattern for expression of MMP-19 as well as a tissue-specific expression pattern showing high levels of expression in the brain for this gene. Two other families, ET-17 and ET-19 were also analyzed; however the results were not able to identify variant cosegregating with ET in these families. Identification of the new genes related with ET will provide invaluable insights into the underlying mechanism of thıs most common movement disorder and will potentially open new avenues for its treatment.
Open Access
Identification of candidate genes for familial essential tremor
(2016-09) Şen, Merve
Essential tremor (ET) is one of the most common movement disorders in humans and is characterized by action tremors that occur during voluntary motion. However, due to the strong heterogeneity exhibited by ET patients at etiological, clinical and pathological levels, the genetic architecture and pathophysiology of the disease remain largely unknown. In this thesis, whole exome sequencing and pedigree analysis were performed in 3 ET families with histories consistent with an autosomal dominant pattern of inheritance. In two independent families, we observed a rare variant that cosegregated with the disease and was predicted to affect the function of the protein. In one of these families, a homozygous variant was identified in one affected patient and a heterozygous variant was determined in five affected family members. In a second, four-generation Turkish family, the same heterozygous variant was identified in three ET cases while remaining absent in unaffected family members. In addition, whole exome sequencing allowed us to demonstrate that other missense mutation segregate with essential tremor in a different consanguineous Turkish family. Both variants were observed to involve amino acid substitutions of highly conserved domains. Furthermore, both of the affected genes are expressed in the brain and function as regulatory elements of the central nervous system. Consequently, we propose that these variants are risk factors involved in the etiology of hereditary ET, and suggest that whole exome sequencing can serve as an effective means of identifying other alleles associated with the disease.