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Permanent URI for this collectionhttps://hdl.handle.net/20.500.14288/3

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Department: search.filters.department.Department of Molecular Biology and GeneticsSubject: search.filters.subject.Clinical neurology

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    A novel BHLHE41 variant is associated with short sleep and resistance to sleep deprivation in humans
    (Oxford University Press (OUP), 2014) Pellegrino, Renata; Goel, Namni; Cardinale, Christopher J.; Dinges, David F.; Kuna, Samuel T.; Maislin, Greg; Van Dongen, Hans P. A.; Tufik, Sergio; Hogenesch, John B.; Hakonarson, Hakon; Pack, Allan I.; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; Kavaklı, İbrahim Halil; Faculty Member; Department of Chemical and Biological Engineering; Department of Molecular Biology and Genetics; College of Engineering; 40319
    Study Objectives: Earlier work described a mutation in DEC2 also known as BHLHE41 (basic helix-loop-helix family member e41) as causal in a family of short sleepers, who needed just 6 h sleep per night. We evaluated whether there were other variants of this gene in two well-phenotyped cohorts. Design: Sequencing of the BHLHE41 gene, electroencephalographic data, and delta power analysis and functional studies using cell-based luciferase. Results: We identified new variants of the BHLHE41 gene in two cohorts who had either acute sleep deprivation (n = 200) or chronic partial sleep deprivation (n = 217). One variant, Y362H, at another location in the same exon occurred in one twin in a dizygotic twin pair and was associated with reduced sleep duration, less recovery sleep following sleep deprivation, and fewer performance lapses during sleep deprivation than the homozygous twin. Both twins had almost identical amounts of non rapid eye movement (NREM) sleep. This variant reduced the ability of BHLHE41 to suppress CLOCK/BMAL1 and NPAS2/BMAL1 transactivation in vitro. Another variant in the same exome had no effect on sleep or response to sleep deprivation and no effect on CLOCK/BMAL1 transactivation. Random mutagenesis identified a number of other variants of BHLHE41 that affect its function. Conclusions: There are a number of mutations of BHLHE41. Mutations reduce total sleep while maintaining NREM sleep and provide resistance to the effects of sleep loss. Mutations that affect sleep also modify the normal inhibition of BHLHE41 of CLOCK/BMAL1 transactivation. Thus, clock mechanisms are likely involved in setting sleep length and the magnitude of sleep homeostasis.
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    Clinical and molecular findings in a Turkish family who had a (c.869-1g > a) splicing variant in psen1 gene with a rare condition: the variant alzheimer's disease with spastic paraparesis
    (Bentham Science, 2022) Dogan, Mustafa; Eroz, Recep; Tecellioglu, Mehmet; Gezdirici, Alper; Cevik, Betul; Department of Molecular Biology and Genetics; Barış, İbrahim; Teaching Faculty; Department of Molecular Biology and Genetics; College of Sciences; 111629
    Background: Early-onset Alzheimer's disease (EOAD) is commonly diagnosed with an onset age of earlier than 65 years and accounts for 5-10% of all Alzheimer's disease (AD) cases. To date, although only 10-15% of familial EOAD cases have been explained, the genetic cause of the vast proportion of cases has not been explained. The variant Alzheimer's disease with spastic paraparesis (varAD) is defined as a rare clinical entity characterized by early-onset dementia, spasticity of the lower extremities, and gait disturbance. Although the disease was first associated with variants in exon 9 of the PSEN1 gene, it was later shown that variations in other exons were also responsible for the disease. Objective: The current study aims to raise awareness of varAD, which occurs as a rare phenotype due to pathogenic variants in PSEN1. In addition, we aimed to evaluate the spectrum of mutations in varAD patients identified to date. Methods: Detailed family histories and clinical data were recorded. Whole exome sequencing was performed and co-segregation analysis of the family was done by Sanger sequencing. Also, a review of the molecularly confirmed patients with (varAD) from the literature was evaluated. Results: We identified a heterozygous splicing variant (c.869-1G>A) in the PSEN1 gene, in a family with two affected individuals who present with varAD. We reported the clinical and genetic findings from the affected individuals. Conclusion: We present the detailed clinical and genetic profiles of a Turkish patient with the diagnosis of varAD together with subjects from the literature. Together, we think that the clinical characteristics and the effect of the (c.869-1G>A) variant will facilitate our understanding of the PSEN1 gene in AD pathogenesis.