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Permanent URI for this collectionhttps://hdl.handle.net/11443/932

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Author: search.filters.author.Temel, Sehime Gulsun

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    A novel homozygous nonsense mutation in CAST associated with PLACK syndrome
    (SPRINGER, 2019-01-01) Temel, Sehime Gulsun; Karakas, B.; Seker, U.; Turkgenc, B.; Zorlu, O.; Saricaoglu, H.; Ogur, C.; Kutuk, O.; Kelsell, D. P.; Yakicier, M. C.
    Peeling skin syndrome is a heterogeneous group of rare disorders. Peeling skin, leukonychia, acral punctate keratoses, cheilitis and knuckle pads (PLACK syndrome, OMIM616295) is a newly described form of PSS with an autosomal recessive mode of inheritance. We report a 5.5-year-old boy with features of PLACK syndrome. Additionally, he had mild cerebral atrophy and mild muscle involvements. Whole exome sequencing was performed in genomic DNA of this individual and subsequent analysis revealed a homozygous c.544G > T (p.Glu182{*}) nonsense mutation in the CAST gene encoding calpastatin. Sanger sequencing confirmed this variant and demonstrated that his affected aunt was also homozygous. Real-time qRT-PCR and immunoblot analysis showed reduced calpastatin expression in skin fibroblasts derived from both affected individuals compared to heterozygous family members. In vitro calpastatin activity assays also showed decreased activity in affected individuals. This study further supports a key role for calpastatin in the tight regulation of proteolytic pathways within the skin.
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    Structural analysis of M1AP variants associated with severely impaired spermatogenesis causing male infertility
    (PEERJ INC, 2022-01-01) Gerlevik, Umut; Ergoren, Mahmut Cerkez; Sezerman, Osman Ugur; Temel, Sehime Gulsun
    Background: Impaired meiosis can result in absence of sperm in the seminal fluid. This condition, namely non-obstructive azoospermia (NOA), is one of the reasons of male infertility. Despite the low number of studies on meiosis 1-associated protein (M1AP) in the literature, MIAP is known to be crucial for spermatogenesis. Recently, seven variants (five missense, one frameshift, one splice-site) have been reported in the MIAP gene as associated with NOA, cryptozoospermia and oligozoospermia in two separate studies. However, all missense variants were evaluated as variant of uncertain significance by these studies. Therefore, we aimed to analyze their structural impacts on the M1AP protein that could lead to NOA. Methods: We firstly performed an evolutionary conservation analysis for the variant positions. Afterwards, a comprehensive molecular modelling study was performed for the M1AP structure. By utilizing this model, protein dynamics were sampled for the wild-type and variants by performing molecular dynamics (MD) simulations. Results: All variant positions are highly conserved, indicating that they are potentially important for function. In MD simulations, none of the variants led to a general misfolding or loss of stability in the protein structure, but they did cause severe modifications in the conformational dynamics of M1AP, particularly through changes in local interactions affecting flexibility, hinge and secondary structure. Conclusions: Due to critical perturbations in protein dynamics, we propose that these variants may cause NOA by affecting important interactions regulating meiosis, particularly in wild-type M1AP deficiency since the variants are reported to be homozygous or bi-allelic in the infertile individuals. Our results provided reasonable insights about the MIAP structure and the effects of the variants to the structure and dynamics, which should be further investigated by experimental studies to validate.