Sarıtaş, Merve

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A Novel Germline Pregnane X Receptor (PXR) Variant Predisposing to Hodgkin Lymphoma in Two Siblings
(Elsevier, 2024) Khodzhaev, Khusan; Sudutan, Tugce; Erbilgin, Yucel; Saritas, Merve; Yegen, Gulcin; Bozkurt, Ceyhun; Kebudi, Rejin
Hodgkin's lymphoma (HL) is the most common cancer in adolescents and young adults. A family history of HL increases the risk of developing HL in other family members. Identification of genetic predisposition variants in HL is important for understanding disease aetiology, prognosis, and response to treatment. Aberrant activation of the NF-kappa B pathway is a hallmark feature of HL, contributing to the survival and proliferation of the malignant cells' characteristic of HL. The family with multiple consanguineous marriages with siblings of diagnosed HL was examined by whole-exome sequencing. We found a germline homozygous variation in the PXR ligand binding domain (NM_003889.3:c.811G>A, p.(Asp271Asn)), which was classified as pathogenic by prediction tools and segregated in HL cases. Increased PXR expression was found in homozygous variant carriers compared to heterozygous carriers by quantitative real time PCR (qRT-PCR) and immunofluorescence staining of patients' formalin-fixed paraffin-embedded tissues showed upregulation of PXR, particularly in Hodgkin Reed/Sternberg (HRS) cells. Patients with homozygous PXR variant showed significantly high expression compared to PXR wild-type HL, heterozygous and controls (p = 0.0001, p = 0.0004 and p = 0.0001, respectively). PXR homozygous HRS cells had significantly higher PXR expression compared to PXR wild-type HRS cells (p < 0.0001, 3.27-fold change). Albeit PXR's prominent expression in cytoplasm of HRS cells, homozygous PXR HRS cells showed increased PXR expression in nucleus (p < 0.001). PXR is a member of the nuclear receptor superfamily and previous studies have demonstrated a pleiotropic effect of PXR on malignant transformation. Expression analysis showed that cell proliferation, apoptosis and inflammation related genes were deregulated, in homozygous PXR HL cases. This study provided clinical evidence to previously reported Sxr(-/-) mice model that develop multifocal lymphomas, had an aberrantly increased NF-kappa B expression and consistent inflammation. Further functional studies are needed to elucidate the exact mechanisms of action of PXR in HL pathogenesis.
Identification of Nonsense Variants in the ATM Gene Mimicking SCID Phenotype: A Brief Report
(Springer, 2025) Firtina, Sinem; Saritas, Merve; Ng, Yuk Yin; Nepesov, Serdar; Kiykim, Ayca; Bozkurt, Selcen; Sayitoglu, Muge
Severe combined immunodeficiency (SCID) represents a life-threatening inborn error of immunity, necessitating rapid diagnosis and intervention to prevent fatal outcomes. While SCID is characterized by profound T-cell lymphopenia, it may overlap with other conditions like ataxia-telangiectasia (AT), which also presents with T-cell deficiencies. This study examines two cases of suspected SCID in infants, later identified as AT due to pathogenic variants in the ATM gene. Despite initial negative results from SCID-targeted gene panels, further genetic testing revealed nonsense mutations (p.Y2036X and p.E1996X) in the FAT domain of the ATM gene, confirmed by Sanger sequencing. The patients exhibited significant T-cell lymphopenia and reduced ATM protein activity, indicative of AT. These findings highlight the importance of comprehensive genetic screening beyond common SCID-associated genes, especially in patients with atypical presentations. Early and accurate diagnosis can prevent mismanagement and guide appropriate therapies, improving patient outcomes.

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European Journal of Medical Genetics	1
Immunologic Research	1

Sarıtaş, Merve

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