PARN, poly(A)‐specific ribonuclease, regulates the turnover of mRNAs and the maturation and stabilization of the h TR RNA component of telomerase. Biallelic PARN mutations were associated with Høyeraal–Hreidarsson (HH) syndrome, a rare telomere biology disorder that, because of its severity, is likely not exclusively due to h TR down‐regulation. Whether PARN deficiency was affecting the expression of telomere‐related genes was still unclear. Using cells from two unrelated HH individuals carrying novel PARN mutations and a human PARN knock‐out (KO) cell line with inducible PARN complementation, we found that PARN deficiency affects both telomere length and stability and down‐regulates the expression of TRF1 , TRF2 , TPP1 , RAP1 , and POT1 shelterin transcripts. Down‐regulation of dyskerin‐encoding DKC1 mRNA was also observed and found to result from p53 activation in PARN‐deficient cells. We further showed that PARN deficiency compromises ribosomal RNA biogenesis in patients' fibroblasts and cells from heterozygous Parn KO mice. Homozygous Parn KO however resulted in early embryonic lethality that was not overcome by p53 KO. Our results refine our knowledge on the pleiotropic cellular consequences of PARN deficiency.

Chediak–Higashi syndrome (CHS) is caused by autosomal recessive mutations in LYST, resulting in enlarged lysosomal compartments in multiple cell types. CHS patients display oculocutaneous albinism and may develop life-threatening hemophagocytic lymphohistiocytosis (HLH). While NK cell-mediated cytotoxicity has been reported to be uniformly defective, variable defects in T cell-mediated cytotoxicity has been observed. The latter has been linked to the degree of HLH susceptibility. Since the discrepancies in NK cell- and T cell-mediated cellular cytotoxicity might result from differences in regulation of cytotoxic granule release, we here evaluated perforin-containing secretory lysosome size and number in freshly isolated lymphocytes from CHS patients and furthermore compared their exocytic capacities. Whereas NK cells from CHS patients generally contained a single, gigantic perforin-containing granule, cytotoxic T cells predominantly contained several smaller granules. Nonetheless, in a cohort of 21 CHS patients, cytotoxic T cell and NK cell granule exocytosis were similarly impaired upon activating receptor stimulation. Mechanistically, polarization of cytotoxic granules was defective in cytotoxic lymphocytes from CHS patients, with EEA1, a marker of early endosomes, mislocalizing to lysosomal structures. The results leads to the conclusion that lysosome enlargement corresponds to loss of distinct organelle identity in the endocytic pathway, which on a subcellular level more adversely affects NK cells than T cells. Hence, vesicular size or numbers do not per se dictate the impairment of lysosomal exocytosis in the two cell types studied.

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Amaç: Hemofili A (HA), faktör 8 (F8) genindeki hemizigot mutasyonların neden olduğu X'e bağlı kalıtsal kanama bozukluğudur. Bu çalışmanın amacı, Türkiye'den büyük bir HA kohortunda F8 geninin mutasyon spektrumunu belirlemek ve fenotip-genotip korelasyonu oluşturmaktır. Gereç ve Yöntemler: Mart 2017-Mart 2018 tarihleri arasında Ege Üniversitesi Pediatrik Genetik Moleküler Laboratuvarı'nda moleküler olarak analiz edilen tüm HA hastaları (270 hasta) çalışmaya dahil edildi. "İntron 22 inversiyonu" (Inv22), "intron 1 inversiyonu" (Inv1), "küçük delesyon/duplikasyonlar" ve "nokta mutasyonları" tanımlamak için F8'in moleküler analizleri, uygun bir algoritma kullanılarak gerçekleştirildi. Bulgular: Mutasyon saptama başarı oranı %95,2'ydi. Yüz altı hastada (%39,3) Inv22 pozitif, 4 hastada (%1,5) Inv1, 137 hastada (%50,6) Yüz altı farklı hastalık yapıcı sekans varyantı saptandı. On hastada (%3,7), büyük intragenik delesyonlar olduğu öngörülen bir veya daha

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