Neuroacanthocytosis associated with a defect of the 4.1R membrane protein

BACKGROUND: Neuroacanthocytosis (NA) denotes a heterogeneous group of diseases that are characterized by nervous system abnormalities in association with acanthocytosis in the patients' blood. The 4.1R protein of the erythrocyte membrane is critical for the membrane-associated cytoskeleton structure and in central neurons it regulates the stabilization of AMPA receptors on the neuronal surface at the postsynaptic density. We report clinical, biochemical, and genetic features in four patients from four unrelated families with NA in order to explain the cause of morphological abnormalities and the relationship with neurodegenerative processes. CASE PRESENTATION: All patients were characterised by atypical NA with a novel alteration of the erythrocyte membrane: a 4.1R protein deficiency. The 4.1R protein content was significantly lower in patients (3.40 ± 0.42) than in controls (4.41 ± 0.40, P < 0.0001), reflecting weakened interactions of the cytoskeleton with the membrane. In patients IV:1 (RM23), IV:3 (RM15), and IV:6 (RM16) the 4.1 deficiency seemed to affect the horizontal interactions of spectrin and an impairment of the dimer self-association into tetramers was detected. In patient IV:1 (RM16) the 4.1 deficiency seemed to affect the skeletal attachment to membrane and the protein band 3 was partially reduced. CONCLUSION: A decreased expression pattern of the 4.1R protein was observed in the erythrocytes from patients with atypical NA, which might reflect the expression pattern in the central nervous system, especially basal ganglia, and might lead to dysfunction of AMPA-mediated glutamate transmission

Changes in cortical cytoskeletal and extracellular matrix gene expression in prostate cancer are related to oncogenic ERG deregulation

Abstract Background The cortical cytoskeleton network connects the actin cytoskeleton to various membrane proteins, influencing cell adhesion, polarity, migration and response to extracellular signals. Previous studies have suggested changes in the expression of specific components in prostate cancer, especially of 4.1 proteins (encoded by EPB41 genes) which form nodes in this network. Methods Expression of EPB41L1, EPB41L2, EPB41L3 (protein: 4.1B), EPB41L4B (EHM2), EPB41L5, EPB49 (dematin), VIL2 (ezrin), and DLG1 (summarized as „cortical cytoskeleton" genes) as well as ERG was measured by quantitative RT-PCR in a well-characterized set of 45 M0 prostate adenocarcinoma and 13 benign tissues. Hypermethylation of EPB41L3 and GSTP1 was compared in 93 cancer tissues by methylation-specific PCR. Expression of 4.1B was further studied by immunohistochemistry. Results EPB41L1 and EPB41L3 were significantly downregulated and EPB41L4B was upregulated in cancer tissues. Low EPB41L1 or high EPB41L4B expression were associated with earlier biochemical recurrence. None of the other cortical cytoskeleton genes displayed expression changes, in particular EPB49 and VIL2, despite hints from previous studies. EPB41L3 downregulation was significantly associated with hypermethylation of its promoter and strongly correlated with GSTP1 hypermethylation. Protein 4.1B was detected most strongly in the basal cells of normal prostate epithelia. Its expression in carcinoma cells was similar to the weaker one in normal luminal cells. EPB41L3 downregulation and EPB41L4B upregulation were essentially restricted to the 22 cases with ERG overexpression. Expression changes in EPB41L3 and EPB41L4B closely paralleled those previously observed for the extracellular matrix genes FBLN1 and SPOCK1, respectively. Conclusions Specific changes in the cortical cytoskeleton were observed during prostate cancer progression. They parallel changes in the expression of extracellular matrix components and all together appear to be associated with oncogenic ERG overexpression. We hypothesize that these alterations may contribute to the increased invasivity conferred to prostate cancer cells by ERG deregulation.</p

Genetic instability and anti-HPV immune response as drivers of infertility associated with HPV infection

Funding Information: RFBR grant 17–54-30002, Ministry of Science and Higher Education of the Russian Federation (Agreement No. 075–15–2019-1660) to Olga Smirnova. Publisher Copyright: © 2021, The Author(s).Human papillomavirus (HPV) is a sexually transmitted infection common among men and women of reproductive age worldwide. HPV viruses are associated with epithelial lesions and cancers. HPV infections have been shown to be significantly associated with many adverse effects in reproductive function. Infection with HPVs, specifically of high-oncogenic risk types (HR HPVs), affects different stages of human reproduction, resulting in a series of adverse outcomes: 1) reduction of male fertility (male infertility), characterized by qualitative and quantitative semen alterations; 2) impairment of couple fertility with increase of blastocyst apoptosis and reduction of endometrial implantation of trophoblastic cells; 3) defects of embryos and fetal development, with increase of spontaneous abortion and spontaneous preterm birth. The actual molecular mechanism(s) by which HPV infection is involved remain unclear. HPV-associated infertility as Janus, has two faces: one reflecting anti-HPV immunity, and the other, direct pathogenic effects of HPVs, specifically, of HR HPVs on the infected/HPV-replicating cells. Adverse effects observed for HR HPVs differ depending on the genotype of infecting virus, reflecting differential response of the host immune system as well as functional differences between HPVs and their individual proteins/antigens, including their ability to induce genetic instability/DNA damage. Review summarizes HPV involvement in all reproductive stages, evaluate the adverse role(s) played by HPVs, and identifies mechanisms of viral pathogenicity, common as well as specific for each stage of the reproduction process.publishersversionPeer reviewe