• MeSH
• Antilymphocyte Serum therapeutic use   MeSH
• Kidney Transplantation MeSH
• Transplantation Immunology drug effects   MeSH
• Publication type
• Monograph MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• nefrologie
• transplantologie

• MeSH
• Kidney Failure, Chronic MeSH
• Nephrology MeSH
• Publication type
• Congress MeSH
• Collected Work MeSH

• Conspectus
• Patologie. Klinická medicína
• NML Fields
• nefrologie
• urologie

• MeSH
• Metabolism MeSH
• Pyelonephritis MeSH
• Sodium MeSH

• MeSH
• Joint Dislocations therapy   MeSH
• Humans MeSH
• Patella surgery   MeSH
• Check Tag
• Humans MeSH

• MeSH
• Arthroplasty MeSH
• Adult MeSH
• Hip Joint surgery   MeSH
• Humans MeSH
• Joint Prosthesis MeSH
• Check Tag
• Adult MeSH
• Humans MeSH

Mutations in HFE, the most common cause of hereditary hemochromatosis, lead to iron overload. The iron overload is characterized by increased iron uptake due to lower levels of the hepatic, iron regulatory hormone hepcidin. HFE was cloned 21 years ago, but the signaling pathway is still unknown. Because bone morphogenetic protein (BMP) signaling is impaired in patients with hereditary hemochromatosis, and the interaction of HFE and the BMP type I receptor ALK3 was suggested in vitro, in vivo experiments were performed. In vivo, hepatocyte-specific Alk3-deficient and control mice were injected with either AAV2/8-Hfe-Flag or PBS. HFE overexpression in control mice results in increased hepatic hepcidin levels, p-Smad1/5 levels, and iron deficiency anemia, whereas overexpression of HFE in hepatocyte-specific Alk3-deficient mice results in no change in hepcidin, p-Smad1/5 levels, or blood parameters. These results indicate that HFE signals predominantly via ALK3 to induce hepcidin in vivo.

• Publication type
• Journal Article MeSH

Although the relationship between hereditary hemochromatosis and mutations in the HFE gene was discovered more than 20 years ago, information on the in vivo regulation of HFE protein expression is still limited. The purpose of the study was to determine the response of liver HFE protein content to iron deficiency in mice and rats by immunoblotting. Attempts to visualize the HFE protein in whole liver homogenates were unsuccessful; however, HFE could be detected in liver microsomes or in plasma membrane-enriched fractions. Five-week-old male C57BL/6 mice fed an iron-deficient diet for 4 wk presented with a significant decrease in liver iron content and liver Hamp expression, as well as with a significant decrease in liver HFE protein content. Rats fed an iron-deficient diet for 4 wk also displayed significant decrease in liver Hamp expression and liver HFE protein content. These results suggest that the downregulation of HFE-dependent signaling may contribute to decreased Hamp gene expression in states of prolonged iron deficiency. It has recently been proposed that HFE protein could be a potential target of matriptase-2, a hepatocyte protease mutated in iron-refractory iron deficiency anemia. However, immunoblot analysis of HFE protein in the livers from Tmprss6-mutated mask mice did not show evidence of matriptase-2-dependent HFE protein cleavage. In addition, no indication of HFE protein cleavage was seen in iron-deficient rats, whereas the full-length matriptase-2 protein content in the same animals was significantly increased. These results suggest that HFE is probably not a major physiological target of matriptase-2. NEW & NOTEWORTHY Feeding of iron-deficient diet for 4 wk decreased liver HFE protein content in both mice and rats, suggesting that decreased HFE-dependent signaling may contribute to hepcidin downregulation in iron deficiency. There was no difference in HFE protein band appearance between matriptase-2-mutated mask mice and wild-type mice, indicating that HFE is probably not a major physiological substrate of matriptase-2-mediated protease activity in vivo.

• MeSH
• Anemia, Iron-Deficiency genetics   metabolism   MeSH
• Iron Deficiencies MeSH
• Liver metabolism   MeSH
• Rats MeSH
• Membrane Proteins genetics   metabolism   MeSH
• RNA, Messenger genetics   metabolism   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Rats, Wistar MeSH
• Hemochromatosis Protein genetics   metabolism   MeSH
• Proteolysis MeSH
• Serine Endopeptidases genetics   metabolism   MeSH
• Iron MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Hepcidin deficiency leads to iron overload by increased dietary iron uptake and iron release from storage cells. The most frequent mutation in Hfe leads to reduced hepcidin expression and thereby causes iron overload. Recent findings suggested that HFE activates hepcidin expression predominantly via the BMP type I receptor ALK3. Here, we investigated whether HFE exclusively utilizes ALK3 or other signaling mechanisms also. We generated mice with double deficiency of Hfe and hepatocyte-specific Alk3 and compared the iron overload phenotypes of these double knockout mice to single hepatocyte-specific Alk3 deficient or Hfe knockout mice. Double Hfe-/-/hepatic Alk3fl/fl;Alb-Cre knockouts develop a similar iron overload phenotype compared to single hepatocyte-specific Alk3 deficient mice hallmarked by serum iron levels, tissue iron content and hepcidin levels of similar grades. HFE protein levels were increased in Alk3fl/fl;Alb-Cre mice compared to Alk3fl/fl mice, which was caused by iron overload - and not by Alk3 deficiency. The data provide evidence by genetic means that 1. HFE exclusively uses the BMP type I receptor ALK3 to induce hepcidin expression and 2. HFE protein expression is induced by iron overload, which further emphasizes the iron sensing function of HFE.

• MeSH
• Hepcidins * genetics   MeSH
• Histocompatibility Antigens Class I genetics   MeSH
• Liver metabolism   MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Iron Overload * genetics   MeSH
• Hemochromatosis Protein genetics   MeSH
• Bone Morphogenetic Protein Receptors, Type I MeSH
• Signal Transduction MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

OBJECTIVE: Genomics Quality Assessment has provided external quality assessments (EQAs) for preimplantation genetic testing (PGT) for 12 years for eight monogenic diseases to identify sub-optimal PGT strategies, testing and reporting of results, which can be shared with the genomics community to aid optimised standards of PGT services for couples. METHOD: The EQAs were provided in two stages to mimic end-to-end protocols. Stage 1 involved DNA feasibility testing of a couple undergoing PGT and affected proband. Participants were required to report genotyping results and outline their embryo testing strategy. Lymphoblasts were distributed for mock embryo testing for stage 2. Submitted clinical reports and haplotyping results were assessed against peer-ratified criteria. Performance was monitored to identify poor performance. RESULTS: The most common testing methodology was short tandem repeat linkage analysis (59%); however, the adoption of single nucleotide polymorphism-based platforms was observed and a move from blastomere to trophectoderm testing. There was a variation in testing strategies, assigning marker informativity and understanding test limitations, some clinically unsafe. Critical errors were reported for genotyping and interpretation. CONCLUSION: EQA provides an overview of the standard of preimplantation genetic testing-M clinical testing and identifies areas of improvement for accurate detection of high-risk embryos.

• MeSH
• Aneuploidy MeSH
• Blastocyst MeSH
• Genetic Testing methods   MeSH
• Humans MeSH
• Preimplantation Diagnosis * methods   MeSH
• Pregnancy MeSH
• Check Tag
• Humans MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Bryant-Li-Bhoj syndrome (BLBS), which became OMIM-classified in 2022 (OMIM: 619720, 619721), is caused by germline variants in the two genes that encode histone H3.3 (H3-3A/H3F3A and H3-3B/H3F3B) [1-4]. This syndrome is characterized by developmental delay/intellectual disability, craniofacial anomalies, hyper/hypotonia, and abnormal neuroimaging [1, 5]. BLBS was initially categorized as a progressive neurodegenerative syndrome caused by de novo heterozygous variants in either H3-3A or H3-3B [1-4]. Here, we analyze the data of the 58 previously published individuals along 38 unpublished, unrelated individuals. In this larger cohort of 96 people, we identify causative missense, synonymous, and stop-loss variants. We also expand upon the phenotypic characterization by elaborating on the neurodevelopmental component of BLBS. Notably, phenotypic heterogeneity was present even amongst individuals harboring the same variant. To explore the complex phenotypic variation in this expanded cohort, the relationships between syndromic phenotypes with three variables of interest were interrogated: sex, gene containing the causative variant, and variant location in the H3.3 protein. While specific genotype-phenotype correlations have not been conclusively delineated, the results presented here suggest that the location of the variants within the H3.3 protein and the affected gene (H3-3A or H3-3B) contribute more to the severity of distinct phenotypes than sex. Since these variables do not account for all BLBS phenotypic variability, these findings suggest that additional factors may play a role in modifying the phenotypes of affected individuals. Histones are poised at the interface of genetics and epigenetics, highlighting the potential role for gene-environment interactions and the importance of future research.

• MeSH
• Child MeSH
• Adult MeSH
• Phenotype * MeSH
• Histones * genetics   MeSH
• Humans MeSH
• Intellectual Disability genetics   pathology   MeSH
• Adolescent MeSH
• Neurodegenerative Diseases genetics   pathology   MeSH
• Neurodevelopmental Disorders genetics   pathology   MeSH
• Child, Preschool MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH