Becoming Donor-Conceived

While it has been argued that anonymity in gamete donation has been brought to an end by legal changes and technological developments, Amelie Baumann suggests that this is in fact still in transformation. By focusing on the narratives of those who were conceived with anonymously donated gametes in the UK and Germany, she examines this transformative process and the role which donor-conceived persons play in it. This book shows that it is not someone's decision to procreate that turns »being donor-conceived« into a meaningful categorisation. Rather, kinship knowledge gets activated by the donor-conceived in specific ways for »being donor-conceived« to become a powerful identification

Becoming Donor-Conceived

While it has been argued that anonymity in gamete donation has been brought to an end by legal changes and technological developments, Amelie Baumann suggests that this is in fact still in transformation. By focusing on the narratives of those who were conceived with anonymously donated gametes in the UK and Germany, she examines this transformative process and the role which donor-conceived persons play in it. This book shows that it is not someone's decision to procreate that turns »being donor-conceived« into a meaningful categorisation. Rather, kinship knowledge gets activated by the donor-conceived in specific ways for »being donor-conceived« to become a powerful identification

Functional characterization of novel or yet uncharacterized ATP7B missense variants detected in patients with clinical Wilson's disease

Wilson's disease (WD, MIM#277900) is an autosomal recessive disorder resulting in copper excess caused by biallelic variants in the ATP7B gene (MIM#606882) encoding a copper transporting P-type ATPase. ATP7B variants of unknown significance (VUS) are detected frequently, sometimes impeding a clear diagnosis. Functional analyses can help to classify these variants as benign or pathogenic. Additionally, variants already classified as (likely) pathogenic benefit from functional analyses to understand their pathomechanism, thus contribute to the development of personalized treatment approaches in the future. We described clinical features of six WD patients and functionally characterized five ATP7B missense variants (two VUS, three yet uncharacterized likely pathogenic variants), detected in these patients. We determined the protein level, copper export capacity, and cellular localization in an in vitro model and potential structural consequences using an ATP7B protein model based on AlphaFold. Our analyses give insight into the pathomechanism and allowed reclassification for the two VUS to likely pathogenic and for two of the three likely pathogenic variants to pathogeni

Attenuated Aβ42 Responses to Low Potency γ-Secretase Modulators Can Be Overcome for Many Pathogenic Presenilin Mutants by Second-generation Compounds*

Sequential processing of the β-amyloid precursor protein by β- and γ-secretase generates the amyloid β-peptide (Aβ), which is widely believed to play a causative role in Alzheimer disease. Selective lowering of the pathogenic 42-amino acid variant of Aβ by γ-secretase modulators (GSMs) is a promising therapeutic strategy. Here we report that mutations in presenilin (PS), the catalytic subunit of γ-secretase, display differential responses to non-steroidal anti-inflammatory drug (NSAID)-type GSMs and more potent second-generation compounds. Although many pathogenic PS mutations resisted lowering of Aβ42 generation by the NSAID sulindac sulfide, the potent NSAID-like second-generation compound GSM-1 was capable of lowering Aβ42 for many but not all mutants. We further found that mutations at homologous positions in PS1 and PS2 can elicit differential Aβ42 responses to GSM-1, suggesting that a positive GSM-1 response depends on the spatial environment in γ-secretase. The aggressive pathogenic PS1 L166P mutation was one of the few pathogenic mutations that resisted GSM-1, and Leu-166 was identified as a critical residue with respect to the Aβ42-lowering response of GSM-1. Finally, we found that GSM-1-responsive and -resistant PS mutants behave very similarly toward other potent second-generation compounds of different structural classes than GSM-1. Taken together, our data show that a positive Aβ42 response for PS mutants depends both on the particular mutation and the GSM used and that attenuated Aβ42 responses to low potency GSMs can be overcome for many PS mutants by second generation GSMs

Monogenic Early-Onset Lymphoproliferation and Autoimmunity: The Natural History of STAT3 GOF Syndrome.

Background In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. Objective This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. Methods We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. Results Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4−CD8−) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. Conclusion : STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome. Key word