Aberrant phase separation and nucleolar dysfunction in rare genetic diseases.

Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact of most variants is unknown as they occur within intrinsically disordered protein regions that have poorly defined functions1-3. Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates, such as the nucleolus4,5. This suggests that mutations in disordered proteins may alter condensate properties and function6-8. Here we show that a subset of disease-associated variants in disordered regions alter phase separation, cause mispartitioning into the nucleolus and disrupt nucleolar function. We discover de novo frameshift variants in HMGB1 that cause brachyphalangy, polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome. The frameshifts replace the intrinsically disordered acidic tail of HMGB1 with an arginine-rich basic tail. The mutant tail alters HMGB1 phase separation, enhances its partitioning into the nucleolus and causes nucleolar dysfunction. We built a catalogue of more than 200,000 variants in disordered carboxy-terminal tails and identified more than 600 frameshifts that create arginine-rich basic tails in transcription factors and other proteins. For 12 out of the 13 disease-associated variants tested, the mutation enhanced partitioning into the nucleolus, and several variants altered rRNA biogenesis. These data identify the cause of a rare complex syndrome and suggest that a large number of genetic variants may dysregulate nucleoli and other biomolecular condensates in humans.

Fracture sonography - Literature review and current recommendations.

PURPOSE: Over the course of more than two years, an expert group of 9 professional societies has created the S2e guidelines for fracture sonography. This publication summarizes the key points regarding the individual indications. MATERIALS AND METHODS: A systematic literature search was performed in PubMed, Google Scholar, and the Cochrane Database of Systematic Reviews from 2000 to March 2021 with evaluation of the literature lists. Randomized controlled clinical trials, observational clinical trials, meta-analyses, and systematic reviews were included. Guidelines, conferences, reviews, case reports, and expert opinions were excluded. Evidence was graded using the SIGN grading system 1999-2012, and the SIGN tables were then presented to the expert group. These were used to develop specific recommendations for the use of fracture sonography. All recommendations were discussed in detail and finally unanimously agreed upon. RESULTS: Of the 520 primary literature sources found, 182 sources (146 clinical studies and 36 meta-analyses and systematic reviews) were evaluated after screening and content assessment. 21 indications that allow reasonable application of fracture sonography were identified. CONCLUSION: Ultrasound is a sensible, easy-to-use diagnostic method that is feasible for a large number of indications.

Fracture sonography-review of literature and current recommendations.

Over a span of more than two years, a collaborative expert group consisting of 9 professional societies has meticulously crafted the S2e guideline on fracture sonography. This publication encapsulates the essential insights pertaining to specific indications. A thorough and systematic literature search, covering the period from 2000 to March 2021, was conducted across PubMed, Google Scholar, and the Cochrane Database of Systematic Reviews, complemented by an evaluation of bibliographies. Inclusion criteria encompassed randomized controlled clinical trials, observational clinical trials, meta-analyses, and systematic reviews, while guidelines, conferences, reviews, case reports, and expert opinions were excluded. The SIGN grading system (1999-2012) was applied to assess evidence, and resultant SIGN tables were presented to the expert group. Specific recommendations for the application of fracture sonography were then derived through unanimous consensus after detailed discussions. Out of the initial pool of 520 literature sources, a meticulous screening and content assessment process yielded 182 sources (146 clinical studies and 36 meta-analyses and systematic reviews) for evaluation. The comprehensive analysis identified twenty-one indications that substantiate the judicious use of fracture sonography. Ultrasound emerges as a pragmatic and user-friendly diagnostic method, showcasing feasibility across a diverse range of indications.