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Johan P de Winter and colleagues report the identification of mutations in SLX4 in a new Fanconi anemia subtype. SLX4 regulates structure-specific endonucleases, important enzymes in the DNA damage response. DNA interstrand crosslink repair requires several classes of proteins, including structure-specific endonucleases and Fanconi anemia proteins. SLX4, which coordinates three separate endonucleases, was recently recognized as an important regulator of DNA repair. Here we report the first human individuals found to have biallelic mutations in SLX4 . These individuals, who were previously diagnosed as having Fanconi anemia, add SLX4 as an essential component to the FA-BRCA genome maintenance pathway.

The autosomal recessive immunodeficiency-centromeric instability-facial anomalies syndrome (ICF) is characterized by immunodeficiency, developmental delay, and facial anomalies. ICF2, caused by biallelic ZBTB24 gene mutations, is acknowledged primarily as an isolated B-cell defect. Here, we extend the phenotype spectrum by describing, in particular, for the first time the development of a combined immune defect throughout the disease course as well as putative autoimmune phenomena such as granulomatous hepatitis and nephritis. We also demonstrate impaired cell-proliferation and increased cell death of immune and non-immune cells as well as data suggesting a chromosome separation defect in addition to the known chromosome condensation defect.

Objective To identify the cause of a so‐far unreported phenotype of infantile‐onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). Methods We characterized a consanguineous family of Yazidian‐Turkish descent with IMNEPD. The two affected children suffer from intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of liver fibrosis. We performed whole‐exome sequencing followed by bioinformatic analysis and Sanger sequencing on affected and unaffected family members. The effect of mutations in the candidate gene was studied in wild‐type and mutant mice and in patient and control fibroblasts. Results In a consanguineous family with two individuals with IMNEPD, we identified a homozygous frameshift mutation in the previously not disease‐associated peptidyl‐tRNA hydrolase 2 (PTRH2) gene. PTRH2 encodes a primarily mitochondrial protein involved in integrin‐mediated cell survival and apoptosis signaling. We show that PTRH2 is highly expressed in the developing brain and is a key determinant in maintaining cell survival during human tissue development. Moreover, we link PTRH2 to the mTOR pathway and thus the control of cell size. The pathology suggested by the human phenotype and neuroimaging studies is supported by analysis of mutant mice and patient fibroblasts. Interpretation We report a novel disease phenotype, show that the genetic cause is a homozygous mutation in the PTRH2 gene, and demonstrate functional effects in mouse and human tissues. Mutations in PTRH2 should be considered in patients with undiagnosed multisystem neurologic, endocrine, and pancreatic disease.

Functional and conservation data can be useful in the evaluation of variants, but in vitro functional effects do not necessarily imply that the variant has clinical sequelae. [...]as we and others have shown (for example, in studies of the breast cancer susceptibility genes BRIP1 and ATM), such an assumption can result in incorrect attribution of pathogenicity14,15. [...]most of the variants discussed here are predicted to affect amino-acid residues conserved in at least three of the five RAD51 paralogs, and the effects of the variants have been characterized by functional approaches.

Crassulacean acid metabolism (CAM) is an adaptation to environments where water availability is seasonal or extremely low. It serves to ensure survival and/ or maintain productivity in these adverse environments. CAM has repeatedly evolved although it requires a large and complex set of enzymes and transporters and regulatory processes to control metabolite flux and pools. To test potential regulatory levels, we analyze the CAM plant Kalanchoë laxiflora embedded in the context of available CAM genome and transcriptome sequences. We show that CAM associated transcripts and proteins do not show a binary on/off pattern between day and night in K. laxiflora. Instead, we observe that many CAM plants display shared amino acid changes compared to C3 plants especially in starch metabolism. Phosphoproteomics identifies phosphoproteome changes in K. laxiflora between day and night. Taken together, the analyses demonstrate the CAM photosynthesis is regulated at the levels of transcripts and proteins. Regulation of CAM cannot be explained by transcript and protein abundance alone but is also dependent on adaptive changes in proteins and posttranslational modifications.

Plant lipid droplets (LDs) and their associated proteins have numerous subcellular and physiological functions. While considerable progress has been made for LDs in many tissues, the function and composition of LDs in roots remains largely unexplored.We investigated the changes of the number of LDs and of the lipidome in heat-stressed Arabidopsis thaliana roots. Furthermore, we isolated root LDs from the Arabidopsis mutant trigalactosyldiacylglycerol 1-1 sugar dependent 1-4 and investigated their proteome and lipidome.Heat stress lead to a degradation of membrane lipids and an increase in TAGs and LDs. while, fatty acid SEs decreased, probably acting as precursors for acylated sterol glycosides. A variety of proteins were enriched in root LDs, which are thus far not described as LD proteins. Transient expression of these proteins in many cases confirmed their LD localization, for example of the triterpene biosynthetic enzymes thalianol synthase and marneral synthase. We could furthermore show that the educts and products of these enzymes are enriched in root LDs, too.We conclude that root LDs simultaneously act as a sink and source during heat stress-induced membrane remodeling. Furthermore, root LDs play a pivotal role in triperpene synthesis and storage, thereby highlighting LDs as hubs in specialized metabolism. Plant lipid droplets (LDs) and their associated proteins have numerous subcellular and physiological functions. While considerable progress has been made for LDs in many tissues, the function and composition of LDs in roots remains largely unexplored. We investigated the changes of the number of LDs and of the lipidome in heat-stressed Arabidopsis thaliana roots. Furthermore, we isolated root LDs from the Arabidopsis mutant trigalactosyldiacylglycerol 1-1 sugar dependent 1-4 and investigated their proteome and lipidome. Heat stress lead to a degradation of membrane lipids and an increase in TAGs and LDs. while, fatty acid SEs decreased, probably acting as precursors for acylated sterol glycosides. A variety of proteins were enriched in root LDs, which are thus far not described as LD proteins. Transient expression of these proteins in many cases confirmed their LD localization, for example of the triterpene biosynthetic enzymes thalianol synthase and marneral synthase. We could furthermore show that the educts and products of these enzymes are enriched in root LDs, too. We conclude that root LDs simultaneously act as a sink and source during heat stress-induced membrane remodeling. Furthermore, root LDs play a pivotal role in triperpene synthesis and storage, thereby highlighting LDs as hubs in specialized metabolism.

Seed dormancy determines germination timing and thereby critically influences seed plant adaptation and overall fitness. DELAY OF GERMINATION1 (DOG1) is a conserved central regulator of dormancy acting in concert with the phytohormone abscisic acid (ABA) through negative regulation of ABA HYPERSENSITIVE GERMINATION (AHG) 1 and AHG3 phosphatases. The current molecular mechanism of DOG1 signaling proposes that it regulates the activation state of central ABA-related SnRK2 kinases. Here, we unveil DOG1’s functional autonomy from the regulation of ABA core signaling components and unravel its pivotal control over the activation of ABSCISIC ACID INSENSITIVE FIVE BINDING PROTEINs (AFPs). Our data revealed a DOG1-AHG1-AFP relay in which AFPs’ genuine activation by AHG1 is contained by DOG1 to prevent the breakdown of maturation-imposed ABA responses independently of ABA-related kinase activation status. This work offers a molecular understanding of how plants fine-tune germination timing, while preserving seed responsiveness to adverse environmental cues, and thus represents a milestone in the realm of conservation and breeding programs. Autonomous control of maturation-imposed ABA responses by DOG1 enables seeds to regulate dormancy and stress-reactivity traits independently.