Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function

Next‐generation sequencing (NGS) has been instrumental in solving the genetic basis of rare inherited diseases, especially neurodevelopmental syndromes. However, functional workup is essential for precise phenotype definition and to understand the underlying disease mechanisms. Using whole exome (WES) and whole genome sequencing (WGS) in four independent families with hypotonia, neurodevelopmental delay, facial dysmorphism, loss of white matter, and thinning of the corpus callosum, we identified four previously unreported homozygous truncating PPP1R21 alleles: c.347delT p.(Ile116Lysfs*25), c.2170_2171insGGTA p.(Ile724Argfs*8), c.1607dupT p.(Leu536Phefs*7), c.2063delA p.(Lys688Serfs*26) and found that PPP1R21 was absent in fibroblasts of an affected individual, supporting the allele's loss of function effect. PPP1R21 function had not been studied except that a large scale affinity proteomics approach suggested an interaction with PIBF1 defective in Joubert syndrome. Our co‐immunoprecipitation studies did not confirm this but in contrast defined the localization of PPP1R21 to the early endosome. Consistent with the subcellular expression pattern and the clinical phenotype exhibiting features of storage diseases, we found patient fibroblasts exhibited a delay in clearance of transferrin‐488 while uptake was normal. In summary, we delineate a novel neurodevelopmental syndrome caused by biallelic PPP1R21 loss of function variants, and suggest a role of PPP1R21 within the endosomal sorting process or endosome maturation pathway

Aberrant function of the C-terminal tail of HIST1H1E Aacelerates cellular senescence and causes premature aging

Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging

TBC1D24 genotype-phenotype correlation: Epilepsies and other neurologic features

Objective: To evaluate the phenotypic spectrum associated with mutations in TBC1D24. Methods: We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24). Results: Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function. Conclusions: TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes

Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies

Genetics of disease, diagnosis and treatmen

Human Dectin-1 Deficiency Impairs Macrophage-Mediated Defense Against Phaeohyphomycosis

Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic inoculation. Severe or disseminated infection can occur in CARD9 deficiency or after transplantation, but the mechanisms protecting against phaeohyphomycosis remain unclear. We evaluated a patient with progressive, refractory Corynespora cassiicola phaeohyphomycosis and found that he carried biallelic deleterious mutations in CLEC7A encoding the CARD9-coupled, β-glucan-binding receptor, Dectin-1. The patient\u27s PBMCs failed to produce TNF-α and IL-1β in response to β-glucan and/or C. cassiicola. To confirm the cellular and molecular requirements for immunity against C. cassiicola, we developed a mouse model of this infection. Mouse macrophages required Dectin-1 and CARD9 for IL-1β and TNF-α production, which enhanced fungal killing in an interdependent manner. Deficiency of either Dectin-1 or CARD9 was associated with more severe fungal disease, recapitulating the human observation. Because these data implicated impaired Dectin-1 responses in susceptibility to phaeohyphomycosis, we evaluated 17 additional unrelated patients with severe forms of the infection. We found that 12 out of 17 carried deleterious CLEC7A mutations associated with an altered Dectin-1 extracellular C-terminal domain and impaired Dectin-1-dependent cytokine production. Thus, we show that Dectin-1 and CARD9 promote protective TNF-α- and IL-1β-mediated macrophage defense against C. cassiicola. More broadly, we demonstrate that human Dectin-1 deficiency may contribute to susceptibility to severe phaeohyphomycosis by certain dematiaceous fungi

New accelerators for elastomer vulcanization

Ciecze jonowe w postaci soli alkiloimidazoliowych i alkiloamoniowych 2-merkaptobenzotiazolu zastosowano jako przyśpieszacze wulkanizacji siarkowej elastomeru etylenowo-propylenowo-dienowego (EPDM) alternatywnie do tradycyjnie stosowanego układu przyśpieszaczy. Ciecze jonowe wykazywały katalityczny wpływ na reakcje sieciowania i mogą zastąpić tradycyjnie stosowany jako przyśpieszacz ditiokarbaminian cynku. Pozwalają uzyskać wulkanizaty o podwyższonych właściwościach mechanicznych i porównywalnej gęstości usieciowania w stosunku do tradycyjnych, wykazujące jednocześnie lepszą stabilność termiczną i odporność na starzenie termooksydacyjne.Ionic liquids, such as alkylimidazolium and alkylammonium salts of 2-mercaptobenzothiazole were applied as accelerators for sulfur vulcanization of ethylene-propylene-diene elastomer, alternatively to traditionally used accelerators. Ionic liquids catalyzed the curing reactions and could replace the traditionally used zinc dithiocarbamate. The mechanical properties and the crosslink density were higher or comparable to vulcanizates containing traditional accelerators. Ionic liquids increased the thermal stability of the vulcanizates and their resistance to thermo-oxidative aging

The influence of anion type in imidazolium ionic liquids on tribological properties

Celem pracy jest poszukiwanie nowych, efektywnych baz substancji smarowych, obniżających opory ruchu i zużycie. W artykule wykazano, że ciecze jonowe mogą wpływać na niezawodność i trwałość układów tribologicznych. Substancje te występują w temperaturach "pokojowych" w stanie ciekłym w postaci jonów. W pracy określano charakterystyki tribologiczne trzech związków zaliczanych do imidazoliowych cieczy jonowych, różniących się rodzajem anionu. Badania tribologiczne prowadzono w skojarzeniu materiałowym stal–stal (aparat czterokulowy T-02). Analizowano opory ruchu i zużycie, których miarą było odpowiednio współczynnik tarcia oraz średnica skazy. Po testach analizowano profile zużycia skazy kulek. Z uzyskanych rezultatów badań tribologicznych wynika, że badane ciecze jonowe charakteryzują się niższymi oporami ruchu oraz mniejszym zużyciem w porównaniu z olejem parafinowym. Najniższymi wartościami współczynnika tarcia 0,08 charakteryzuje się ciecz jonowa zawierająca anion 3-aminotriazolanowy. Analiza uzyskanych rezultatów wskazuje, że imidazoliowe ciecze jonowe mogą być bardzo skutecznymi i efektywnymi bazami substancji smarowych.This paper concerns research on new, effective lubricant bases that reduce friction and seizure. It is shown, that ionic liquids are substances that influence the reliability and durability of tribosystems. At room temperatures, they are liquids and consist of only ions. Tribological characteristics of three imidazolium compounds differing in anion were researched. Tribological investigation was carried out on a four-ball tester (T-02), steel-steel contact. Motion resistance (friction coefficient) and seizure (wear scar diameter) were analysed. Profiles of balls after tests were also analysed. Ionic liquids researched have better tribological characteristics in comparison to paraffin oil. The lowest (0.08) friction coefficient value was obtained for an ionic liquid containing 3-aminotriazolan anion. It is stated that imidazolium ionic liquids can be an effective base for lubricants

Tribological characteristics of ionic liquids with ammonium cation

W poszukiwaniu nowych aktywnych baz olejowych wskazano na ciecze jonowe, które występują w temperaturach "pokojowych" w stanie ciekłym. Mają one wiele interesujących właściwości, które mogą wpłynąć na niezawodność (właściwości przeciwzatarciowe) i trwałość (właściwości przeciwzużyciowe) układów tribologicznych. Wykonano dwa rodzaje testów: zatarciowe z liniowym narostem obciążenia (T02) oraz przy stałym obciążeniu (T11) dla dwóch rodzajów cieczy jonowych 1,2,4-triazolanu didecylodimetyloamoniowego ([124TA][DMA]) i 1,2,4-triazolanu benzalkoniowego ([124TA][BA]) oraz oleju parafinowego, który stanowi ich medium odniesienia. Z uzyskanych rezultatów wynika, że ciecze jonowe jako bazy w większym stopniu wpływają na zdolność układu do przeciwdziałania zacieraniu niż na obniżenie oporów ruchu i zużycia.Ionic liquids which are liquids at room temperatures were chosen asnew active base oils. They have lots of interesting properties which can affect in reliability and permanence of tribological systems. Two types of tests were carried out: automatic, continuous increasing of the load during the run (four-ball testing machine) and with constant load (ball – on – disc tester) for two types of ionic liquids 1,2,4-triazolan didecyldimethyloammonium ([124TA][DMA]) and 1,2,4-triazolan benzalkonium ([124TA][BA]). What is more paraffinic liquid was tested as a model base oil. It can be stated that ionic liquids as base oils have better characteristics according to extreme pressure properties rather than lowering wear and motion resistance

Tribological properties of selected ionic liquids in the material pairs: steel-PA6 and steel-PMMA

Jednym z kierunków poszukiwań nowych baz substancji smarowych lub dodatków do baz są ciecze jonowe. Rekomendowane są one jako należące do tzw. "zielonej chemii". Ciecze te osiągają temperaturę topnienia rzędu "temperatur pokojowych". W pracy przedstawiono wyniki badań tribologicznych w skojarzeniu: stalowa kulka–tarcza wykonana alternatywnie z: poliamidu 6 oraz polimetakrylanu (Tester T-11). Wyznaczono współczynnik tarcia i profile zużycia w warunkach tarcia suchego i w obecności: wody, oleju parafinowego oraz dwóch rodzajów cieczy jonowych. Stwierdzono, że ciecze jonowe charakteryzują się niskimi oporami ruchu i zużyciem porównywalnymi z olejem parafinowym, który jest stosowany jako standardowa baza. W związku z tym można postulować, że ciecze jonowe mogą być traktowane jako nowy rodzaj bazy substancji smarowych.Ionic liquids are one of novel substances used as bases of lubricating oils or as additives. They are among so called "green chemistry" group of substances. Melting point of ionic liquids occurs at room temperatures. Authors present research results of tribological tests at ball – on – disc tester. Balls were made of steal and discs alternatively: polyamide 6 and poly(methyl methacrylate) (PMMA). Wear profiles and friction coefficients were researched during dry friction and in presence of water, paraffinic oil and two types of ionic liquids. According to paraffinic oil which is standard base oil ionic liquids have low motion resistance and wear. That is why it can be stated that ionic liquids can be treated as new type of base oils