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01 juli 2023, Item does not contain fulltext, PURPOSE: Rothmund-Thomson syndrome (RTS) is characterized by poikiloderma, sparse hair, small stature, skeletal defects, cancer, and cataracts, resembling features of premature aging. RECQL4 and ANAPC1 are the 2 known disease genes associated with RTS in >70% of cases. We describe RTS-like features in 5 individuals with biallelic variants in CRIPT (OMIM 615789). METHODS: Two newly identified and 4 published individuals with CRIPT variants were systematically compared with those with RTS using clinical data, computational analysis of photographs, histologic analysis of skin, and cellular studies on fibroblasts. RESULTS: All CRIPT individuals fulfilled the diagnostic criteria for RTS and additionally had neurodevelopmental delay and seizures. Using computational gestalt analysis, CRIPT individuals showed greatest facial similarity with individuals with RTS. Skin biopsies revealed a high expression of senescence markers (p53/p16/p21) and the senescence-associated ß-galactosidase activity was elevated in CRIPT-deficient fibroblasts. RECQL4- and CRIPT-deficient fibroblasts showed an unremarkable mitotic progression and unremarkable number of mitotic errors and no or only mild sensitivity to genotoxic stress by ionizing radiation, mitomycin C, hydroxyurea, etoposide, and potassium bromate. CONCLUSION: CRIPT causes an RTS-like syndrome associated with neurodevelopmental delay and epilepsy. At the cellular level, RECQL4- and CRIPT-deficient cells display increased senescence, suggesting shared molecular mechanisms leading to the clinical phenotypes.

01 juli 2023, Contains fulltext : 294778.pdf (Publisher’s version ) (Open Access), PURPOSE: Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) regulates cell growth in response to nutritional status. Central to the mTORC1 function is the Rag-GTPase heterodimer. One component of the Rag heterodimer is RagC (Ras-related GTP-binding protein C), which is encoded by the RRAGC gene. METHODS: Genetic testing via trio exome sequencing was applied to identify the underlying disease cause in 3 infants with dilated cardiomyopathy, hepatopathy, and brain abnormalities, including pachygyria, polymicrogyria, and septo-optic dysplasia. Studies in patient-derived skin fibroblasts and in a HEK293 cell model were performed to investigate the cellular consequences. RESULTS: We identified 3 de novo missense variants in RRAGC (NM_022157.4: c.269C>A, p.(Thr90Asn), c.353C>T, p.(Pro118Leu), and c.343T>C, p.(Trp115Arg)), which were previously reported as occurring somatically in follicular lymphoma. Studies of patient-derived fibroblasts carrying the p.(Thr90Asn) variant revealed increased cell size, as well as dysregulation of mTOR-related p70S6K (ribosomal protein S6 kinase 1) and transcription factor EB signaling. Moreover, subcellular localization of mTOR was decoupled from metabolic state. We confirmed the key findings for all RRAGC variants described in this study in a HEK293 cell model. CONCLUSION: The above results are in line with a constitutive overactivation of the mTORC1 pathway. Our study establishes de novo missense variants in RRAGC as cause of an early-onset mTORopathy with unfavorable prognosis.

Fluvial morphology is affected by a wide range of forcing factors, which can be external, such as faulting and changes in climate, or internal, such as variations in rock hardness or degree of fracturing. It is a challenge to separate internal and external forcing factors when they are co-located or occur coevally. Failure to account for both factors leads to potential misinterpretations. For example, steepening of channel network due to lithologic contrasts could be misinterpreted to be a function of increased tectonic displacements. These misinterpretations are enhanced over large areas, where landscape properties needed to calculate channel steepness (e.g., channel concavity) can vary significantly in space. In this study, we investigate relative channel steepness over the Eastern Carpathians, where it has been proposed that active rock uplift in the Southeastern Carpathians (SEC) gives way N- and NW-wards to ca. 8 Myrs of post-orogenic quiescence. We develop a technique to quantify relative channel steepness, the relative steepness index, based on a wide range of concavities, and show that the main signal shows an increase in relative steepness index from east to west across the range. Rock hardness measurements and geological studies suggest this difference is driven by lithology. When we isolate channel steepness by lithology to test for ongoing rock uplift along the range, we find steeper channels in the south of the study area compared to the same units in the North. This supports interpretations from longer timescale geological data that active rock uplift is fastest in the southern SEC.