Methotrexate and bone formation and turnover in rheumatoid arthritis

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De novo missense variants in FBXO11 alter its protein expression and subcellular localization.

Recently, we and others identified de novo FBXO11 variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs

De novo missense variants in FBXO11 alter its protein expression and subcellular localization.

Recently, we and others identified de novo FBXO11 variants as causative for a variable neurodevelopmental disorder (NDD). We now assembled clinical and mutational information on 23 additional individuals. The phenotypic spectrum remains highly variable, with developmental delay and/or intellectual disability as the core feature and behavioral anomalies, hypotonia and various facial dysmorphism as frequent aspects. The mutational spectrum includes intragenic deletions, likely gene disrupting and missense variants distributed across the protein. To further characterize the functional consequences of FBXO11 missense variants, we analyzed their effects on protein expression and localization by overexpression of 17 different mutant constructs in HEK293 and HeLa cells. We found that the majority of missense variants resulted in subcellular mislocalization and/or reduced FBXO11 protein expression levels. For instance, variants located in the nuclear localization signal and the N-terminal F-Box domain lead to altered subcellular localization with exclusion from the nucleus or the formation of cytoplasmic aggregates and to reduced protein levels in western blot. In contrast, variants localized in the C-terminal Zn-finger UBR domain lead to an accumulation in the cytoplasm without alteration of protein levels. Together with the mutational data our functional results suggest that most missense variants likely lead to a loss of the original FBXO11 function and thereby highlight haploinsufficiency as the most likely disease mechanism for FBXO11-associated NDDs

Outcome after 40 years with rheumatoid arthritis: a prospective study of function, disease activity and mortality

In an inception cohort of 100 patients with rheumatoid arthritis (RA) we studied course and outcome after 40 years, regarding function, disease activity, cause and age of death, and prognostic factors. Function, joint count, erythrocyte sedimentation rate (ESR), hemoglobin (Hb), rheumatoid factor (RF), and the number of orthopedic operations were measured in 100 consecutive referrals between 1957 and 1963 with either definite or classical RA at one year after onset of symptoms. Subjects have been followed for a mean of 40 years, or until death. In May 1999, 84 subjects had died. Of the 16 survivors, 8 (50%) were severely disabled from RA while 5 (31%) had normal function. The mean joint score had gradually increased over 40 years. Death was directly attributable to RA in 13, while RA or its treatment contributed to death in 11 subjects. In the other 60 deceased subjects, cardiovascular causes accounted for 28 deaths (33% of total deaths). Features at one year that were associated with mortality up to 40 years after onset by regression analysis were: older age (p < 0.0001), lower Hb (p = 0.0461), and worse function (p < 0.0001). The standardized mortality ratio of the cohort at 40 years was 2.13 (confidence interval 1.26-3.60), and median survival was reduced by 10 years for men and 11 years for women compared to the general population. In conclusion, RA is a progressive disease impairing function up to 40 years after onset, with shortened life span. The leading cause of death was cardiovascular disease