BackgroundImerslund-Gräsbeck syndrome (IGS) was described just over 50 years ago by Olga Imerslund and Ralph Gräsbeck and colleagues. IGS is caused by specific malabsorption of cobalamin (Cbl) due to bi-allelic mutations in either the cubilin gene (CUBN) or the human amnionless homolog (AMN). Mutations in the two genes are commonly seen in founder populations or in societies with a high degree of consanguineous marriages. One particular mutation in AMN, c.208-2A>G, causing an out-of-frame loss of exon 4 in the mRNA, is responsible for some 15% of IGS cases globally. We present evidence that this founder mutation causes a substantial percentage of cases among diverse ethnicities and that the mutation is as old as human civilization.MethodsPartial genotyping indicated a founder event but its presence in diverse peoples of Arabic, Turkish, Jewish, and Hispanic ancestry suggested that the mutation might be recurrent. We therefore studied the flanking sequence spanning 3.5 Mb to elucidate the origin of the haplotype and estimate the age of the mutation using a Bayesian inference method based on observed linkage disequilibrium.ResultsThe mutation's distribution, the size of the shared haplotype, and estimates of growth rate and carrier frequency indicated that the mutation was a single prehistoric event. Dating back to the ancient Middle East around 11,600 BC, the mutation predates the advent of writing, farming, and the monotheistic religions of the region.ConclusionsThis mutation causes over 50% of the IGS cases among Arabic, Turkish, and Sephardic Jewish families, making it a primary target for genetic screening among diverse IGS cases originating from the Middle East. Thus, rare founder mutations may cause a substantial number of cases, even among diverse ethnicities not usually thought to be related.
bQuasispecies theory is a case of mutation-selection balance for evolution at high mutation rates, such as those observed in RNA viruses. One of the main predictions of this model is the selection for robustness, defined as the ability of an organism to remain phenotypically unchanged in the face of mutation. We have used a collection of vesicular stomatitis virus strains that had been evolving either under positive selection or under random drift. We had previously shown that the former increase in fitness while the latter have overall fitness decreases (I. S. Novella, J. B. Presloid, T. Zhou, S. D. Smith-Tsurkan, B. E. Ebendick-Corpus, R. N. Dutta, K. L. Lust, and C. O. Wilke, J. Virol. 84:4960 -4968, 2010). Here, we determined the robustness of these strains and demonstrated that strains under positive selection not only increase in fitness but also increase in robustness. In contrast, strains under drift not only decreased in fitness but also decreased in robustness. There was a good overall correlation between fitness and robustness. We also tested whether there was a correlation between fitness and thermostability, and we observed that the correlation was imperfect, indicating that the fitness effects of mutations are exerted in part at a level other than changing the resistance of the protein to temperature. E rror-prone replication in RNA viruses results in the development of quasispecies populations (1-4), clouds of closely related mutants in mutation-selection balance (5-7). In quasispecies populations, increased genetic robustness can provide a selective advantage (8-11), because a smaller number of offspring are lost to deleterious or lethal mutations. Genetic robustness here is defined as phenotypic invariance despite mutational pressure (12). In terms of fitness landscapes, selection for robustness favors those populations that sit on broad fitness peaks instead of narrow fitness peaks. Studies on digital organisms showed the preference for this type of broad peaks and led to the expression "survival of the flattest" (13). Many of the studies addressing the relevance of genetic robustness on the evolution of RNA molecules are computer analyses and simulated evolution (11,(14)(15)(16)(17). This approach has led to the identification of selection for robustness in hepatitis C virus genomes (18) and microRNA (19).Vesicular stomatitis virus (VSV) provided the first evidence that a low-fitness strain could outcompete a high-fitness strain (20), and these results were confirmed with phage phi-6 (21). One can predict that, all else being equal, the evolution of robustness is a function of the strength of selection, and that environmental factors that diminish selection also result in less robustness. Complementation is one such factor (22-25), because the phenotype of one strain is not always determined by its genetic makeup and, instead, is the result of a gene product from another strain. High levels of complementation, which occur at a high multiplicity of infection (MOI), would result in lower overall...
Differentiation of Embryonic Stem Cells 1 (Dies1) was recently identified as a novel type I immunoglobulin (IgG) domain-containing plasma membrane protein important for effective differentiation of a murine pluripotent embryonic stem cell line. In this setting, Dies1 enhances bone morphogenetic protein 4 (BMP4) signaling. Here we show Dies1 transcript expression is induced ∼225-fold during in vitro adipogenesis of 3T3-L1 murine preadipocytes. Immunocytochemical imaging using ectopic expression of Flag-tagged Dies1 in 3T3-L1 adipocytes revealed localization to the adipocyte plasma membrane. Modulation of adipocyte phenotype with with tumor necrosis factor-α (TNFα) treatment or by siRNA knockdown of the master pro-adipogenic transcription factor peroxisome proliferator activated receptor gamma (PPARγ) resulted in a 90% and 60% reduction of Dies1 transcript levels, respectively. Moreover, siRNA-mediated Dies1 knockdown in 3T3-L1 preadipocytes inhibited adipogenic conversion. Such cultures had a 35% decrease in lipid content and a 45%–65% reduction in expression of key adipocyte transcripts, including that for PPARγ. The standard protocol for full in vitro adipogenic conversion of committed preadipocytes, such as 3T3-L1, does not include BMP4 treatment. Thus we posit the positive role of Dies1 in adipogenesis, unlike that for Dies1 in differentiation of embryonic stem cells, does not include its pro-BMP4 effects. In support of this idea, 3T3-L1 adipocytes knocked down for Dies1 did not evidence decreased phospho-Smad1 levels upon BMP4 exposure. qPCR analysis of Dies1 transcript in multiple murine and human tissues reveals high enrichment in white adipose tissue (WAT). Interestingly, we observed a 10-fold induction of Dies1 transcript in WAT of fasted vs. fed mice, suggesting a role for Dies1 in nutritional response of mature fat cells in vivo. Together our data identify Dies1 as a new differentiation-dependent adipocyte plasma membrane protein whose expression is required for effective adipogenesis and that may also play a role in regard to nutritional status in WAT.
We report a rare case of juvenile cobalamin deficiency who presented at the age of seventeen years. He was underweight and had skin changes, normocytic anemia and autonomic dysfunction which lead to adynamic ileus and acute post-renal failure. The expected macrocytosis was masked by an underlying alpha thalassemia trait. The patient had an excellent response to parenteral cobalamin treatment.
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