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Anemia in <jats:styled-content style=\"fixed-case\">XLSA<\/jats:styled-content> is extremely variable, characteristically microcytic and hypochromic with poikilocytosis, and the red blood cell distribution width is increased and prominent dimorphism of the red cell population. Anemia in <jats:styled-content style=\"fixed-case\">XLSA<\/jats:styled-content> patients responds variably to supplementation with pyridoxine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>We report four patients with <jats:styled-content style=\"fixed-case\">XLSA<\/jats:styled-content> and three mutations in <jats:italic><jats:styled-content style=\"fixed-case\">ALAS<\/jats:styled-content>2<\/jats:italic>: c.611G&gt;A (p.Arg204Gln), c.1218G&gt;T (p.Leu406Phe) and c.1499A&gt;G (p.Tyr500Cys). The in silico predictions of three <jats:styled-content style=\"fixed-case\">ALAS<\/jats:styled-content>2 mutations and the functional consequences of two <jats:styled-content style=\"fixed-case\">ALAS<\/jats:styled-content>2 mutations were assessed. We performed in silico analysis of these mutations using ten different softwares, and all of them predicted that the p.Tyr500Cys mutation was deleterious. The in\u00a0vitro prokaryotic expression showed that the p.Leu406Phe and p.Tyr500Cys mutations reduced the <jats:styled-content style=\"fixed-case\">ALAS<\/jats:styled-content>2 specific activity (SA) to 14% and 7% of the control value, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In view of the results obtained in this study, a clear relationship between genotype and phenotype cannot be established; clinical variability or severity of anemia may be influenced by allelic variants in other genes or transcription factors and environmental conditions.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.202","type":"journal-article","created":{"date-parts":[[2016,1,14]],"date-time":"2016-01-14T09:16:43Z","timestamp":1452763003000},"page":"273-282","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Sideroblastic anemia: functional study of two novel missense mutations in 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