{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:00:43Z","timestamp":1753891243565,"version":"3.41.2"},"reference-count":22,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T00:00:00Z","timestamp":1739145600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>X-linked sideroblastic anemia (XLSA) (MIM 300752) is the most common genetic form of sideroblastic anemia, a heterogeneous group of disorders characterized by iron deposits in the mitochondria of erythroid precursors. It is due to mutations of the erythroid-specific enzyme <jats:italic>ALAS2<\/jats:italic>, the first enzyme of the heme biosynthetic pathway. Herein, we report a novel 11-bp deletion in exon 11 leading to a frameshift in the C-terminal region of the <jats:italic>ALAS2<\/jats:italic> gene with a non-functional longer polypeptide of 614 amino acids leading to a loss-of-function mutation manifested as an X-linked sideroblastic anemia phenotype. The proband was a 29-year-old man with moderately severe microcytic hypochromic anemia with splenomegaly and increased ring sideroblasts in the bone marrow with considerable iron overload. Sanger sequencing documented a missense mutation leading to a frameshift with an elongated polypeptide of 614 AA instead of the normal 587 AA protein c.1743_1753 del (p.Gln581Hisfs*35). This mutation affected the interaction with cofactor pyridoxal 5\u2032-phosphate since the patient\u2019s hemoglobin improved with oral administration of pyridoxine tablets. His iron overload also responded to sustained oral iron chelation therapy with deferasirox. The screening of the entire family\u2019s kindred revealed that two other male siblings were also hemizygous for the same mutation with hypochromic microcytic anemia and tissue iron overload, whereas, three female siblings and their mother were heterozygous for the mutant allele. They did not have anemia or iron overload.<\/jats:p>","DOI":"10.3389\/fmed.2024.1452873","type":"journal-article","created":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T04:11:17Z","timestamp":1739160677000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case report: A novel 11-bp deletion in exon 11 causing a frameshift in the C-terminal of the ALAS2 gene leading to X-linked sideroblastic anemia\u2014a family study"],"prefix":"10.3389","volume":"11","author":[{"given":"Salam","family":"Al kindi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Altaf","family":"Al-Mamari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shoaib","family":"Al-Zadjali","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohamed","family":"Al-Rawahi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ali","family":"Al Madhani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anil V.","family":"Pathare","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,2,10]]},"reference":[{"key":"ref1","first-page":"865","article-title":"Hereditary and acquired sideroblastic anemias","volume-title":"Williams 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Disease: sideroblastic anaemia","volume":"115","author":"Pereira","year":"2004","journal-title":"Hum Genet."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"4236","DOI":"10.1182\/blood-2002-03-0685","article-title":"Absent phenotypic expression of X-linked sideroblastic anemia in one of 2 brothers with a novel ALAS2 mutation","volume":"100","author":"Cazzola","year":"2002","journal-title":"Blood."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1007\/s12185-010-0688-4","article-title":"Hereditary sideroblastic anemia: pathophysiology and gene mutations","volume":"92","author":"Harigae","year":"2010","journal-title":"Int J Hematol."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"e158","DOI":"10.3324\/haematol.2013.095513","article-title":"Mutation spectrum in Chinese patients affected by congenital sideroblastic anemia and a search for a genotype-phenotype relationship","volume":"98","author":"Liu","year":"2013","journal-title":"Haematologica."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"28943","DOI":"10.1074\/jbc.M111.306423","article-title":"X-linked sideroblastic anemia due to carboxyl-terminal ALAS2 mutations that cause loss of binding to the \u03b2-subunit of succinyl-CoA synthetase (SUCLA2)","volume":"287","author":"Bishop","year":"2012","journal-title":"Biol Chem."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1046\/j.1365-2141.1999.01479.x","article-title":"A novel mutation of the erythroid-specific delta-aminolaevulinate synthase gene in a patient with X-linked sideroblastic anaemia","volume":"106","author":"Harigae","year":"1999","journal-title":"Br J Haematol."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1002\/humu.21455","article-title":"Sideroblastic anemia: molecular analysis of the ALAS2 gene in a series of 29 probands and functional studies of 10 missense mutations","volume":"32","author":"Ducamp","year":"2011","journal-title":"Hum Mutat."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1443","DOI":"10.1182\/blood-2011-03-342873","article-title":"ALAS2 acts as a modifier gene in patients with congenital erythropoietic porphyria","volume":"118","author":"Ducamp","year":"2011","journal-title":"Blood"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"18","DOI":"10.2119\/molmed.2013.00003","article-title":"Molecular expression and characterization of erythroid-specific 5-aminolevulinate synthase gain-of-function mutations causing X-linked protoporphyria","volume":"19","author":"Bishop","year":"2013","journal-title":"Mol Med."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2024.1452873\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T04:11:22Z","timestamp":1739160682000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2024.1452873\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,10]]},"references-count":22,"alternative-id":["10.3389\/fmed.2024.1452873"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2024.1452873","relation":{},"ISSN":["2296-858X"],"issn-type":[{"type":"electronic","value":"2296-858X"}],"subject":[],"published":{"date-parts":[[2025,2,10]]},"article-number":"1452873"}}