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Since 2019, three cases of a genetic neurodegenerative syndrome resulting from compound heterozygous mutations in <jats:italic>IREB2<\/jats:italic> have been documented, highlighting the crucial role of IRP2 in regulating iron metabolism homeostasis. This study aims to investigate the molecular basis in a single proband born to non-consanguineous healthy parents, presenting with severe psychomotor developmental abnormalities and microcytic anemia.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Trio-whole exome sequencing (WES) was applied to identify the disease-causing gene in an 8-month-old male patient from China. In silico tools were used to predict the pathogenicity of the identified variants, and in vitro functional studies were performed to evaluate the molecular mechanism.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>WES identified novel biallelic variants, c.1111\u00a0A\u2009&gt;\u2009G (P.Ile371Val) and c.2477\u00a0A\u2009&gt;\u2009T (P.Asp826Val), in the <jats:italic>IREB2<\/jats:italic> gene, which encodes the iron metabolism-related protein, IRP2. Functional studies revealed that c.2477\u00a0A\u2009&gt;\u2009T resulted in a significant degradation of IRP2, which led to the misregulation of intracellular ferric iron.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>We report the identification of the first functional domain associated with the degradation of IRP2. The biallelic variants that affect protein degradation likely underlie the pathogenesis of the IRP2-related neurodegenerative disorder. Moreover, the use of proteasome inhibitors can potentially restore the expression of IRP2, highlighting a promising therapeutic target for patients with IRP2deficiency.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13023-024-03465-7","type":"journal-article","created":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T10:01:26Z","timestamp":1732528886000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Novel biallelic variants in IREB2 cause an early-onset neurodegenerative disorder in a Chinese pedigree"],"prefix":"10.1186","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6251-3093","authenticated-orcid":false,"given":"Zhenglong","family":"Guo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dawei","family":"Huo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingying","family":"Shao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenke","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinming","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuwei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hai","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bingtao","family":"Hao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shixiu","family":"Liao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,11,25]]},"reference":[{"key":"3465_CR1","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1146\/annurev.physiol.69.031905.164337","volume":"69","author":"NC Andrews","year":"2007","unstructured":"Andrews NC, Schmidt PJ. 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