{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T11:19:21Z","timestamp":1740136761969,"version":"3.37.3"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2023,8,14]],"date-time":"2023-08-14T00:00:00Z","timestamp":1691971200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,5,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>To identify the TMPRSS6 gene variants in Mexican patients with iron treatment refractoriness, to describe hematological and iron profile parameters, and to use bioinformatic prediction and protein modeling tools to assess a possible biological impact for the detected missense variants.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Nineteen patients referred with iron treatment refractoriness were studied. Peripheral blood was collected to determine hematic cytometry, iron profile, hemoglobin electrophoresis, and quantification. Molecular screening was carried out for exons 15 through 18 of the TMPRSS6 gene by Sanger sequencing and for frequent thalassemia variants by amplification-refractory mutation system-polymerase chain reaction (PCR) and gap-PCR. The biological impact of the detected missense variants was assessed using bioinformatic prediction and protein modeling tools.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We found 5 genetic variants in the matriptase-2 catalytic domain: 1 at intron-15\/exon-16 junction (rs60484081) and 4 exonic, 3 missense (rs377054987, p.Gly626Asp; rs1384127820, p.Ser672Thr; rs855791, p.Val727Ala) and 1 synonymous (rs2235321, p.Tyr730=), with frequencies ranging from 0.18 to 0.53. No significant differences were observed in the hematological parameters or iron profile, considering type and number of variants. Bioinformatic predictions suggested a possible biological impact only for rs377054987.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>The TMPRSS6 variants observed in Mexican patients with oral iron treatment refractoriness have high frequencies; nevertheless, their relationship with hematological and iron profile parameters needs further research. The possible biological impact for rs377054987 is due to size and amino acid hydrophobicity changes and hydrogen bond modifications.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/labmed\/lmad077","type":"journal-article","created":{"date-parts":[[2023,8,14]],"date-time":"2023-08-14T15:15:09Z","timestamp":1692026109000},"page":"277-284","source":"Crossref","is-referenced-by-count":0,"title":["Genetic analysis of <i>TMPRSS6<\/i> catalytic domain variants in Mexican patients with iron treatment refractoriness"],"prefix":"10.1093","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2988-0868","authenticated-orcid":false,"given":"Rubiceli","family":"Hern\u00e1ndez-Pe\u00f1a","sequence":"first","affiliation":[{"name":"Doctorado en Gen\u00e9tica Humana, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara , M\u00e9xico"},{"name":"Divisi\u00f3n de Gen\u00e9tica, Centro de Investigaci\u00f3n Biom\u00e9dica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara , M\u00e9xico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric Jonathan","family":"Maciel-Cruz","sequence":"additional","affiliation":[{"name":"Doctorado en Gen\u00e9tica Humana, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara , M\u00e9xico"},{"name":"Divisi\u00f3n de Gen\u00e9tica, Centro de Investigaci\u00f3n Biom\u00e9dica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara , M\u00e9xico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lourdes Del Carmen","family":"Rizo-De La Torre","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Medicina Molecular, Centro de Investigaci\u00f3n Biom\u00e9dica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara , M\u00e9xico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francisco Javier","family":"Perea-D\u00edaz","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Gen\u00e9tica, Centro de Investigaci\u00f3n Biom\u00e9dica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara , M\u00e9xico"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bertha","family":"Ibarra-Cort\u00e9s","sequence":"additional","affiliation":[{"name":"Instituto de Gen\u00e9tica Humana \u201cDr. Enrique Corona Rivera,\u201d Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara , M\u00e9xico"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,8,14]]},"reference":[{"year":"2017","author":"World Health Organization","key":"2024050210574761000_CIT0001"},{"key":"2024050210574761000_CIT0002","first-page":"260","article-title":"Iron metabolism and iron disorders revisited in the hepcidin era","volume-title":"Haematologica.","author":"Camaschella","year":"2020"},{"key":"2024050210574761000_CIT0003","first-page":"e2021028","article-title":"Acquired refractory iron deficiency anemia","volume-title":"Mediterr J Hematol Infect Dis","author":"Migone De Amicis","year":"2021"},{"key":"2024050210574761000_CIT0004","first-page":"647","article-title":"A novel splicing mutation of TMPRSS6 in a Chinese child with iron-refractory iron deficiency anaemia","volume-title":"Br J Haematol.","author":"Xiong","year":"2015"},{"key":"2024050210574761000_CIT0005","first-page":"38","article-title":"Two novel mutations in TMPRSS6 associated with iron-refractory iron deficiency anemia in a mother and child","volume-title":"Blood Cells Mol Dis.","author":"Yaish","year":"2017"},{"key":"2024050210574761000_CIT0006","first-page":"3873","article-title":"Practice guidelines for the diagnosis and management of microcytic anemias due to genetic disorders of iron metabolism or heme synthesis","volume-title":"Blood.","author":"Donker","year":"2014"},{"key":"2024050210574761000_CIT0007","first-page":"e0273825","article-title":"Functionally impaired isoforms regulate TMPRSS6 proteolytic activity","volume-title":"PLoS One.","author":"Dion","year":"2022"},{"key":"2024050210574761000_CIT0008","first-page":"D418","article-title":"InterPro in 2022","volume-title":"Nucleic Acids Res.","author":"Paysan-Lafosse","year":"2022"},{"key":"2024050210574761000_CIT0009","first-page":"2498","article-title":"Transcriptome analysis reveals TMPRSS6 isoforms with distinct functionalities","volume-title":"J Cell Mol Med.","author":"Dion","year":"2018"},{"key":"2024050210574761000_CIT0010","first-page":"nzab014","article-title":"Common variants in the TMPRSS6 gene alter hepcidin but not plasma iron in response to oral iron in healthy Gambian adults: a recall-by-genotype study","volume-title":"Curr Dev Nutr.","author":"Jallow","year":"2021"},{"key":"2024050210574761000_CIT0011","first-page":"e6401","article-title":"Double trouble: a case of fraternal twins with iron-refractory iron-deficiency anemia","volume-title":"Clin Case Rep","author":"Malherbe","year":"2022"},{"key":"2024050210574761000_CIT0012","first-page":"2124","article-title":"TMPRSS6, but not TF, TFR2 or BMP2 variants are associated with increased risk of iron-deficiency anemia","volume-title":"Hum Mol Genet.","author":"An","year":"2012"},{"key":"2024050210574761000_CIT0013","first-page":"144767","article-title":"Study the association of transmembrane serine protease 6 gene polymorphisms with iron deficiency status in Saudi Arabia","volume-title":"Gene.","author":"Al-Amer","year":"2020"},{"key":"2024050210574761000_CIT0014","first-page":"41","article-title":"Genetic analysis of TMPRSS6 gene in Saudi female patients with iron deficiency anemia","volume-title":"Hematol Oncol Stem Cell Ther","author":"Al-Jamea","year":"2021"},{"key":"2024050210574761000_CIT0015","first-page":"201","article-title":"The role of TMPRSS6 gene variants in iron- related hematological parameters in Turkish patients with iron deficiency anemia","volume-title":"Gene.","author":"Batar","year":"2018"},{"key":"2024050210574761000_CIT0016","first-page":"1502","article-title":"Common single nucleotide polymorphism of TMPRSS6, an iron regulation gene, associated with variable red blood cell indices in deletional \u03b1-globin genotypes","volume-title":"Genes","author":"Suksangpleng","year":"2022"},{"key":"2024050210574761000_CIT0017","first-page":"2782","article-title":"TMPRSS6 rs855791 polymorphism status in children with celiac disease and anemia","volume-title":"Nutrients","author":"Urbaszek","year":"2021"},{"volume-title":"The Hemoglobinopathies: Techniques of Identification","year":"1977","author":"Huisman","key":"2024050210574761000_CIT0018"},{"key":"2024050210574761000_CIT0019","first-page":"1215","article-title":"A simple salting out procedure for extracting DNA from human nucleated cells","volume-title":"Nucleic Acids Res.","author":"Miller","year":"1988"},{"key":"2024050210574761000_CIT0020","first-page":"48","article-title":"A structured approach to iron refractory iron deficiency anemia (IRIDA) diagnosis (SAID): the more is \u201cSAID\u201d about iron, the less it is","volume-title":"Pediatr Hematol Oncol J.","author":"Bhatia","year":"2017"},{"key":"2024050210574761000_CIT0021","first-page":"247","article-title":"Molecular and hematological analysis of alpha- and beta-thalassemia in a cohort of Mexican patients","volume-title":"Genet Test Mol Biomarkers.","author":"Rizo-de la Torre","year":"2021"},{"key":"2024050210574761000_CIT0022","first-page":"1928","article-title":"SNPStats: a web tool for the analysis of association studies","volume-title":"Bioinformatics.","author":"Sol\u00e9","year":"2006"},{"key":"2024050210574761000_CIT0023","first-page":"845","article-title":"The Phyre2 web portal for protein modeling, prediction and analysis","volume-title":"Nat Protoc","author":"Kelley","year":"2015"},{"key":"2024050210574761000_CIT0024","first-page":"2525","article-title":"Improving the physical realism and structural accuracy of protein models by a two-step atomic-level energy minimization","volume-title":"Biophys J.","author":"Xu","year":"2011"},{"key":"2024050210574761000_CIT0025","first-page":"1511","article-title":"Verification of protein structures: patterns of nonbonded atomic interactions","volume-title":"Protein Sci.","author":"Colovos","year":"1993"},{"key":"2024050210574761000_CIT0026","first-page":"2745","article-title":"PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels","volume-title":"Bioinformatics.","author":"Choi","year":"2015"},{"issue":"13","key":"2024050210574761000_CIT0027","doi-asserted-by":"crossref","first-page":"3812","DOI":"10.1093\/nar\/gkg509","article-title":"SIFT: Predicting amino acid changes that affect protein function","volume":"31","author":"Ng","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"2024050210574761000_CIT0028","first-page":"e1003440","article-title":"PredictSNP: robust and accurate consensus classifier for prediction of disease-related mutations","volume-title":"PLoS Comput Biol.","author":"Bendl","year":"2014"},{"key":"2024050210574761000_CIT0029","first-page":"W446","article-title":"MutationTaster2021","volume-title":"Nucleic Acids Res.","author":"Steinhaus","year":"2021"},{"key":"2024050210574761000_CIT0030","first-page":"248","article-title":"A method and server for predicting damaging missense mutations","volume-title":"Nat Methods.","author":"Adzhubei","year":"2010"},{"issue":"11","key":"2024050210574761000_CIT0031","doi-asserted-by":"crossref","first-page":"3823","DOI":"10.1093\/nar\/gkm238","article-title":"SNAP: Predict effect of non-synonymous polymorphisms on function","volume":"35","author":"Bromberg","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"2024050210574761000_CIT0032","first-page":"5918","article-title":"Inferring the molecular and phenotypic impact of amino acid variants with MutPred2","volume-title":"Nat Commun.","author":"Pejaver","year":"2020"},{"key":"2024050210574761000_CIT0033","first-page":"295","article-title":"Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral","volume-title":"J Med Genet.","author":"Tavtigian","year":"2006"},{"key":"2024050210574761000_CIT0034","first-page":"548","article-title":"Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces","volume-title":"BMC Bioinf.","author":"Venselaar","year":"2010"},{"key":"2024050210574761000_CIT0035","first-page":"2197","article-title":"Can predicted protein 3D structures provide reliable insights into whether missense variants are disease associated","volume-title":"J Mol Biol.","author":"Ittisoponpisan","year":"2019"},{"key":"2024050210574761000_CIT0036","first-page":"1605","article-title":"UCSF Chimera--a visualization system for exploratory research and analysis","volume-title":"J Comput Chem.","author":"Pettersen","year":"2004"},{"key":"2024050210574761000_CIT0037","first-page":"401","article-title":"Prevalence of iron deficiency was stable and anemia increased during 12 years (2006-2018) in Mexican women 20-49 years of age","volume-title":"Salud Publica Mex.","author":"Mej\u00eda-Rodr\u00edguez","year":"2021"},{"key":"2024050210574761000_CIT0038","first-page":"434","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume-title":"Nature.","author":"Karczewski","year":"2020"},{"key":"2024050210574761000_CIT0039","first-page":"311","article-title":"Systematic evaluation of paediatric cohort with iron refractory iron deficiency anaemia (IRIDA) phenotype reveals multiple TMPRSS6 gene variations","volume-title":"Br J Haematol.","author":"Bhatia","year":"2017"},{"key":"2024050210574761000_CIT0040","first-page":"559","article-title":"A child with severe iron-deficiency anemia and a complex TMPRSS6 genotype","volume-title":"Hematology","author":"Capra","year":"2017"},{"key":"2024050210574761000_CIT0041","article-title":"Single amino acid change mutation in the hydrophobic core of the N-terminal domain of P22 TSP affects the proteins stability","author":"Ayariga","year":"2021","journal-title":"bioRxiv"},{"key":"2024050210574761000_CIT0042","first-page":"1776","article-title":"Molecular insights into protein synthesis with proline residues","volume-title":"EMBO Rep.","author":"Melnikov","year":"2016"},{"key":"2024050210574761000_CIT0043","first-page":"3346","article-title":"Effect of proline and glycine residues on dynamics and barriers of loop formation in polypeptide chains","volume-title":"J Am Chem Soc.","author":"Krieger","year":"2005"},{"key":"2024050210574761000_CIT0044","first-page":"1555","article-title":"A proline to glycine mutation in the Lck SH3-domain affects conformational sampling and increases ligand binding affinity","volume-title":"FEBS Lett.","author":"Bauer","year":"2007"},{"key":"2024050210574761000_CIT0045","doi-asserted-by":"crossref","DOI":"10.1002\/9780470015902.a0003011.pub2","article-title":"Hydrogen bonds in proteins: role and strength","volume-title":"Encyclopedia of Life Sciences (ELS)","author":"Hubbard","year":"2010"},{"key":"2024050210574761000_CIT0046","first-page":"528","article-title":"The molecular evolution of genes and proteins: a tale of two serines","volume-title":"Nature.","author":"Brenner","year":"1988"},{"key":"2024050210574761000_CIT0047","first-page":"124","article-title":"Common TMPRSS6 mutations and iron, erythrocyte, and pica phenotypes in 48 women with iron deficiency or depletion","volume-title":"Blood Cells Mol Dis.","author":"Lee","year":"2012"}],"container-title":["Laboratory Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/labmed\/article-pdf\/55\/3\/277\/57370155\/lmad077.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/labmed\/article-pdf\/55\/3\/277\/57370155\/lmad077.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,2]],"date-time":"2024-05-02T10:58:19Z","timestamp":1714647499000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/labmed\/article\/55\/3\/277\/7242347"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,14]]},"references-count":47,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,8,14]]},"published-print":{"date-parts":[[2024,5,2]]}},"URL":"https:\/\/doi.org\/10.1093\/labmed\/lmad077","relation":{},"ISSN":["0007-5027","1943-7730"],"issn-type":[{"type":"print","value":"0007-5027"},{"type":"electronic","value":"1943-7730"}],"subject":[],"published-other":{"date-parts":[[2024,5,1]]},"published":{"date-parts":[[2023,8,14]]}}}