{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T16:59:27Z","timestamp":1768409967037,"version":"3.49.0"},"reference-count":44,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T00:00:00Z","timestamp":1709856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Swiss Government Excellence Scholarship (ESKAS)","award":["2020.0557"],"award-info":[{"award-number":["2020.0557"]}]},{"name":"University of Bern and swissuniversities","award":["2020.0557"],"award-info":[{"award-number":["2020.0557"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Rabson\u2013Mendenhall syndrome (RMS) is a rare autosomal recessive disorder characterized by severe insulin resistance, resulting in early-onset diabetes mellitus. We report the first case of RMS in a Paraguayan patient. The patient is a 6-year-old girl who presented with hypertrichosis, acanthosis nigricans, nephrocalcinosis, and elevated levels of glucose and insulin that served as diagnostic indicators for RMS. Genetic testing by next-generation sequencing (NGS) revealed two pathogenic variants in exons 2 and 19 of the INSR gene: c.332G&gt;T (p.Gly111Val) and c.3485C&gt;T (p.Ala1162Val), in combined heterozygosis. The novel INSR c. 332G&gt;T variant leads to the substitution of glycine to valine at position 111 in the protein, and multiple in silico software programs predicted it as pathogenic. The c.3485C&gt;T variant leads to the substitution of alanine to valine at position 1162 in the protein previously described for insulin resistance and RMS. The management of RMS is particularly challenging in children, and the use of metformin is often limited by its side effects. The patient was managed with nutritional measures due to the early age of onset. This report expands the knowledge of RMS to the Paraguayan population and adds a novel pathogenic variant to the existing literature.<\/jats:p>","DOI":"10.3390\/ijms25063143","type":"journal-article","created":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T11:47:30Z","timestamp":1709898450000},"page":"3143","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Novel Mutation in the INSR Gene Causes Severe Insulin Resistance and Rabson\u2013Mendenhall Syndrome in a Paraguayan Patient"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9132-681X","authenticated-orcid":false,"given":"Maria Natalia","family":"Rojas Velazquez","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University Children\u2019s Hospital Bern, Inselspital, 3010 Bern, Switzerland"},{"name":"Translational Hormone Research Program, Department of Biomedical Research, University of Bern, 3010 Bern, Switzerland"},{"name":"Graduate School for Cellular and Biomedical Sciences, University of Bern, 3010 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabiola","family":"Blanco","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias M\u00e9dicas, Universidad Nacional de Asunci\u00f3n, Asunci\u00f3n 111241, Paraguay"},{"name":"Instituto de Previsi\u00f3n Social, Asunci\u00f3n 172755, Paraguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5844-1445","authenticated-orcid":false,"given":"Ana","family":"Ayala-Lugo","sequence":"additional","affiliation":[{"name":"Laboratorio de Gen\u00e9tica Molecular, Departamento de Gen\u00e9tica, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunci\u00f3n, Asunci\u00f3n 111241, Paraguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lady","family":"Franco","sequence":"additional","affiliation":[{"name":"Laboratorio de Gen\u00e9tica Molecular, Departamento de Gen\u00e9tica, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunci\u00f3n, Asunci\u00f3n 111241, Paraguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valerie","family":"Jolly","sequence":"additional","affiliation":[{"name":"Laboratorio de Gen\u00e9tica Molecular, Departamento de Gen\u00e9tica, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunci\u00f3n, Asunci\u00f3n 111241, Paraguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denisse","family":"Di Tore","sequence":"additional","affiliation":[{"name":"Laboratorio de Gen\u00e9tica Molecular, Departamento de Gen\u00e9tica, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunci\u00f3n, Asunci\u00f3n 111241, Paraguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Idoia","family":"Mart\u00ednez de Lapiscina","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University Children\u2019s Hospital Bern, Inselspital, 3010 Bern, Switzerland"},{"name":"Translational Hormone Research Program, Department of Biomedical Research, University of Bern, 3010 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Janner","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University Children\u2019s Hospital Bern, Inselspital, 3010 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christa E.","family":"Fl\u00fcck","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University Children\u2019s Hospital Bern, Inselspital, 3010 Bern, Switzerland"},{"name":"Translational Hormone Research Program, Department of Biomedical Research, University of Bern, 3010 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8331-5902","authenticated-orcid":false,"given":"Amit V.","family":"Pandey","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University Children\u2019s Hospital Bern, Inselspital, 3010 Bern, Switzerland"},{"name":"Translational Hormone Research Program, Department of Biomedical Research, University of Bern, 3010 Bern, Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2713","DOI":"10.2337\/db17-0301","article-title":"Structural Basis and Genotype-Phenotype Correlations of INSR Mutations Causing Severe Insulin Resistance","volume":"66","author":"Hosoe","year":"2017","journal-title":"Diabetes"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1507\/endocrj.EJ11-0032","article-title":"Functional characterization of insulin receptor gene mutations contributing to Rabson-Mendenhall syndrome\u2014Phenotypic heterogeneity of insulin receptor gene mutations","volume":"58","author":"Jiang","year":"2011","journal-title":"Endocr. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.gde.2018.02.002","article-title":"Genetic syndromes of severe insulin resistance","volume":"50","author":"Melvin","year":"2018","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"842","DOI":"10.2337\/diabetes.53.3.842","article-title":"Genetic variants in human sterol regulatory element binding protein-1c in syndromes of severe insulin resistance and type 2 diabetes","volume":"53","author":"Laudes","year":"2004","journal-title":"Diabetes"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e32266","DOI":"10.1097\/MD.0000000000032266","article-title":"INSR novel mutations identified in a Chinese family with severe INSR-related insulin resistance syndromes: A case report","volume":"101","author":"Yu","year":"2022","journal-title":"Medicine"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.ejmg.2015.11.015","article-title":"A novel homozygous missense mutation in the insulin receptor gene results in an atypical presentation of Rabson-Mendenhall syndrome","volume":"59","author":"Azzouz","year":"2016","journal-title":"Eur. J. Med. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1172\/JCI1283","article-title":"Two aberrant splicings caused by mutations in the insulin receptor gene in cultured lymphocytes from a patient with Rabson-Mendenhall\u2019s syndrome","volume":"101","author":"Takahashi","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1093\/ajcp\/26.3.283","article-title":"Familial hypertrophy of pineal body, hyperplasia of adrenal cortex and diabetes mellitus; report of 3 cases","volume":"26","author":"Rabson","year":"1956","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1515\/jpem-2022-0214","article-title":"Management challenges of Rabson Mendenhall syndrome in a resource limited country: A case report","volume":"35","author":"Aftab","year":"2022","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1007\/s00592-022-01971-3","article-title":"Incomplete phenotypic presentation in a girl with rare Rabson-Mendenhall syndrome","volume":"60","author":"Chrzanowska","year":"2023","journal-title":"Acta Diabetol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1007\/s12098-020-03433-6","article-title":"Rare Ocular Complication in a Patient with Rabson-Mendenhall Syndrome","volume":"88","author":"Kumar","year":"2021","journal-title":"Indian. J. Pediatr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1007\/s13340-020-00455-5","article-title":"Insulin resistance and exaggerated insulin sensitivity triggered by single-gene mutations in the insulin signaling pathway","volume":"12","author":"Kushi","year":"2021","journal-title":"Diabetol. Int."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"312","DOI":"10.4274\/jcrpe.galenos.2021.2021.0256","article-title":"Syndrome of Congenital Insulin Resistance Caused by a Novel INSR Gene Mutation","volume":"15","author":"Rojek","year":"2023","journal-title":"J. Clin. Res. Pediatr. Endocrinol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1159\/000506722","article-title":"Two Novel Variants and One Previously Reported Variant in the Insulin Receptor Gene in Two Cases with Severe Insulin Resistance Syndrome","volume":"11","author":"Saidov","year":"2020","journal-title":"Mol. Syndromol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1507\/endocrj.EJ21-0725","article-title":"New classification and diagnostic criteria for insulin resistance syndrome","volume":"69","author":"Ogawa","year":"2022","journal-title":"Endocr. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"100","DOI":"10.4103\/njms.NJMS_55_20","article-title":"Severe insulin resistance syndrome\u2014A rare case report and review of literature","volume":"12","author":"Joshi","year":"2021","journal-title":"Natl. J. Maxillofac. Surg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"97","DOI":"10.2337\/diaclin.34.2.97","article-title":"Treatment Approach to Patients with Severe Insulin Resistance","volume":"34","author":"Church","year":"2016","journal-title":"Clin. Diabetes"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"606964","DOI":"10.3389\/fendo.2021.606964","article-title":"Clinical and Functional Characterization of Novel INSR Variants in Two Families With Severe Insulin Resistance Syndrome","volume":"12","author":"Zhou","year":"2021","journal-title":"Front. Endocrinol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1097\/01.md.0000133625.73570.54","article-title":"Clinical course of genetic diseases of the insulin receptor (type A and Rabson-Mendenhall syndromes): A 30-year prospective","volume":"83","author":"Musso","year":"2004","journal-title":"Medicine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e1032","DOI":"10.1210\/clinem\/dgab782","article-title":"Long-Term Effects of Metreleptin in Rabson-Mendenhall Syndrome on Glycemia, Growth, and Kidney Function","volume":"107","author":"Okawa","year":"2022","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1046\/j.1464-5491.2002.00779.x","article-title":"Genetic variants of insulin receptor substrate-1 (IRS-1) in syndromes of severe insulin resistance. Functional analysis of Ala513Pro and Gly1158Glu IRS-1","volume":"19","author":"Berger","year":"2002","journal-title":"Diabet. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1210\/er.2010-0020","article-title":"Genetic syndromes of severe insulin resistance","volume":"32","author":"Semple","year":"2011","journal-title":"Endocr. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1159\/000519613","article-title":"Use of a Sodium-Glucose Cotransporter 2 Inhibitor, Empagliflozin, in a Patient with Rabson-Mendenhall Syndrome","volume":"94","author":"Ramaldes","year":"2021","journal-title":"Horm. Res. Paediatr."},{"key":"ref_24","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":"ref_25","doi-asserted-by":"crossref","first-page":"2745","DOI":"10.1093\/bioinformatics\/btv195","article-title":"PROVEAN web server: A tool to predict the functional effect of amino acid substitutions and indels","volume":"31","author":"Choi","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_26","first-page":"7.20.1","article-title":"Predicting Functional Effect of Human Missense Mutations Using PolyPhen-2","volume":"76","author":"Adzhubei","year":"2013","journal-title":"Curr. Protoc. Hum. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/pro.4218","article-title":"PANTHER: Making genome-scale phylogenetics accessible to all","volume":"31","author":"Thomas","year":"2022","journal-title":"Protein Sci"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"W446","DOI":"10.1093\/nar\/gkab266","article-title":"MutationTaster2021","volume":"49","author":"Steinhaus","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"D1143","DOI":"10.1093\/nar\/gkad989","article-title":"CADD v1.7: Using protein language models, regulatory CNNs and other nucleotide-level scores to improve genome-wide variant predictions","volume":"52","author":"Schubach","year":"2024","journal-title":"Nucleic Acids Res"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1002\/humu.21047","article-title":"Functional annotations improve the predictive score of human disease-related mutations in proteins","volume":"30","author":"Calabrese","year":"2009","journal-title":"Human Mutation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5918","DOI":"10.1038\/s41467-020-19669-x","article-title":"Inferring the molecular and phenotypic impact of amino acid variants with MutPred2","volume":"11","author":"Pejaver","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2454","DOI":"10.1007\/s00125-010-1879-5","article-title":"Multidrug therapy in a patient with Rabson-Mendenhall syndrome","volume":"53","author":"Moreira","year":"2010","journal-title":"Diabetologia"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"8060","DOI":"10.1016\/S0021-9258(18)53063-5","article-title":"Substitution of glutamic acid for alanine 1135 in the putative \u201ccatalytic loop\u201d of the tyrosine kinase domain of the human insulin receptor. A mutation that impairs proteolytic processing into subunits and inhibits receptor tyrosine kinase activity","volume":"268","author":"Cama","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1515\/jpem-2019-0503","article-title":"A novel heterozygous mutation in the insulin receptor gene presenting with type A severe insulin resistance syndrome","volume":"33","author":"Aghababaie","year":"2020","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_35","first-page":"e13126","article-title":"Insulin, Insulin Everywhere: A Rare Case Report of Rabson-Mendenhall Syndrome","volume":"13","author":"Gosavi","year":"2021","journal-title":"Cureus"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"802","DOI":"10.2337\/diab.35.7.802","article-title":"Insulin-Receptor Biosynthesis in Cultured Lymphocytes From an Insulin-Resistant Patient (Rabson-Mendenhall Syndrome): Evidence for Defect Before Insertion of Receptor Into Plasma Membrane","volume":"35","author":"Moncada","year":"1986","journal-title":"Diabetes"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"19143","DOI":"10.1016\/S0021-9258(17)30636-1","article-title":"Substitution of lysine for asparagine at position 15 in the alpha-subunit of the human insulin receptor. A mutation that impairs transport of receptors to the cell surface and decreases the affinity of insulin binding","volume":"265","author":"Kadowaki","year":"1990","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1210\/jcem-56-4-856","article-title":"Decreased Insulin Binding to Cultured Cells from a Patient with the Rabson-Mendenhall Syndrome: Dichotomy between Studies with Cultured Lymphocytes and Cultured Fibroblasts*","volume":"56","author":"Taylor","year":"1983","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1210\/jc.2003-031952","article-title":"Efficacy of Recombinant Methionyl Human Leptin Therapy for the Extreme Insulin Resistance of the Rabson-Mendenhall Syndrome","volume":"89","author":"Cochran","year":"2004","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1038\/nprot.2015.105","article-title":"Genomic variant annotation and prioritization with ANNOVAR and wANNOVAR","volume":"10","author":"Yang","year":"2015","journal-title":"Nat. Protoc."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Camats, N., Fluck, C.E., and Audi, L. (2020). Oligogenic Origin of Differences of Sex Development in Humans. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21051809"},{"key":"ref_42","first-page":"405","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med. Off. J. Am. Coll. Med. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"5572","DOI":"10.1093\/emboj\/16.18.5572","article-title":"Crystal structure of the activated insulin receptor tyrosine kinase in complex with peptide substrate and ATP analog","volume":"16","author":"Hubbard","year":"1997","journal-title":"EMBO J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1002\/jcc.23899","article-title":"New ways to boost molecular dynamics simulations","volume":"36","author":"Krieger","year":"2015","journal-title":"J. Comput. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/6\/3143\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:11:12Z","timestamp":1760105472000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/6\/3143"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,8]]},"references-count":44,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["ijms25063143"],"URL":"https:\/\/doi.org\/10.3390\/ijms25063143","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,8]]}}}