{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T13:01:54Z","timestamp":1770814914780,"version":"3.50.1"},"reference-count":38,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-DK105448"],"award-info":[{"award-number":["R01-DK105448"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Genetic lipodystrophies are a heterogeneous group of autosomal dominant and recessive disorders characterized by generalized or partial loss of body fat. Most patients with familial partial lipodystrophy (FPLD) have dominant inheritance with heterozygous pathogenic missense variants in LMNA. Here, we report two females with rare biallelic variants in LMNA presenting with divergent lipodystrophic phenotypes. Proband 1, a 32-year-old female, has near-generalized lipodystrophy (body fat 12.7%) due to compound heterozygous c.1745G&gt;T (p.R582L) and c.1750C&gt;T (p.R584C) LMNA variants. She was diagnosed with diabetes at age 17, hypertriglyceridemia at age 18, and metabolic dysfunction-associated steatotic liver disease (MASLD) at age 20. She was treated with metreleptin with only partial improvement in metabolic parameters. Her parents, heterozygous carriers of these variants, did not have lipodystrophy. Proband 2, a 35-year-old female, has partial lipodystrophy (body fat 21.2%) due to a homozygous c.1750C&gt;T (p.R584C) LMNA variant. She was diagnosed with diabetes at age 19 and had a history of hypertriglyceridemia and mild hepatic steatosis. Her parents reportedly did not have lipodystrophy. These cases highlight the expression of LMNA variants in the homozygous or compound heterozygous state, manifesting in near-generalized and partial loss of body fat with distinct phenotypic heterogeneity.<\/jats:p>","DOI":"10.3390\/ijms27041724","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T09:15:12Z","timestamp":1770801312000},"page":"1724","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Familial Generalized and Partial Lipodystrophies Due to Rare Biallelic Variants in LMNA"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-5546-6812","authenticated-orcid":false,"given":"Michael","family":"Hwang","sequence":"first","affiliation":[{"name":"National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlita","family":"Worthy","sequence":"additional","affiliation":[{"name":"National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elaine","family":"Cochran","sequence":"additional","affiliation":[{"name":"National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan","family":"Startzell","sequence":"additional","affiliation":[{"name":"National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ranganath","family":"Muniyappa","sequence":"additional","affiliation":[{"name":"National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1838-0502","authenticated-orcid":false,"given":"Chao","family":"Xing","sequence":"additional","affiliation":[{"name":"Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"O\u2019Donnell School of Public Health, UT Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abhimanyu","family":"Garg","sequence":"additional","affiliation":[{"name":"Section of Nutrition and Metabolic Diseases, Division of Endocrinology, Department of Internal Medicine, Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca J.","family":"Brown","sequence":"additional","affiliation":[{"name":"National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1056\/NEJMra025261","article-title":"Acquired and Inherited Lipodystrophies","volume":"350","author":"Garg","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1038\/nrendo.2015.123","article-title":"Congenital Generalized Lipodystrophies\u2014New Insights into Metabolic Dysfunction","volume":"11","author":"Patni","year":"2015","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.1210\/jc.2014-4491","article-title":"Partial and Generalized Lipodystrophy: Comparison of Baseline Characteristics and Response to Metreleptin","volume":"100","author":"Cochran","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/j.ecl.2017.01.012","article-title":"Genetics of Lipodystrophy","volume":"46","author":"Lightbourne","year":"2017","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1093\/hmg\/9.1.109","article-title":"Nuclear Lamin A\/C R482Q Mutation in Canadian Kindreds with Dunnigan-Type Familial Partial Lipodystrophy","volume":"9","author":"Cao","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"ref_6","first-page":"408","article-title":"A Novel Heterozygous Mutation in Peroxisome Proliferator-Activated Receptor-\u03b3 Gene in a Patient with Familial Partial Lipodystrophy","volume":"87","author":"Agarwal","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1056\/NEJMoa1007487","article-title":"Perilipin Deficiency and Autosomal Dominant Partial Lipodystrophy","volume":"364","author":"Gandotra","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_8","first-page":"315","article-title":"Postreceptor Insulin Resistance Contributes to Human Dyslipidemia and Hepatic Steatosis","volume":"119","author":"Semple","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e86870","DOI":"10.1172\/jci.insight.86870","article-title":"Whole-Exome Sequencing Identifies ADRA2A Mutation in Atypical Familial Partial Lipodystrophy","volume":"1","author":"Garg","year":"2016","journal-title":"JCI Insight"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"427","DOI":"10.2337\/db24-0624","article-title":"Gain of Function NOTCH3 Variants Cause Familial Partial Lipodystrophy Due to Activation of Senescence Pathways","volume":"74","author":"Garg","year":"2025","journal-title":"Diabetes"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"e198888","DOI":"10.1172\/JCI198888","article-title":"A recurrent ACAA2 variant causes a dominant syndrome of lipodystrophy, lipomatosis, infantile steatohepatitis, and hypoglycemia","volume":"136","author":"Simha","year":"2026","journal-title":"J. Clin. Investig."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1002\/emmm.200900037","article-title":"Partial Lipodystrophy and Insulin Resistant Diabetes in a Patient with a Homozygous Nonsense Mutation in CIDEC","volume":"1","author":"Puri","year":"2009","journal-title":"EMBO Mol. Med."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Patni, N., Xing, C., Huang, C.Y., Brown, R.J., and Garg, A. (2026). Novel Homozygous Variants in CIDEC and WRN in a Young Female with Lipodystrophy and Thyroid Cancer. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27020646"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1002\/ajmg.a.37880","article-title":"Homozygous LIPE Mutation in Siblings with Multiple Symmetric Lipomatosis, Partial Lipodystrophy, and Myopathy","volume":"173","author":"Zolotov","year":"2017","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8901","DOI":"10.1073\/pnas.1408523111","article-title":"Mutations Disrupting the Kennedy Phosphatidylcholine Pathway in Humans with Congenital Lipodystrophy and Fatty Liver Disease","volume":"111","author":"Payne","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1186\/gb-2011-12-5-222","article-title":"The Lamin Protein Family","volume":"12","author":"Dittmer","year":"2011","journal-title":"Genome Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s40842-020-00100-9","article-title":"Homozygous LMNA p.R582H Pathogenic Variant Reveals Increasing Effect on the Severity of Fat Loss in Lipodystrophy","volume":"6","author":"Soyaltin","year":"2020","journal-title":"Clin. Diabetes Endocrinol."},{"key":"ref_18","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_19","doi-asserted-by":"crossref","unstructured":"Davydov, E.V., Goode, D.L., Sirota, M., Cooper, G.M., Sidow, A., and Batzoglou, S. (2010). Identifying a High Fraction of the Human Genome to Be under Selective Constraint Using GERP++. PLoS Comput. Biol., 6.","DOI":"10.1371\/journal.pcbi.1001025"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1249\/00005768-198023000-00009","article-title":"Generalized Equations for Predicting Body Density of Women","volume":"12","author":"Jackson","year":"1980","journal-title":"Med. Sci. Sports Exerc."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1079\/BJN19780152","article-title":"Generalized Equations for Predicting Body Density of Men","volume":"40","author":"Jackson","year":"1978","journal-title":"Br. J. Nutr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e1739","DOI":"10.1210\/clinem\/dgab760","article-title":"Endogenous Leptin Concentrations Poorly Predict Metreleptin Response in Patients with Partial Lipodystrophy","volume":"107","author":"Meral","year":"2022","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e1204","DOI":"10.1210\/clinem\/dgad606","article-title":"Deciphering the Clinical Presentations in LMNA-Related Lipodystrophy: Report of 115 Cases and a Systematic Review","volume":"109","author":"Besci","year":"2024","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Desgrouas, C., Varlet, A.-A., Dutour, A., Galant, D., Merono, F., Bonello-Palot, N., Bourgeois, P., Lasbleiz, A., Petitjean, C., and Ancel, P. (2020). Unraveling LMNA Mutations in Metabolic Syndrome: Cellular Phenotype and Clinical Pitfalls. Cells, 9.","DOI":"10.3390\/cells9020310"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.ahj.2014.12.021","article-title":"Metabolic and Cardiac Phenotype Characterization in 37 Atypical Dunnigan Patients with Nonfarnesylated Mutated Prelamin A","volume":"169","author":"Andre","year":"2015","journal-title":"Am. Heart J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"E856","DOI":"10.1210\/jc.2010-2234","article-title":"A Homozygous Mutation of Prelamin-A Preventing Its Farnesylation and Maturation Leads to a Severe Lipodystrophic Phenotype: New Insights into the Pathogenicity of Nonfarnesylated Prelamin-A","volume":"96","author":"Schneebeli","year":"2011","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_27","first-page":"3431","article-title":"Heterogeneity of Nuclear Lamin A Mutations in Dunnigan-Type Familial Partial Lipodystrophy","volume":"85","author":"Hegele","year":"2000","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1007\/s00125-004-1360-4","article-title":"Familial Partial Lipodystrophy Associated with Compound Heterozygosity for Novel Mutations in the LMNA Gene","volume":"47","author":"Savage","year":"2004","journal-title":"Diabetologia"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1086\/302836","article-title":"Mutational and Haplotype Analyses of Families with Familial Partial Lipodystrophy (Dunnigan Variety) Reveal Recurrent Missense Mutations in the Globular C-Terminal Domain of Lamin A\/C","volume":"66","author":"Speckman","year":"2000","journal-title":"Am. J. Hum. Genet."},{"key":"ref_30","first-page":"59","article-title":"Phenotypic Heterogeneity in Patients with Familial Partial Lipodystrophy (Dunnigan Variety) Related to the Site of Missense Mutations in Lamin a\/c Gene","volume":"86","author":"Garg","year":"2001","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.ejmg.2014.06.006","article-title":"Biallelic Mutations at PPARG Cause a Congenital, Generalized Lipodystrophy Similar to the Berardinelli-Seip Syndrome","volume":"57","author":"Dyment","year":"2014","journal-title":"Eur. J. Med. Genet."},{"key":"ref_32","first-page":"e79","article-title":"Unusual Presentations of Lmna-Associated Lipodystrophy with Complex Phenotypes and Generalized Fat Loss: When the Genetic Diagnosis Uncovers Novel Features","volume":"6","author":"Adiyaman","year":"2020","journal-title":"AACE Clin. Case Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1136\/jmedgenet-2019-106395","article-title":"A Novel Autosomal Recessive Lipodystrophy Syndrome Due to Homozygous LMNA Variant","volume":"57","author":"Patni","year":"2020","journal-title":"J. Med. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Montenegro, R.M., Costa-Riquetto, A.D., Fernandes, V.O., Montenegro, A.P.D.R., de Santana, L.S., de Lima Jorge, A.A., de Azevedo Souza Karbage, L.B., Aguiar, L.B., Carvalho, F.H.C., and Teles, M.G. (2018). Homozygous and Heterozygous Nuclear Lamin A p.R582C Mutation: Different Lipodystrophic Phenotypes in the Same Kindred. Front. Endocrinol., 9.","DOI":"10.3389\/fendo.2018.00458"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1970","DOI":"10.2337\/db20-1001","article-title":"Adipocyte-Specific Deletion of Lamin A\/C Largely Models Human Familial Partial Lipodystrophy Type 2","volume":"70","author":"Corsa","year":"2021","journal-title":"Diabetes"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/s41467-021-27869-2","article-title":"Genomic Loci Mispositioning in Tmem120a Knockout Mice Yields Latent Lipodystrophy","volume":"13","author":"Czapiewski","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1001\/jamacardio.2020.0013","article-title":"A New Equation for Calculation of Low-Density Lipoprotein Cholesterol in Patients with Normolipidemia and\/or Hypertriglyceridemia","volume":"5","author":"Sampson","year":"2020","journal-title":"JAMA Cardiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2132","DOI":"10.1210\/clinem\/dgaa137","article-title":"Diagnostic Value of Anthropometric Measurements for Familial Partial Lipodystrophy, Dunnigan Variety","volume":"105","author":"Vasandani","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/1724\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T09:20:22Z","timestamp":1770801622000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/1724"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,11]]},"references-count":38,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ijms27041724"],"URL":"https:\/\/doi.org\/10.3390\/ijms27041724","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,11]]}}}