{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T11:26:31Z","timestamp":1777375591938,"version":"3.51.4"},"reference-count":31,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,9,26]],"date-time":"2021-09-26T00:00:00Z","timestamp":1632614400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Pathogenic variants in the LMNA gene cause a group of heterogeneous genetic disorders, called laminopathies. In particular, homozygous or compound heterozygous variants in LMNA have been associated with \u201cmandibuloacral dysplasia type A\u201d (MADA), an autosomal recessive disorder, characterized by mandibular hypoplasia, growth retardation mainly postnatal, pigmentary skin changes, progressive osteolysis of the distal phalanges and\/or clavicles, and partial lipodystrophy. The detailed characteristics of this multisystemic disease have yet to be specified due to its rarity and the limited number of cases described. Here, we report three unrelated Egyptian patients with variable severity of MAD features. Next-generation sequencing using a gene panel revealed a homozygous c.1580G&gt;A-p.Arg527His missense variant in LMNA exon 9 in an affected individual with a typical MADA phenotype. Another homozygous c.1580G&gt;T-p.Arg527Leu variant affecting the same amino acid was identified in two additional patients, who both presented with severe manifestations very early in life. We combined our observations together with data from all MADA cases reported in the literature to get a clearer picture of the phenotypic variability in this disease. This work raises the number of reported MADA families, argues for the presence of the founder effect in Egypt, and strengthens genotype\u2013phenotype correlations.<\/jats:p>","DOI":"10.3390\/genes12101508","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T04:55:33Z","timestamp":1632718533000},"page":"1508","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Two Decades after Mandibuloacral Dysplasia Discovery: Additional Cases and Comprehensive View of Disease Characteristics"],"prefix":"10.3390","volume":"12","author":[{"given":"Isabelle","family":"J\u00e9ru","sequence":"first","affiliation":[{"name":"Inserm UMR_S938, Saint-Antoine Research Center, Institute of Cardiometabolism and Nutrition, Sorbonne University, 75012 Paris, France"},{"name":"Department of Molecular Biology and Genetics, Assistance Publique-H\u00f4pitaux de Paris, Saint-Antoine University Hospital, 75012 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amira","family":"Nabil","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gehad","family":"El-Makkawy","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olivier","family":"Lascols","sequence":"additional","affiliation":[{"name":"Inserm UMR_S938, Saint-Antoine Research Center, Institute of Cardiometabolism and Nutrition, Sorbonne University, 75012 Paris, France"},{"name":"Department of Molecular Biology and Genetics, Assistance Publique-H\u00f4pitaux de Paris, Saint-Antoine University Hospital, 75012 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8181-4721","authenticated-orcid":false,"given":"Corinne","family":"Vigouroux","sequence":"additional","affiliation":[{"name":"Inserm UMR_S938, Saint-Antoine Research Center, Institute of Cardiometabolism and Nutrition, Sorbonne University, 75012 Paris, France"},{"name":"Department of Molecular Biology and Genetics, Assistance Publique-H\u00f4pitaux de Paris, Saint-Antoine University Hospital, 75012 Paris, France"},{"name":"National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), Department of Endocrinology, Assistance Publique-H\u00f4pitaux de Paris, Saint-Antoine University Hospital, 75012 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ebtesam","family":"Abdalla","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria 21561, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,26]]},"reference":[{"key":"ref_1","first-page":"291","article-title":"New syndrome manifested by mandibular hypoplasia, acroosteolysis, stiff joints and cutaneous atrophy (mandibuloacral dysplasia) in two unrelated boys","volume":"7","author":"Young","year":"1971","journal-title":"Birth Defects Orig. Artic. Ser."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1086\/341908","article-title":"Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A\/C","volume":"71","author":"Novelli","year":"2002","journal-title":"Amer. J. Hum. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1093\/hmg\/ddg213","article-title":"Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia","volume":"12","author":"Agarwal","year":"2003","journal-title":"Hum. Mol. Genet."},{"key":"ref_4","first-page":"1","article-title":"Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology","volume":"11","author":"Elouej","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.1016\/j.yexcr.2007.03.028","article-title":"\u201cLaminopathies\u201d: A wide spectrum of human diseases","volume":"313","author":"Worman","year":"2007","journal-title":"Exp. Cell Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5259","DOI":"10.1210\/jc.2004-2560","article-title":"A novel homozygous Ala529Val LMNA mutation in Turkish patients with mandibuloacral dysplasia","volume":"90","author":"Garg","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4467","DOI":"10.1210\/jc.2007-0116","article-title":"Compound heterozygosity for mutations in LMNA in a patient with a myopathic and lipodystrophic mandibuloacral dysplasia type A phenotype","volume":"92","author":"Lombardi","year":"2007","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/s10038-003-0025-3","article-title":"LMNA is mutated in Hutchinson-Gilford progeria (MIM 176670) but not in Wiedemann-Rautenstrauch progeroid syndrome (MIM 264090)","volume":"48","author":"Cao","year":"2003","journal-title":"J. Hum. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1136\/jmg.2004.019661","article-title":"Homozygous missense mutation in the lamin A\/C gene causes autosomal recessive Hutchinson-Gilford progeria syndrome","volume":"41","author":"Plasilova","year":"2004","journal-title":"J. Med. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1093\/hmg\/ddl172","article-title":"Compound heterozygosity for mutations in LMNA causes a progeria syndrome without prelamin A accumulation","volume":"15","author":"Verstraeten","year":"2006","journal-title":"Hum. Mol. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1002\/ajmg.a.32259","article-title":"Association of homozygous LMNA mutation R471C with new phenotype: Mandibuloacral dysplasia, progeria, and rigid spine muscular dystrophy","volume":"146","author":"Zirn","year":"2008","journal-title":"Am. J. Med.Genet. Part A"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4617","DOI":"10.1210\/jc.2008-0123","article-title":"Severe mandibuloacral dysplasia-associated lipodystrophy and progeria in a young girl with a novel homozygous Arg527Cys LMNA mutation","volume":"93","author":"Agarwal","year":"2008","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1038\/ejhg.2012.77","article-title":"A novel homozygous p. Arg527Leu LMNA mutation in two unrelated Egyptian families causes overlapping mandibuloacral dysplasia and progeria syndrome","volume":"20","author":"Kozlowski","year":"2012","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_14","first-page":"940","article-title":"Mandibuloacral Dysplasia Mutation Detection in Three Egyptian Families: A Report of a Novel Mutation","volume":"9","author":"Amr","year":"2012","journal-title":"Life Sci. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1146\/annurev-biochem-060614-034115","article-title":"Lamins: Nuclear Intermediate Filament Proteins with Fundamental Functions in Nuclear Mechanics and Genome Regulation","volume":"84","author":"Gruenbaum","year":"2015","journal-title":"Ann. Rev. Biochem."},{"key":"ref_16","first-page":"150","article-title":"Alterations of nuclear envelope and chromatin organization in mandibuloacral dysplasia, a rare form of laminopathy Physiol","volume":"23","author":"Filesi","year":"2005","journal-title":"Genomics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1093\/hmg\/ddi158","article-title":"Altered pre-lamin A processing is a common mechanism leading to lipodystrophy","volume":"14","author":"Capanni","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1007\/s00418-012-0977-5","article-title":"Altered chromatin organization and SUN2 localization in mandibuloacral dysplasia are rescued by drug treatment","volume":"138","author":"Camozzi","year":"2012","journal-title":"Histochem. Cell Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.arr.2017.12.001","article-title":"Mandibuloacral dysplasia: A premature ageing disease with aspects of physiological ageing","volume":"42","author":"Cenni","year":"2018","journal-title":"Ageing Res. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6025","DOI":"10.1210\/jc.2019-00849","article-title":"Diagnostic challenge in PLIN1-associated Familial Partial Lipodystrophy","volume":"104","author":"Vantyghem","year":"2019","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","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."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2821","DOI":"10.1210\/jc.2002-021575","article-title":"Genetic and phenotypic heterogeneity in patients with mandibuloacral dysplasia-associated lipodystrophy","volume":"88","author":"Simha","year":"2003","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1136\/jmg.40.11.854","article-title":"Mandibuloacral dysplasia caused by homozygosity for the R527H mutation in lamin A\/C","volume":"40","author":"Shen","year":"2003","journal-title":"J. Med. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2258","DOI":"10.1002\/ajmg.a.33005","article-title":"Mandibuloacral dysplasia type A in childhood","volume":"149","author":"Garavelli","year":"2009","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2598","DOI":"10.1002\/ajmg.a.31983","article-title":"Mandibuloacral dysplasia and a novel LMNA mutation in a woman with severe progressive skeletal changes","volume":"143A","author":"Kosho","year":"2007","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Luo, D.Q., Wang, X.Z., Meng, Y., He, D.Y., Chen, Y.M., Ke, Z.Y., Yan, M., Huang, Y., and Chen, D.F. (2014). Mandibuloacral dysplasia type A-associated progeria caused by homozygous LMNA mutation in a family from Southern China. BMC Pediatr., 14.","DOI":"10.1186\/1471-2431-14-256"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.gene.2015.08.071","article-title":"A novel homozygous LMNA mutation (p. Met540Ile) causes mandibuloacral dysplasia type A","volume":"577","author":"Yassaee","year":"2016","journal-title":"Gene"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"104138","DOI":"10.1016\/j.ejmg.2021.104138","article-title":"Mandibuloacral dysplasia type A in five tunisian patients","volume":"64","author":"Sakka","year":"2021","journal-title":"Eur. J. Med. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1016\/j.bbadis.2011.03.006","article-title":"Osteoblasts from a mandibuloacral dysplasia patient induce human blood precursors to differentiate into active osteoclasts","volume":"1812","author":"Avnet","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"17381","DOI":"10.1074\/jbc.C200038200","article-title":"Structure of the globular tail of nuclear lamin","volume":"277","author":"Werner","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/S0969-2126(02)00777-3","article-title":"The Ig-like structure of the C-terminal domain of lamin A\/C, mutated in muscular dystrophies, cardiomyopathy, and partial lipodystrophy","volume":"10","author":"Krimm","year":"2002","journal-title":"Structure"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/10\/1508\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:05:10Z","timestamp":1760166310000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/10\/1508"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,26]]},"references-count":31,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["genes12101508"],"URL":"https:\/\/doi.org\/10.3390\/genes12101508","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,26]]}}}