Lamins and Lamin-Associated Proteins in Gastrointestinal Health and Disease

The nuclear lamina is a multi-protein lattice composed of A- and B-type lamins and their associated proteins. This protein lattice associates with heterochromatin and integral inner nuclear membrane proteins, providing links among the genome, nucleoskeleton, and cytoskeleton. In the 1990s, mutations in EMD and LMNA were linked to Emery-Dreifuss muscular dystrophy. Since then, the number of diseases attributed to nuclear lamina defects, including laminopathies and other disorders, has increased to include more than 20 distinct genetic syndromes. Studies of patients and mouse genetic models have pointed to important roles for lamins and their associated proteins in the function of gastrointestinal organs, including liver and pancreas. We review the interactions and functions of the lamina in relation to the nuclear envelope and genome, the ways in which its dysfunction is thought to contribute to human disease, and possible avenues for targeted therapies. The nuclear lamina is a multi-protein lattice composed of A- and B-type lamins and their associated proteins. This protein lattice associates with heterochromatin and integral inner nuclear membrane proteins, providing links among the genome, nucleoskeleton, and cytoskeleton. In the 1990s, mutations in EMD and LMNA were linked to Emery-Dreifuss muscular dystrophy. Since then, the number of diseases attributed to nuclear lamina defects, including laminopathies and other disorders, has increased to include more than 20 distinct genetic syndromes. Studies of patients and mouse genetic models have pointed to important roles for lamins and their associated proteins in the function of gastrointestinal organs, including liver and pancreas. We review the interactions and functions of the lamina in relation to the nuclear envelope and genome, the ways in which its dysfunction is thought to contribute to human disease, and possible avenues for targeted therapies. In metazoan cells, a structural and functional link between the genome and the cytoskeleton is required to allow cells to quickly and appropriately respond to mechanical, chemical, inflammatory, and other stimuli. This link is provided by nuclear envelope proteins, which have collective and individual structural and regulatory roles. Nuclear pore complexes allow regulated nuclear translocation of transcription factors and co-regulators.1Beck M. Hurt E. The nuclear pore complex: understanding its function through structural insight.Nat Rev Mol Cell Biol. 2017; 18: 73-89Crossref PubMed Scopus (142) Google Scholar The linker of the nucleoskeleton and cytoskeleton (LINC) complex tethers the nuclear envelope to cytoplasmic cytoskeletal networks, allowing transmission of mechanical and shear stress to the nucleus.2Lee Y.L. Burke B. LINC complexes and nuclear positioning.Semin Cell Dev Biol. 2017 Nov 27; (pii: S1084–9521(17)30455-X) ([Epub ahead of print] Review)https://doi.org/10.1016/j.semcdb.2017.11.008Crossref Scopus (0) Google Scholar On the inner surface of the nuclear envelope, large regions of the genome, typically dominated by heterochromatin, are tethered to a multi-protein lattice3Gonzalez-Sandoval A. Gasser S.M. On TADs and LADs: spatial control over gene expression.Trends Genet. 2016; 32: 485-495Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 4Luperchio T.R. Wong X. Reddy K.L. Genome regulation at the peripheral zone: lamina associated domains in development and disease.Curr Opin Genet Dev. 2014; 25: 50-61Crossref PubMed Scopus (35) Google Scholar (Figure 1). This complex of proteins, the nuclear lamina, lies beneath the inner nuclear membrane and physically associates with nuclear pore proteins and a variety of transmembrane and integral membrane proteins, and is in direct contact with large portions of the genome. The primary components of the nuclear lamina are lamins, which are type V intermediate filament proteins—the most common intermediate filament proteins in the nucleus (although other intermediate filament proteins, such as keratins, are also found at much lower levels in the nucleus).5Hobbs R.P. Jacob J.T. Coulombe P.A. Keratins are going nuclear.Dev Cell. 2016; 38: 227-233Abstract Full Text Full Text PDF PubMed Google Scholar, 6Omary M.B. “IF-pathies”: a broad spectrum of intermediate filament-associated diseases.J Clin Invest. 2009; 119: 1756-1762Crossref PubMed Scopus (96) Google Scholar, 7Butin-Israeli V. Adam S.A. 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Perini G. et al.The gene for a novel human lamin maps at a highly transcribed locus of chromosome 19 which replicates at the onset of S-phase.Mol Cell Biol. 1992; 12: 3499-3506Crossref PubMed Google Scholar The B-type lamins are expressed ubiquitously and throughout development, whereas A-type lamins are primarily expressed in differentiated cells.12Stewart C. Burke B. Teratocarcinoma stem cells and early mouse embryos contain only a single major lamin polypeptide closely resembling lamin B.Cell. 1987; 51: 383-392Abstract Full Text PDF PubMed Scopus (253) Google Scholar, 13Rober R.A. Weber K. Osborn M. Differential timing of nuclear lamin A/C expression in the various organs of the mouse embryo and the young animal: a developmental study.Development. 1989; 105: 365-378PubMed Google Scholar Together these proteins form a lattice that creates an interface with the inner nuclear membrane, nuclear pore complexes, transcription factors and co-regulatory proteins, and chromatin. Anchoring of the lamina to the inner nuclear membrane is achieved via B-type lamin farnesylation and lamin binding to transmembrane proteins that include lamina-associated polypeptide 1 and LEM-domain containing proteins, such as LAP2β, emerin, and MAN1 (also called LEMD3),14Lin F. Blake D.L. Callebaut I. et al.MAN1, an inner nuclear membrane protein that shares the LEM domain with lamina-associated polypeptide 2 and emerin.J Biol Chem. 2000; 275: 4840-4847Crossref PubMed Scopus (0) Google Scholar whereas anchoring to the genome is thought to occur via adaptor proteins, including barrier to autointegration factor (BANF1), the lamin B receptor (LBR), and direct binding of lamins to chromatin.15Haraguchi T. Koujin T. Segura-Totten M. et al.BAF is required for emerin assembly into the reforming nuclear envelope.J Cell Sci. 2001; 114: 4575-4585Crossref PubMed Google Scholar, 16Burke B. Stewart C.L. Functional architecture of the cell's nucleus in development, aging, and disease.Curr Top Dev Biol. 2014; 109: 1-52Crossref PubMed Scopus (80) Google Scholar, 17Margalit A. Segura-Totten M. Gruenbaum Y. et al.Barrier-to-autointegration factor is required to segregate and enclose chromosomes within the nuclear envelope and assemble the nuclear lamina.Proc Natl Acad Sci U S A. 2005; 102: 3290-3295Crossref PubMed Scopus (0) Google Scholar, 18Stierle V. Couprie J. Ostlund C. et al.The carboxyl-terminal region common to lamins A and C contains a DNA binding domain.Biochemistry. 2003; 42: 4819-4828Crossref PubMed Scopus (0) Google Scholar Lamin C does not require post-translational modification to localize to the inner nuclear membrane. Lamin A, however, requires stepwise post-translational processing at the carboxy terminus via cysteine farnesylation at a cysteine–aliphatic–aliphatic–any amino acid (CAAX) motif, then proteolytic cleavage of the –AAX portion, carboxymethylation of the farnesylcysteine, and final clipping of the 15 carboxy-terminal residues, including the farnesylated cysteine, by the zinc metallopeptidase STE24 (ZMPSTE24).19Bergo M.O. Gavino B. Ross J. et al.Zmpste24 deficiency in mice causes spontaneous bone fractures, muscle weakness, and a prelamin A processing defect.Proc Natl Acad Sci U S A. 2002; 99: 13049-13054Crossref PubMed Scopus (301) Google Scholar, 20Corrigan D.P. Kuszczak D. Rusinol A.E. et al.Prelamin A endoproteolytic processing in vitro by recombinant Zmpste24.Biochem J. 2005; 387: 129-138Crossref PubMed Scopus (0) Google Scholar, 21Beck L.A. Hosick T.J. Sinensky M. Isoprenylation is required for the processing of the lamin A precursor.J Cell Biol. 1990; 110: 1489-1499Crossref PubMed Scopus (0) Google Scholar, 22Weber K. Plessmann U. Traub P. Maturation of nuclear lamin A involves a specific carboxy-terminal trimming, which removes the polyisoprenylation site from the precursor; implications for the structure of the nuclear lamina.FEBS Lett. 1989; 257: 411-414Crossref PubMed Scopus (142) Google Scholar Although the B-type lamins are permanently farnesylated and found exclusively at the inner nuclear membrane as part of the nuclear lamina, a portion of LMNA is found in the nucleoplasm. Nucleoplasmic LMNA is stabilized by a mammal-specific isoform of thymopoietin (TMPO or LAP2), called LAP2α, but little is known about its function.23Dechat T. Korbei B. Vaughan O.A. et al.Lamina-associated polypeptide 2alpha binds intranuclear A-type lamins.J Cell Sci. 2000; 113 Pt 19: 3473-3484PubMed Google Scholar, 24Naetar N. Korbei B. Kozlov S. et al.Loss of nucleoplasmic LAP2alpha-lamin A complexes causes erythroid and epidermal progenitor hyperproliferation.Nat Cell Biol. 2008; 10: 1341-1348Crossref PubMed Scopus (100) Google Scholar A- and B-type lamins form an intricate network of overlapping but independent 3-dimensional protein meshes25Turgay Y. Eibauer M. Goldman A.E. et al.The molecular architecture of lamins in somatic cells.Nature. 2017; 543: 261-264Crossref PubMed Scopus (111) Google Scholar that interact with distinct subsets of the nuclear proteome. Lamin interactors include transmembrane LEM domain proteins, such as LAP2β and MAN1; transcription factors such as SREBP1; transcriptional regulators, including RB transcriptional corepressor 1 (RB1); and adaptor proteins, such as BANF1, that might facilitate chromatin binding to the lamina.15Haraguchi T. Koujin T. Segura-Totten M. et al.BAF is required for emerin assembly into the reforming nuclear envelope.J Cell Sci. 2001; 114: 4575-4585Crossref PubMed Google Scholar, 17Margalit A. Segura-Totten M. Gruenbaum Y. et al.Barrier-to-autointegration factor is required to segregate and enclose chromosomes within the nuclear envelope and assemble the nuclear lamina.Proc Natl Acad Sci U S A. 2005; 102: 3290-3295Crossref PubMed Scopus (0) Google Scholar, 26Zastrow M.S. Vlcek S. Wilson K.L. Proteins that bind A-type lamins: integrating isolated clues.J Cell Sci. 2004; 117: 979-987Crossref PubMed Scopus (191) Google Scholar, 27Ozaki T. Saijo M. Murakami K. et al.Complex formation between lamin A and the retinoblastoma gene product: identification of the domain on lamin A required for its interaction.Oncogene. 1994; 9: 2649-2653PubMed Google Scholar Two other critical nuclear envelope structures mediate interactions between the nucleus and cytoplasm: nuclear pore complexes and the LINC complex. Nuclear pore complexes allow transcription factors, nuclear receptors, and signaling proteins to shuttle between the nucleus and cytoplasm.1Beck M. Hurt E. The nuclear pore complex: understanding its function through structural insight.Nat Rev Mol Cell Biol. 2017; 18: 73-89Crossref PubMed Scopus (142) Google Scholar A subset of nuclear pore complex proteins localizes to the nuclear periphery and/or with inactive regions of heterochromatin, whereas others are associated with active areas of euchromatin in the nuclear interior.28Pascual-Garcia P. Debo B. Aleman J.R. et al.Metazoan nuclear pores provide a scaffold for poised genes and mediate induced enhancer-promoter contacts.Mol Cell. 2017; 66: 63-76 e6Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 29Capelson M. Liang Y. Schulte R. et al.Chromatin-bound nuclear pore components regulate gene expression in higher eukaryotes.Cell. 2010; 140: 372-383Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar, 30Raices M. D'Angelo M.A. Nuclear pore complexes and regulation of gene expression.Curr Opin Cell Biol. 2017; 46: 26-32Crossref PubMed Scopus (34) Google Scholar How this is regulated, and whether lamins or adaptor proteins such as BANF1 are involved, is unclear. Finally, the LINC complex2Lee Y.L. Burke B. LINC complexes and nuclear positioning.Semin Cell Dev Biol. 2017 Nov 27; (pii: S1084–9521(17)30455-X) ([Epub ahead of print] Review)https://doi.org/10.1016/j.semcdb.2017.11.008Crossref Scopus (0) Google Scholar forms a key structural and regulatory connection between the nuclear envelope and the cytoskeleton, binding to nuclear lamins and the inner nuclear membrane on one side and actin filaments on the other (Figure 1). Several landmark studies have demonstrated the physical association between large regions of the genome (typically characterized by heterochromatin) and the nuclear lamina.3Gonzalez-Sandoval A. Gasser S.M. On TADs and LADs: spatial control over gene expression.Trends Genet. 2016; 32: 485-495Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 31Perovanovic J. Dell'Orso S. Gnochi V.F. et al.Laminopathies disrupt epigenomic developmental programs and cell fate.Sci Transl Med. 2016; 8: 335ra58Crossref PubMed Google Scholar, 32Finlan L.E. Sproul D. Thomson I. et al.Recruitment to the nuclear periphery can alter expression of genes in human cells.PLoS Genet. 2008; 4 (e1000039)Crossref PubMed Scopus (312) Google Scholar, 33Reddy K.L. Zullo J.M. Bertolino E. et al.Transcriptional repression mediated by repositioning of genes to the nuclear lamina.Nature. 2008; 452: 243-247Crossref PubMed Scopus (506) Google Scholar, 34Zullo J.M. Demarco I.A. Pique-Regi R. et al.DNA sequence-dependent compartmentalization and silencing of chromatin at the nuclear lamina.Cell. 2012; 149: 1474-1487Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar Some genomic regions—usually gene-poor, transcriptionally inactive regions—are associated with the lamina as part of lamina-associated domains (LADs) in numerous cell types, including pluripotent and terminally differentiated cells. In contrast, other regions of the genome may be found within or outside of LADs, depending on the cell type, or may move in and out of LADs during the process of cellular differentiation.3Gonzalez-Sandoval A. Gasser S.M. On TADs and LADs: spatial control over gene expression.Trends Genet. 2016; 32: 485-495Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar, 35Peric-Hupkes D. Meuleman W. Pagie L. et al.Molecular maps of the reorganization of genome-nuclear lamina interactions during differentiation.Mol Cell. 2010; 38: 603-613Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar For example, genomic regions associated with the lamina and transcriptionally silent in embryonic stem cells were found to dissociate from the lamina and become transcriptionally active during astrocyte differentiation.31Perovanovic J. Dell'Orso S. Gnochi V.F. et al.Laminopathies disrupt epigenomic developmental programs and cell fate.Sci Transl Med. 2016; 8: 335ra58Crossref PubMed Google Scholar Association with or dissociation from the nuclear lamina is therefore an important mechanism of transcriptional regulation during development; differential histone post-translational modification (methylation/acetylation) is likely to be involved in this process. Importantly, few studies have explored how disease-associated lamin variants affect organization of the genome and the LAD landscape in the involved tissues.36Paulsen J. Sekelja M. Oldenburg A.R. et al.Chrom3D: three-dimensional genome modeling from Hi-C and nuclear lamin-genome contacts.Genome Biol. 2017; 18: 21Crossref PubMed Scopus (50) Google Scholar Researchers began to realize that alterations in the nuclear lamina can lead to development of disease when genetic mapping and sequencing became widely available in the 1990s. In 1994, mutations in EMD, encoding emerin, an inner nuclear membrane protein, were found to cause X-linked Emery–Dreifuss muscular dystrophy (EDMD).37Bione S. Maestrini E. Rivella S. et al.Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy.Nat Genet. 1994; 8: 323-327Crossref PubMed Scopus (710) Google Scholar Subsequently, autosomal mutations in LMNA were found to cause EDMD.38Bonne G. Di Barletta M.R. Varnous S. et al.Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy.Nat Genet. 1999; 21: 285-288Crossref PubMed Scopus (1006) Google Scholar In the following years, many other monogenic diseases, called laminopathies and envelopathies, were attributed to mutations in lamins or their associated proteins, respectively (Table 1).Table 1Human Diseases Linked to Mutations in Genes Encoding Lamins and Their Associated ProteinsDisease [references]Gene(Phenotype MIM number)PhenotypeEmery–Dreifuss muscular dystrophy 37Bione S. Maestrini E. Rivella S. et al.Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy.Nat Genet. 1994; 8: 323-327Crossref PubMed Scopus (710) Google Scholar, 38Bonne G. Di Barletta M.R. Varnous S. et al.Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy.Nat Genet. 1999; 21: 285-288Crossref PubMed Scopus (1006) Google Scholar, 1Gros-Louis F. Dupre N. Dion P. et al.Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia.Nat Genet. 2007; 39: 80-85Crossref PubMed Scopus (212) Google Scholar, 2Liang W.C. Mitsuhashi H. Keduka E. et al.TMEM43 mutations in Emery-Dreifuss muscular dystrophy-related myopathy.Ann Neurol. 2011; 69: 1005-1013Crossref PubMed Scopus (68) Google Scholar, 3Zhang Q. Bethmann C. Worth N.F. et al.Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity.Hum Mol Genet. 2007; 16: 2816-2833Crossref PubMed Scopus (322) Google ScholarLMNA (181350, 616516)aA-type lamins.EMD (310300)cLamin associated proteins.SYNE1 (612998)cLamin associated proteins.SYNE2 (612999)cLamin associated proteins.TMEM43 (614302)cLamin associated proteins.Skeletal myopathy, cardiomyopathy, early contractures, cardiac conduction defectsLimb girdle muscular dystrophy 46Kayman-Kurekci G. Talim B. Korkusuz P. et al.Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: a novel gene related to nuclear envelopathies.Neuromuscul Disord. 2014; 24: 624-633Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar, 47Muchir A. Bonne G. van der Kooi A.J. et al.Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B).Hum Mol Genet. 2000; 9: 1453-1459Crossref PubMed Google ScholarLMNA (159001)aA-type lamins.TOR1AIP1 (617072)cLamin associated proteins.Progressive limb weakness, late contractures, arrhythmogenic cardiomyopathyMuscular dystrophy, congenital 39Mercuri E. Poppe M. Quinlivan R. et al.Extreme variability of phenotype in patients with an identical missense mutation in the lamin A/C gene: from congenital onset with severe phenotype to milder classic Emery-Dreifuss variant.Arch Neurol. 2004; 61: 690-694Crossref PubMed Scopus (87) Google ScholarLMNA (613205)aA-type lamins.Limb and axial muscle weakness and wastingDilated cardiomyopathy, type 1A 48Fatkin D. MacRae C. Sasaki T. et al.Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease.N Engl J Med. 1999; 341: 1715-1724Crossref PubMed Scopus (945) Google Scholar, 4Brodsky G.L. Muntoni F. Miocic S. et al.Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement.Circulation. 2000; 101: 473-476Crossref PubMed Google ScholarLMNA (115200)aA-type lamins.Cardiac dilation, reduced ejection fractionCardiomyopathy, dilated, with hypergonadotropic hypogonadism 5McPherson E. Turner L. 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Cau P. et al.Lamin a truncation in Hutchinson-Gilford progeria.Science. 2003; 300: 2055Crossref PubMed Scopus (896) Google ScholarLMNA (176670)aA-type lamins.Symptoms of premature ageing, alopecia, scleroderma, lipodystrophy, cardiovascular defectsRestrictive dermopathy 56Navarro C.L. De Sandre-Giovannoli A. Bernard R. et al.Lamin A and ZMPSTE24 (FACE-1) defects cause nuclear disorganization and identify restrictive dermopathy as a lethal neonatal laminopathy.Hum Mol Genet. 2004; 13: 2493-2503Crossref PubMed Scopus (262) Google Scholar, 6Navarro C.L. Cadinanos J. De Sandre-Giovannoli A. et al.Loss of ZMPSTE24 (FACE-1) causes autosomal recessive restrictive dermopathy and accumulation of Lamin A precursors.Hum Mol Genet. 2005; 14: 1503-1513Crossref PubMed Scopus (211) Google ScholarLMNA (275210)aA-type lamins.ZMPSTE24 (275210)dLamin processing proteins.Taut facies, intrauterine growth retardation, death within weeks of extrauterine lifeMandibuloacral dysplasia 54Agarwal A.K. Fryns J.P. Auchus R.J. et al.Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia.Hum Mol Genet. 2003; 12: 1995-2001Crossref PubMed Scopus (279) Google Scholar, 7Novelli G. Muchir A. Sangiuolo F. et al.Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C.Am J Hum Genet. 2002; 71: 426-431Abstract Full Text Full Text PDF PubMed Scopus (392) Google ScholarLMNA (248370)aA-type lamins.ZMPSTE24 (608612)dLamin processing proteins.Mandibular hypoplasia, growth restriction, progressive osteolysis, variable lipodystrophy and progeroid symptomsCharcot–Marie–Tooth disease, type 2B1 59De Sandre-Giovannoli A. Chaouch M. Kozlov S. et al.Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse.Am J Hum Genet. 2002; 70: 726-736Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar, 8Goizet C. Yaou R.B. Demay L. et al.A new mutation of the lamin A/C gene leading to autosomal dominant axonal neuropathy, muscular dystrophy, cardiac disease, and leuconychia.J Med Genet. 2004; 41: e29Crossref PubMed Google ScholarLMNA (605588)aA-type lamins.Lower limb motor and sensory neuropathy, pes cavusFamilial partial lipodystrophy, type 2 62Cao H. Hegele R.A. Nuclear lamin A/C R482Q mutation in canadian kindreds with Dunnigan-type familial partial lipodystrophy.Hum Mol Genet. 2000; 9: 109-112Crossref PubMed Google Scholar, 63Shackleton S. Lloyd D.J. Jackson S.N. et al.LMNA, encoding lamin A/C, is mutated in partial lipodystrophy.Nat Genet. 2000; 24: 153-156Crossref PubMed Scopus (541) Google Scholar, 64Speckman R.A. Garg A. Du F. et al.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.Am J Hum Genet. 2000; 66: 1192-1198Abstract Full Text Full Text PDF PubMed Scopus (222) Google ScholarLMNA (151660)aA-type lamins.Abnormal distribution of subcutaneous fat with cushingoid appearance, metabolic defects including diabetes mellitus and hypertriglyceridemiaLeukodystrophy, adult-onset, autosomal dominant 61Padiath Q.S. Saigoh K. Schiffmann R. et al.Lamin B1 duplications cause autosomal dominant leukodystrophy.Nat Genet. 2006; 38: 1114-1123Crossref PubMed Scopus (0) Google ScholarLMNB1 (169500)bB-type lamins.Multiple-sclerosis-like symptoms, autonomic dysfunction, CNS demyelinationProgressive myoclonic epilepsy-9 60Damiano J.A. Afawi Z. 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Osorio F.G. et al.Exome sequencing and functional analysis identifies BANF1 mutation as the cause of a hereditary progeroid syndrome.Am J Hum Genet. 2011; 88: 650-656Abstract Full Text Full Text PDF PubMed Scopus (118) Google ScholarBANF1 (614008)cLamin associated proteins.Variable lipoatrophy, skeletal and cardiac abnormalitiesGreenberg skeletal dysplasia 58Waterham H.R. Koster J. Mooyer P. et al.Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3 beta-hydroxysterol delta 14-reductase deficiency due to mutations in the lamin B receptor gene.Am J Hum Genet. 2003; 72: 1013-1017Abstract Full Text Full Text PDF PubMed Scopus (0) Google ScholarLBR (215140)cLamin associated proteins.Osteochondroplasia, fetal demise, hydropsPelger-Huet anomaly 9Hoffmann K. Dreger C.K. Olins A.L. et al.Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huet anomaly).Nat Genet. 2002; 31: 410-414Crossref PubMed Scopus (208) Google ScholarLBR (169400)cLamin associated proteins.Skeletal defects, epilepsy, developmental delay, abnormal granulocyte nuclear morphologyBuschke-Ollendorff syndrome 57Hellemans J. Preobrazhenska O. Willaert A. et al.Loss-of-function mutations in LEMD3 result in osteopoikilosis, Buschke-Ollendorff syndrome and melorheostosis.Nat Genet. 2004; 36: 1213-1218Crossref PubMed Scopus (295) Google ScholarLEMD3 (166700)cLamin associated proteins.Multiple nevi, osteopoikilosisSpinocerebellar ataxia, autosomal recessive 8 1Gros-Louis F. Dupre N. Dion P. et al.Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia.Nat Genet. 2007; 39: 80-85Crossref PubMed Scopus (212) Google ScholarSYNE1 (610743)cLamin associated proteins.Ataxia, dysarthria, variable muscle atrophyDeafness, autosomal recessive 76 10Horn H.F. Brownstein Z. Lenz D.R. et al.The LINC complex is essential for hearing.J Clin Invest. 2013; 123: 740-750PubMed Google ScholarSYNE4 (615540)cLamin associated proteins.Progressive high-frequency hearing lossArrhythmogenic right ventricular dysplasia 5 49Merner N.D. Hodgkinson K.A. Haywood A.F. et al.Arrhythmogenic right ventricular cardiomyopathy type 5 is a fully penetrant, lethal arrhythmic disorder caused by a missense mutation in the TMEM43 gene.Am J Hum Genet. 2008; 82: 809-821Abstract Full Text Full Text PDF PubMed Scopus (290) Google ScholarTMEM43 (604400)cLamin associated proteins.Arrhythmogenic cardiomyopathy, right ventricular dysplasia, left ventricular enlargementa A-type lamins.b B-type lamins.c Lamin associated proteins.d Lamin processing proteins. Open table in a new tab The laminopathies are characteristically syndromic and frequently have overlapping features. The pleiotropism of lamins and their associated proteins, combined with overlapping phenotypes, reflects their sophisticated regulation, underlying genetic modifiers, and diverse roles in many tissues.39Mercuri E. Poppe M. Quinlivan R. et al.Extreme variability of phenotype in patients with an identical missense mutation in the lamin A/C gene: from congenital onset with severe phenotype to milder classic Emery-Dreifuss variant.Arch Neurol. 2004; 61: 690-694Crossref PubMed Scopus (87) Google Scholar Shared clinical features among laminopathies were initially interpreted as evidence of a single disease process with a spectrum of manifestations,40Capell B.C. Collins F.S. Human laminopathies: nuclei gone genetically awry.Nat Rev Genet. 2006; 7: 940-952Crossref PubMed Scopus (362) Google Scholar but careful mapping of mutations revealed clear associations between mutations in distinct regions of the LMNA gene and different diseases.41McKenna T. Baek J.-H. Eriksson M. Laminopathies.in: Puiu M. Genetic Disorders. IntechOpen, London2013Crossref Google Scholar For example, most patients with type 2 (Dunnigan) familial partial lipodystrophy (FPLD2) carry mutations in exons 7, 8, or 11 (UMD-LMNA mutations database [http://www.umd.be/LMNA]). Most of these mutations change the surface charge of an immunoglobulin-like motif in LMNA, even though the overall integrity of the motif is ma