laminopathy

Laminopathies and other nuclear envelopathies have a large variety of clinical symptoms including skeletal and/or cardiac muscular dystrophy, lipodystrophy and diabetes, dysplasia, dermo- or neuropathy, leukodystrophy, and progeria (premature aging). Most of these symptoms develop after birth, typically during childhood or adolescence. Some laminopathies however may lead to an early death, and mutations of lamin B1 (LMNB1 gene) may be lethal before or at birth.{{cite journal|vauthors=Vergnes L, Peterfy M, Bergo MO, Young SG, Reue K | title = Lamin B1 is required for mouse development and nuclear integrity | journal = Proc. Natl. Acad. Sci. U.S.A. | year = 2004 | volume = 101 |pages=10428–33 | pmid = 15232008 | doi = 10.1073/pnas.0401424101|issue= 28|pmc= 478588| bibcode = 2004PNAS..10110428V | doi-access = free }}

Patients with classical laminopathy have mutations in the gene coding for lamin A/C (LMNA gene).{{citation needed|date=October 2020}}

Mutations in the gene coding for lamin B2 (LMNB2 gene) have been linked to Barraquer-Simons syndrome{{cite journal | author = Hegele RA, Cao H, Liu DM, Costain GA, Charlton-Menys V, Rodger NW, Durrington PN | year = 2006 | title = Sequencing of the reannotated LMNB2 gene reveals novel mutations in patients with acquired partial lipodystrophy | journal = Am J Hum Genet | volume = 79 | issue = 2 | pages = 383–389 | pmid = 16826530 | doi = 10.1086/505885 | pmc = 1559499 }} and duplication in the gene coding for lamin B1 (LMNB1 gene) cause autosomal dominant leukodystrophy.{{cite journal | author = Padiath QS, Saigoh K, Schiffmann R, Asahara H, Yamada T, Koeppen A, Hogan K, Ptácek LJ, Fu YH | year = 2006 | title = Lamin B1 duplications cause autosomal dominant leukodystrophy | journal = Nat Genet | volume = 38 | issue = 10 | pages = 1114–1123 | doi = 10.1038/ng1872 | pmid = 16951681 | s2cid = 25336497 }}

Mutations implicated in other nuclear envelopathies were found in genes coding for lamin-binding proteins such as lamin B receptor (LBR gene),{{Cite journal |last1=Hoffmann |first1=Katrin |last2=Dreger |first2=Christine K. |last3=Olins |first3=Ada L. |last4=Olins |first4=Donald E. |last5=Shultz |first5=Leonard D. |last6=Lucke |first6=Barbara |last7=Karl |first7=Hartmut |last8=Kaps |first8=Reinhard |last9=Müller |first9=Dietmar |last10=Vayá |first10=Amparo |last11=Aznar |first11=Justo |date=2002-07-15 |title=Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger–Huët anomaly) |url=http://dx.doi.org/10.1038/ng925 |journal=Nature Genetics |volume=31 |issue=4 |pages=410–414 |doi=10.1038/ng925 |pmid=12118250 |s2cid=6020153 |issn=1061-4036|url-access=subscription }}{{Cite journal |last1=Waterham |first1=Hans R. |last2=Koster |first2=Janet |last3=Mooyer |first3=Petra |last4=Noort |first4=Gerard van |last5=Kelley |first5=Richard I. |last6=Wilcox |first6=William R. |last7=Ronald Wanders |first7=J.A. |last8=Raoul Hennekam |first8=C.M. |last9=Jan Oosterwijk |first9=C. |date=April 2003 |title=Autosomal Recessive HEM/Greenberg Skeletal Dysplasia Is Caused by 3β-Hydroxysterol Δ14-Reductase Deficiency Due to Mutations in the Lamin B Receptor Gene |url=http://dx.doi.org/10.1086/373938 |journal=The American Journal of Human Genetics |volume=72 |issue=4 |pages=1013–1017 |doi=10.1086/373938 |pmid=12618959 |pmc=1180330 |issn=0002-9297}}{{Cite journal |last1=Greenberg |first1=Cheryl R. |last2=Rimoin |first2=David L. |last3=Gruber |first3=Helen E. |last4=DeSa |first4=D. J. B. |last5=Reed |first5=M. |last6=Lachman |first6=Ralph S. |last7=Optiz |first7=John M. |last8=Reynolds |first8=James F. |date=March 1988 |title=A new autosomal recessive lethal chondrodystrophy with congenital hydrops |url=http://dx.doi.org/10.1002/ajmg.1320290321 |journal=American Journal of Medical Genetics |volume=29 |issue=3 |pages=623–632 |doi=10.1002/ajmg.1320290321 |pmid=3377005 |issn=0148-7299|url-access=subscription }}{{Cite journal |last=Shultz |first=L. D. |date=2003-01-01 |title=Mutations at the mouse ichthyosis locus are within the lamin B receptor gene: a single gene model for human Pelger-Huet anomaly |journal=Human Molecular Genetics |volume=12 |issue=1 |pages=61–69 |doi=10.1093/hmg/ddg003 |pmid=12490533 |issn=1460-2083|doi-access=free }}{{Cite journal |last1=Young |first1=Alexander Neil |last2=Perlas |first2=Emerald |last3=Ruiz-Blanes |first3=Nerea |last4=Hierholzer |first4=Andreas |last5=Pomella |first5=Nicola |last6=Martin-Martin |first6=Belen |last7=Liverziani |first7=Alessandra |last8=Jachowicz |first8=Joanna W. |last9=Giannakouros |first9=Thomas |last10=Cerase |first10=Andrea |date=2021-04-12 |title=Deletion of LBR N-terminal domains recapitulates Pelger-Huet anomaly phenotypes in mouse without disrupting X chromosome inactivation |url=http://dx.doi.org/10.1038/s42003-021-01944-2 |journal=Communications Biology |volume=4 |issue=1 |page=478 |doi=10.1038/s42003-021-01944-2 |pmid=33846535 |pmc=8041748 |issn=2399-3642}} emerin (EMD gene) and LEM domain-containing protein 3 (LEMD3 gene) and prelamin A-processing enzymes such as the zinc metalloproteinase STE24 (ZMPSTE24 gene).

Mutations causing laminopathies include recessive as well as dominant alleles with rare de novo mutations creating dominant alleles that do not allow their carriers to reproduce before death.{{citation needed|date=October 2020}}

The nuclear envelopathy with the highest frequency in human populations is Emery–Dreifuss muscular dystrophy caused by an X-linked mutation in the EMD gene coding for emerin and affecting an estimated 1 in 100,000 people.{{citation needed|date=October 2020}}

Lamins are intermediate filament proteins that form the nuclear lamina scaffold underneath the nuclear envelope in animal cells. They are attached to the nuclear envelope membrane via farnesyl anchors and interaction with inner nuclear membrane proteins such as lamin B receptor and emerin. The nuclear lamina appears to be an adaptation to mobility in animals as sessile organisms such as plants or fungi do not have lamins{{cite journal|vauthors=Mans BJ, Anantharaman V, Aravind L, Koonin EV | title = Comparative genomics, evolution and origins of the nuclear envelope and nuclear pore complex | journal = Cell Cycle | year = 2004 | volume = 3 |pages=1612–37 | pmid = 15611647|issue= 12 | doi = 10.4161/cc.3.12.1316 | doi-access = free }} and the symptoms of many laminopathies include muscle defects. Mutations in these genes might lead to defects in filament assembly and/or attachment to the nuclear envelope and thus jeopardize nuclear envelope stability in physically stressed tissues such as muscle fibers, bone, skin and connective tissue.{{cite journal|vauthors=Houben F, Ramaekers FC, Snoeckx LH, Broers JL | title = Role of nuclear lamina-cytoskeleton interactions in the maintenance of cellular strength | journal = Biochim. Biophys. Acta |volume=1773 |issue=5 |pages=675–86 |date=May 2007 |pmid=17050008 |doi=10.1016/j.bbamcr.2006.09.018 |doi-access=free }}

Messenger RNA produced from the LMNA gene undergoes alternative splicing and is translated into lamins A and C. Lamin A undergoes farnesylation to attach a membrane anchor to the protein. This version of the protein is also referred to as prelamin A. Farnesylated prelamin A is further processed into mature lamin A by a metalloproteinase removing the last 15 amino acids and its farnesylated cysteine. This allows lamin A to dissociate from the nuclear envelope membrane and fulfill nuclear functions. Mutations causing laminopathies interfere with these processes on different levels.{{citation needed|date=October 2020}}

Missense mutations in the lamin A/C rod and tail domains are the cause for a wide array of genetic disorders, suggesting that lamin A/C protein contains distinct functional domains that are essential for the maintenance and integrity of different cell lineages. Interaction between lamin A and the nuclear envelope protein emerin appears to be crucial in muscle cells, with certain mutations in lamin mimicking mutations in emerin and causing Emery–Dreifuss muscular dystrophy. Different mutations lead to dominant-negative and recessive alleles. Mutations in the lamin rod domain leading to mislocalization of both lamin A and emerin occur in patients with autosomal dominant forms of muscular dystrophy and cardiomyopathy.{{citation needed|date=October 2020}}

Most lamin B mutations appear to be lethal with mutations in lamin B1 causing death at birth in mice. In 2006, lamin B2 missense mutations were identified in patients with acquired partial lipodystrophy.

The most common mutation in the lamin A/C is the homozygous Arg527His (arginine replaced by histidine at position 527) substitution in

exon 9 of the LMNA gene{{cite journal|vauthors=Novelli G, Muchir A, Sangiuolo F, Helbling-Leclerc A, D'Apice MR, Massart C, Capon F, Sbraccia P, Federici M, Lauro R, Tudisco C, Pallotta R, Scarano G, Dallapiccola B, Merlini L, Bonne G | title = Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C | journal = Am. J. Hum. Genet. | year = 2002 | volume = 71 |pages=426–31 | pmid = 12075506 | doi = 10.1086/341908|issue= 2|pmc= 379176}}

Other known mutations are Ala529Val and Arg527His/Val440Met.{{cite journal |vauthors=Zirn B, Kress W, Grimm T, Berthold LD, etal |year= 2008|title= Association of homozygous LMNA mutation R471C with new phenotype: mandibuloacral dysplasia, progeria, and rigid spine muscular dystrophy.|journal= Am J Med Genet A|volume= 146A|issue= 8|pages= 1049–1054|doi= 10.1002/ajmg.a.32259|pmid=18348272|s2cid= 205309256}} Additionally, some mutations such as Arg527Cys, Lys542Asn, Arg471Cys, Thr528Met/Met540Thr, and Arg471Cys/Arg527Cys, Arg527Leu

result in mandibuloacral dysplasia with progeria-like features.{{cite journal |vauthors=Al-Haggar M, Madej-Pilarczyk A, Kozlowski L, Bujnicki JM, Yahia S, Abdel-Hadi D, Shams A, Ahmad N, Hamed S, Puzianowska-Kuznicka M |year= 2012|title= A novel homozygous p.Arg527Leu LMNA mutation in two unrelated Egyptian families causes overlapping mandibuloacral dysplasia and progeria syndrome.|journal= Eur J Hum Genet|volume= 20|issue= 11|pages= 1134–40|doi= 10.1038/ejhg.2012.77|pmc= 3476705|pmid= 22549407}}

Mutations causing progeria are defective in splicing LMNA mRNA, therefore producing abnormal lamin A protein, also known as progerin. The mutations activate a cryptic splice site within exon 11 of the gene, thereby causing the deletion of the processing site on prelamin A. This results in an accumulation of progerin that is unable to mature into lamin A, leading to misshapen nuclei. Missplicing also leads to the complete or partial loss of exon 11 and results in a truncated prelamin A protein in the neonatal lethal tight skin contracture syndrome.

Since the metalloproteinase STE24 is required to process prelamin A into mature lamin A, mutations in this gene abolishing protease activity cause defects similar to laminopathies caused by prelamin A with truncated processing sites. Symptoms in patients with ZMPSTE24 mutation range from mandibuloacral dysplasia, progeroid appearance, and generalized lipodystrophy to infant-lethal restrictive dermopathy.{{citation needed|date=October 2020}}

In the case of autosomal dominant leukodystrophy, the disease is associated with a duplication of the lamin B gene LMNB1. The exact dosage of lamin B in cells appears to be crucial for nuclear integrity as increased expression of lamin B causes a degenerative phenotype in fruit flies and leads to abnormal nuclear morphology.

Antibodies against lamins are detected in the sera of some individuals with autoimmune diseases.{{cite journal | author = Lassoued K, Guilly MN, Danon F, Andre C, Dhumeaux D, Clauvel JP, Brouet JC, Seligmann M, Courvalin JC | year = 1988 | title = Antinuclear autoantibodies specific for lamins. Characterization and clinical significance | journal = Ann Intern Med | volume = 108 | issue = 6 | pages = 829–3 | doi = 10.7326/0003-4819-108-6-829 | pmid = 3285745 }}

A-type lamins promote genetic stability by maintaining the levels of proteins that have key roles in DNA double-strand break repair during the processes of non-homologous end joining and homologous recombination.{{cite journal |vauthors=Redwood AB, Perkins SM, Vanderwaal RP, Feng Z, Biehl KJ, Gonzalez-Suarez I, Morgado-Palacin L, Shi W, Sage J, Roti-Roti JL, Stewart CL, Zhang J, Gonzalo S |title=A dual role for A-type lamins in DNA double-strand break repair |journal=Cell Cycle |volume=10 |issue=15 |pages=2549–60 |year=2011 |pmid=21701264 |pmc=3180193 |doi=10.4161/cc.10.15.16531 }} Mutations in lamin A (LMNA) cause Hutchinson–Gilford progeria syndrome, a dramatic form of premature aging. Mouse cells deficient for maturation of prelamin A show increased DNA damage and chromosome aberrations and are more sensitive to DNA damaging agents.{{cite journal |vauthors=Liu B, Wang J, Chan KM, Tjia WM, Deng W, Guan X, Huang JD, Li KM, Chau PY, Chen DJ, Pei D, Pendas AM, Cadiñanos J, López-Otín C, Tse HF, Hutchison C, Chen J, Cao Y, Cheah KS, Tryggvason K, Zhou Z |title=Genomic instability in laminopathy-based premature aging |journal=Nat. Med. |volume=11 |issue=7 |pages=780–5 |year=2005 |pmid=15980864 |doi=10.1038/nm1266 |s2cid=11798376 }} The inability to adequately repair DNA damages when A-type lamins are defective is likely responsible for some of the aspects of premature aging.{{citation needed|date=October 2020}}

Currently, there is no cure for laminopathies and treatment is largely symptomatic and supportive. Physical therapy and/or corrective orthopedic surgery may be helpful for patients with muscular dystrophies. Laminopathies affecting heart muscle may cause heart failure requiring treatment with medications including ACE inhibitors, beta blockers and aldosterone antagonists, while the abnormal heart rhythms that frequently occur in these patients may require a pacemaker or implantable defibrillator.{{Cite journal|last1=Captur|first1=Gabriella|last2=Arbustini|first2=Eloisa|last3=Bonne|first3=Gisèle|last4=Syrris|first4=Petros|last5=Mills|first5=Kevin|last6=Wahbi|first6=Karim|last7=Mohiddin|first7=Saidi A.|last8=McKenna|first8=William J.|last9=Pettit|first9=Stephen|date=2017-11-25|title=Lamin and the heart|journal=Heart|volume=104|issue=6|pages=468–479|doi=10.1136/heartjnl-2017-312338|issn=1468-201X|pmid=29175975|s2cid=3563474|url=https://hal.sorbonne-universite.fr/hal-03285171/file/Captur%20et%20al.%20-%202018%20-%20Lamin%20and%20the%20heart.pdf}} Treatment for neuropathies may include medication for seizures and spasticity.{{citation needed|date=October 2020}}

The recent progress in uncovering the molecular mechanisms of toxic progerin formation in laminopathies leading to premature aging has opened up the potential for the development of targeted treatment. The farnesylation of prelamin A and its pathological form progerin is carried out by the enzyme farnesyl transferase. Farnesyl transferase inhibitors (FTIs) can be used effectively to reduce symptoms in two mouse model systems for progeria and to revert the abnormal nuclear morphology in progeroid cell cultures. Two oral FTIs, lonafarnib and tipifarnib, are already in use as anti-tumor medication in humans and may become avenues of treatment for children with laminopathic progeria. Nitrogen-containing bisphosphate drugs used in the treatment of osteoporosis reduce farnesyldiphosphate production and thus prelamin A farnesylation. Testing of these drugs may prove them to be useful in treating progeria as well. The use of antisense oligonucleotides to inhibit progerin synthesis in affected cells is another avenue of current research into the development of anti-progerin drugs.{{cite journal|vauthors=Rusinal AE, Sinensky MS | title = Farnesylated lamins, progeroid syndromes and farnesyl transferase inhibitors | journal = J. Cell Sci. | year = 2006 | volume = 119 |pages=3265–72 | pmid = 16899817 | doi = 10.1242/jcs.03156|issue= Pt 16| doi-access = free }}{{cite journal|vauthors=Meta M, Yang SH, Bergo MO, Fong LG, Young SG | title = Protein farnesyltransferase inhibitors and progeria | journal = Trends Mol. Med. | year = 2006 | volume = 12 |pages=480–7 | pmid = 16942914 | doi = 10.1016/j.molmed.2006.08.006|issue= 10}}

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{{Cytoskeletal defects}}

Category:Muscular disorders

Category:Neurological disorders

Category:Muscular dystrophy

Category:Medical conditions related to obesity

Category:Diabetes

Category:Cytoskeletal defects

Category:Genetic diseases and disorders