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Laminopathies ( + ) are a group of rare caused by in genes encoding proteins of the nuclear lamina. Since the first reports of laminopathies in the late 1990s, increased research efforts have started to uncover the vital role of nuclear envelope proteins in cell and tissue integrity in animals. Laminopathies are a group of degenerative diseases, other disorders associated with inner nuclear membrane proteins are known as nuclear envelopathies.
Mutations in the gene coding for lamin B2 (LMNB2 gene) have been linked to Barraquer-Simons syndrome and duplication in the gene coding for lamin B1 (LMNB1 gene) cause autosomal dominant leukodystrophy.
Mutations implicated in other nuclear envelopathies were found in genes coding for lamin-binding proteins such as lamin B receptor (LBR gene), 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 gene as well as Dominant gene with rare de novo mutations creating dominant alleles that do not allow their carriers to reproduce before death.
The nuclear envelopathy with the highest frequency in human populations is Emery–Dreifuss muscular dystrophy caused by an Sex linkage mutation in the EMD gene coding for emerin and affecting an estimated 1 in 100,000 people.
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 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.
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.
Point mutations
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
Other known mutations are Ala529Val and Arg527His/Val440Met. Additionally, some mutations such as Arg527Cys, Lys542Asn, Arg471Cys, Thr528Met/Met540Thr, and Arg471Cys/Arg527Cys, Arg527Leu
result in mandibuloacral dysplasia with progeria-like features.
Splicing defects
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.
Processing defects
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.
Gene dosage effects
In the case of autosomal dominant leukodystrophy, the disease is associated with a duplication of the lamin B gene LMNB1. The exact Gene dosage of lamin B in cells appears to be crucial for nuclear integrity as increased expression of lamin B causes a degenerative phenotype in Drosophila and leads to abnormal nuclear morphology.
Autoimmune antibodies
Antibodies against lamins are detected in the sera of some individuals with autoimmune diseases.
DNA repair
A-type 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. 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. The inability to adequately repair DNA damages when A-type lamins are defective is likely responsible for some of the aspects of premature aging.
Diagnosis
Types of known laminopathies and other nuclear envelopathies
2003 2006 2004 Cardiomyopathy || Lamin A/C || 1999> 2003 2002 1996, 2000 1999 2000 2002 2003 2003 2006 2000 2003 2002 2003 2002 2004 2021
Treatment
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 Cardiac muscle may cause heart failure requiring treatment with medications including , and aldosterone antagonists, while the Heart arrhythmia that frequently occur in these patients may require a pacemaker or implantable defibrillator. Treatment for neuropathies may include medication for and spasticity.
Research
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 to inhibit progerin synthesis in affected cells is another avenue of current research into the development of anti-progerin drugs.
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