The LMNA gene at gene at 1q21.2 codes for lamin A and lamin C by alternate splicing of the 664 amino acid pro-prelanin A/C which is processed also to active prelamin A/C. These are developmentally heavily regulated and are two of the intermediate filament proteins that are the major structural proteins of the nuclear lamina.
Increased phosphorylation of lamins occurs before envelope disintegration and probably plays a role in regulating lamin associations.
Proteolytic cleavage of the C-terminal of 18 residues of prelamin-A/C results in the production of lamin-A/C. The prelamin-A/C maturation pathway includes 4 processing steps which have been well characterised because deficiencies cause a large number of genetic disorders. These are:
- A 15-carbon farnesyl lipid is added to the thiol group of a cysteine four from the chain end by a cytosolic enzyme, protein farnesyltransferase.
- The last three amino acids of the protein are removed by a mechanism involving CAAX prenyl protease 1 homolog and NEDD8-conjugating enzyme Ubc12 both of which can act as CAAX endoproteases.
- The exposed farnesylcysteine is carboxyl-methylated by protein-S-isoprenylcysteine O-methyltransferase, a prenylprotein-specific methyltransferase of the endoplasmic reticulum.
- The last 15 amino acids of the protein, including the farnesylcysteine methyl ester, are clipped off by CAAX prenyl protease 1 homolog and degraded, releasing mature lamin A.
Sumoylation is necessary for the localization to the nuclear envelope. Farnesylation of prelamin-A/C facilitates nuclear envelope targeting.
The two lamins coded for are critical developmentally and have a wide range of function. They are components of the nuclear lamina, and play an important role in nuclear assembly, chromatin organization, nuclear membrane and telomere function. Active lamin A/C is required for development of peripheral nervous system, skeletal muscle, bones (osteoblasts) and for muscle satellite cell proliferation. They prevent fat infiltration of muscle and bone marrow. Prelamin-A/C variants can accelerate smooth muscle cell senescence by disrupting mitosis and allowing DNA damage in vascular smooth muscle, leading to various forms of progeria.
- Hutchinson-Gilford syndrome (HGPS)
- Restrictive dermopathy (RD, Lethal tight skin contracture syndrome)
- Werner syndrome (WRN)
- Emery-Dreifuss muscular dystrophy type 2 (EDMD2)
- Emery-Dreifuss muscular dystrophy type 3 (EDMD3)
- Limb-girdle muscular dystrophy type 1B (LGMD1B)
- Charcot-Marie-Tooth disease type 2B1 (CMT2B1)
- Cardiomyopathy dilated type 1A (CMD1A)
- Cardiomyopathy dilated with quadriceps myopathy (CMDQM)
- Familial atrial fibrillation (ATFB)
- Generalized lipoatrophy associated with diabetes, hepatic steatosis, hypertrophic cardiomyopathy and leukomelanodermic papules (LDHCP)
- Familial partial lipodystrophy type 2 (FPLD2)
- Mandibuloacral dysplasia with type A lipodystrophy (MADA)
- Tendinous calcinosis arthropathy and progeroid features (TCAPF)