LMNA (lamin A/C; HGNC:6636, NCBI Gene ID 4000) is a human locus mapped to chromosome band 1q22 that encodes type V intermediate filament proteins Lamin A (664 aa precursor cleaved to 646 aa) & Lamin C (572 aa). LMNA acts in nuclear lamina mechanical integrity, LINC-complex mechanotransduction & heterochromatin tethering (LADs), together with Nuclear Lamin Intermediate Filament Proteins, SIRT6 (Chromatin Deacetylase Activated by Lamin A), and WRN (Werner Adult Progeria Helicase Gene). Encodes nuclear lamins A and C; mutated in dilated cardiomyopathy, Emery-Dreifuss muscular dystrophy, and Hutchinson-Gilford progeria syndrome.
Approved Symbol
LMNA
Chromosomal Locus
1q22
Encoded Product
Type V intermediate filament proteins Lamin A (664 aa precursor cleaved to 646 aa) & Lamin C (572 aa)
Over 15 laminopathies including dilated cardiomyopathy (DCM1A), FPLD2 & Hutchinson-Gilford Progeria Syndrome (c.1824C>T; treated by lonafarnib & base editing)
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 12-exon gene on chromosome 1q22 that generates Lamin A and Lamin C via alternative splicing inside exon 10: Lamin C terminates in exon 10, whereas Prelamin A extends through exons 11 and 12 to terminate in a C-terminal -CSIM CaaX box that undergoes farnesylation, RCE1 cleavage, ICMT carboxymethylation, and mandatory endoproteolytic removal of the terminal 15 farnesylated residues by ZMPSTE24 (FACE1).
Cellular & Tissue Expression Profile: Absent in early pluripotent embryonic stem cells (which express only B-type lamins), and induced upon tissue differentiation to form the dense filamentous meshwork underlying the inner nuclear membrane of almost all differentiated somatic cells, especially cardiomyocytes, skeletal myocytes, adipocytes, and vascular smooth muscle.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Polymerizes via its central alpha-helical coiled-coil rod domain and C-terminal immunoglobulin-like fold into the nuclear lamina, which shields the nucleus from mechanical rupture in contractile tissues (via the LINC nesprin-SUN complex), organizes peripheral transcriptionally silent Lamina-Associated Domains (LADs), and recruits DNA repair and epigenetic factors including SIRT6 and RB1.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Remarkable allelic pleiotropy causing >15 distinct human "laminopathies": truncating or rod-domain variants cause autosomal dominant dilated cardiomyopathy with conduction system disease (DCM1A, the second most common genetic cause of DCM) and Emery-Dreifuss muscular dystrophy; p.Arg482Trp/Gln causes Dunnigan familial partial lipodystrophy (FPLD2); and the de novo silent point mutation c.1824C>T (p.Gly608Gly) in exon 11 activates a cryptic splice donor site that deletes 50 amino acids (including the ZMPSTE24 cleavage site) to produce permanently farnesylated toxic "progerin," causing Hutchinson-Gilford Progeria Syndrome (HGPS).
Therapeutic & Clinical Pharmacology: Farnesyltransferase inhibitor lonafarnib (Zokinvy) became the first FDA-approved therapy for HGPS in 2020 by blocking progerin farnesylation, while splice-switching ASOs (SRP-2001) and in vivo AAV9 adenine base editing (which directly corrects the c.1824C>T mutation back to wild-type C and doubles lifespan in HGPS mice) are advancing toward clinical translation.