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Lamin A/C (LMNA)


(last modified July 5, 2005)



Lamins are intermediate filament-type proteins which form major components of the nuclear lamina. Lamins form dimers through their rod domain and interact with chromatin and integral proteins of the inner nuclear membrane through binding sites located in their carboxy-terminal globular tail. Mammals have two main type lamins, A and B. B-type lamins B1 and B2 are encoded by two distinct genes, LMNB1 and LMNB2 (Höger et al., 1990). Lamin B3 is germ cell specific protein generated by differential splicing and alternative polyadenylation of the LMNB2 gene (Furukawa & Hotta, 1993). A-type lamins A and C are derived by differential splicing and alternative polyadenylation from one gene, the LMNA gene. Mutations in LMNA have been shown to cause a whole range of human disorders, including autosomal dominant and recessive forms of Emery-Dreifuss muscular dystrophy (EDMD2/3), Limb-Girdle muscular dystrophy (LGMD1B), dilated cardiomyopathy (conduction-system disease, CMD1A), familial autosomal dominant partial lipodystrophy (Dunnigan variety, FPLD), autosomal recessive Charcot-Marie-Tooth disease (CMT2B1), mandibuloacral dysplasia  (MAD),  Hutchinson-Gilford progeria syndrome (HGPS), lipoatrophy with diabetes, hepatic steatosis, hypertrophic cardiomyopathy and leukomelanodermic papules (LDHPC), Werner's syndrome (WRN), cardiocutaneous progeria syndrome (CCPS) and Restrictive Dermopathy (RD).

The lamin A/C gene

Links to other databases:
Gene Symbol nomenclature   LocusLink    OMIM Gene Map   GDB

The LGMB-1B locus was mapped to chromosome 1q11-q21 in .... 

The lamin A/C gene (Gene Symbol LMNA, alternatives CMD1A, EMD2, FPL, FPLD, LFP, LDP1, LMN1, LMNC) maps to chromosome1q21.2-q21.3. The gene is flanked by RAB25 and FLJ12287 (NM_022367). The LMNA gene has 12 exons. The gene measures 57.6 kb. Lamin C is derived from the LMNA gene using an alternative splice site located in intron 10; Lamin C thus differs C-terminally from the lamin A. 

Exon Exon size
(in bp)
Intron size
(in bp)
5' cDNA position Splice after Remarks
lamin A lamin C
86 285 ... - 5' UTR
237 7,286 ... - 5' UTR
112 2,4130 ... - 5' UTR
1 562 15,342 (-212) 2 5' UTR / 356 bp coding
2 157 3,635 357 0
3 126 276 514 0
4 171 211 640 0
5 126 588 811 0
6 221 92 937 2
7 223 484 1158 0
8 108 84 1381 0
9 120 421 1489 0
10 90 744 1609 0
10a 211 - 1609 - 3' UTR / 108 bp coding
11 270 322 1699 0
12 1001 - 1969 - 3' UTR / .. bp coding

Exon: numbering of exons and intron/exon boundaries are according to ... with the first base of the Met-codon counted as position 1 (see Reference Sequence). Exon size: size of exon indicated in basepairs. Intron size: size of intron indicated in kilobasepairs. 5' cDNA position: first base of the exon (according to cDNA sequence reported by ...). Splice after: splicing occurs in between of two coding triplets (0), after the first (1) or the second (2) base of a triplet. Remarks: 5'UTR = 5' untranslated region, 3'UTR = 3' untranslated region.

primers for DNA-amplification

The lamin A/C mRNA

Links to other databases:     UniGene: Hs.77886    RefSeq: NM_170707 (lamin A, isoform 1), NM_005572 (lamin C, isoform 2), NM_170708 (laminAdel10, isoform 3)

On Northern-blot, LMNA RNA expression reveals two clear bands. The upper band represents the lamin A, the lower band the lamin C transcript.

Machiels et al. (1995) detected an irregular A-type lamin protein in intranuclear aggregates of GLC-A1 cells, a lung carcinoma cell line. Later, using RT-PCR specifically directed to the region from exon 6 to 12, the authors (Machiels et al., 1996) detected an alternatively spliced lamin A-type which lacks exon 10 (90 bp smaller). The new isoform, designated lamin Adel10, was present in all RNA's tested (several tissues and cell lines), although at different levels.

The expression of A-type lamins is developmentally regulated. In mouse, A-type lamins are absent from all pre-implantation stage embryonic cells (including embryonal carcinoma cells). Expression appears at about embryonic day 9 within the visceral endoderm and the trophoblast (Stewart & Burke 1987). Later, A-type lamins appear asynchronously in various tissues. In certain cell types the proteins do not appear until after birth (Rober et al. 1989). A few cells, i.e. cells of the immune system, pancreatic islets and Purkinje cells, only express B-type lamins (Rober et al. 1990). These findings indicate that at the cellular level, A-type lamins are nonessential.

primers for RNA-amplification

The lamin A/C protein

Links to other databases:   RefSeq: NP_005563 NP_733821 (lamin A), NP_005563 (lamin C), NP_733822 (laminAdel10)

Lamin A/C is an Intermediate Filament protein. IF proteins are primordial components of the cytoskeleton and the nuclear envelope. They generally form filamentous structures 8 to 14 nm wide. IF proteins are members of a very large multigene family of proteins which has been subdivided in five major subgroups (see SwissProt, PFAM00038); 

Lamin A/C is a type V nuclear lamin. The lamins are components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane which is suggested to provide a framework for the nuclear envelope and may interact with chromatin.

All IF proteins are structurally similar and consist of;

While IF proteins are evolutionary and structurally related, they have limited sequence homologies except in several regions of the rod domain.

Lamin A is a 664 amino acid protein with a molecular weight of 70 kDa (calculated 74,139 Da) and a pI of 7.0 (theoretical pI 7.4). Lamin A consists of a central rod domain flanked by hydrophobic N- and C-terminal domains. After farnesylation at the CAAX-box motif, the 18 most C-terminal amino acids of lamin-A are removed by proteolytic cleavage to generate the mature lamin-A protein (Hennekes & Nigg). Lamin C (572 amino acids) differs from lamin A after amino acid 566, containing an alternative 6 amino acid C-terminal end (VSGSRR). Lamin Adel10 has a Mw of 65 kDa and a pI of 8 (theoretical pI 8.58). It lacks the region encoded by exon 10 , resulting in the loss of an acidic and a polyhistidine domain. 

Lamin A/C contains several protein domains;

amino acids protein domain
1-33 head region, Ser22 phosphorylated in cdc2 pathways
34-388 34-70 coiled region 1A rod domain, suggested binding with lamin B from 35-250, IF-signature aa373-381
71-80 linker 1
81-218 coiled region 1B
219-242 linker 2
243-388 coiled region 2
389-661 tail region
390-550 suggested emerin and LAP2alpha binding between
417-422 nuclear location signal (NLS)
425-539 conserved IF-tail 
566+1_576+6 unique lamin-C C-terminal sequence (VSGSRR)
625 Ser 625, potential phosphorylation site
647-664 C-terminal amino acids removed by proteolytic cleavage after farnesylation at the CAAX-box motif
661-664 CAAX-motif (prenyl group binding site in PROSITE)

Ser22 is phosphorylated in cdc2 pathways (Draetta [1990], Nigg [1992]), inhibiting head-to-tail assembly of lamins (Peter 1990). Mutations in the phosphoacceptor site strongly interfere with lamina disassembly (Heald & McKeon 1990). Lamins A/C form dimers through their rod domain (...). They bind and assemble on the surface of mitotic chromosomes at specific sites on the rod and associate with integral proteins of the nuclear envelope (like lamin-associated polypeptides 1A and 1B, lamin B receptor and emerin).

See also Functionally tested variants.

lamin A/C antibodies

Novelli et al. (2002) describe the use of monoclonal anti-LMNA antibody 4A7 (kindly provided by G. Morris).

lamin A/C and disease: LGMD-1B

Links to other databases:   OMIM: 181350 (EDMD2); 604929 (EDMD3); 159001 (LGMD1B); 115200 (CMD1A); 151660 (FPLD); CMT2B1 (605588); 248370 (MAD); 176670 (HGPS); 608056 (LDHPC); 277700 (WRN); OMIM- (CCPS); OMIM: 275210 (RD)

LGMB-1B is an autosomal dominantly inherited, slowly progressive limb girdle muscular dystrophy. LGMD-1B patients present with slowly progressive pelvic girdle weakness with late involvement of humeral muscles and sparing of the peroneal and tibial muscles, age-related atrioventricular cardiac conduction disturbances and dilated cardiomyopathy. The disease was linked to chromosome 1q11-q21, with maximum LOD-scores >6 at theta=0 (van der Kooi et al., 1997). The region contained the LMNA-gene shown by Bonne et al. to be mutated in the autosomal dominant form of Emery-Dreifuss muscular dystrophy (AD-EDMD). To identify whether or not LGMD1B and AD-EDMD are allelic disorders, Muchir et al. performed a search for mutations in the LMNA gene in patients from three LGMD1B families linked to chromosome 1q11-q21. Mutations were identified in all affected members of the three families: a missense mutation, a deletion of a codon and a splice donor site mutation, respectively (Muchir).

Mutations in lamin A/C have been shown to cause a series of diseases (lamin A/C sequence variation database);

Functionally tested variants

Mutations in the phosphoacceptor site (Ser22...) strongly interfere with lamina disassembly (Heald & McKeon 1990). Mutations in the two segments at either end of the ~45 kDa alpha-helical rod domain showed that these play a crucial role in in the assembly of IF-dimers into higher order oligomers (McCormick [1993], Stuurman [1996]).

The Arg482Gln mutation was tested by Holt et al. (2001) in transfected COS-cells; it did not affect the ability of lamin A to form a nuclear lamina or to interact with the nuclear membrane protein emerin. The consequences of changes in the lamin A/C sequence have also been studied by Brown CA et al. (ASHG-meeting 2002, abstract 2185, Am.J.Hum.Genet. 71: S542). Expression of an EGFP-lamin A fusion protein in mouse C2C12 or monkey COS7 cells showed;

An increased number of irregular shaped fibroblast nuclei have been seen in combination with some LMNA mutations, e.g. Leu140Arg (419T>G) Chen [2003] causing atypical Werner's syndrome.

lamin A/C sequence variations (mutations and polymorphisms)

Animal models

By deleting exons 8-11, Sullivan et al. (1999) generated a LMNA knock-out mouse. The mice lack detectable lamins A/C and show a dystrophic condition related to EDMD, i.e. the appearance of skeletal and cardiac muscle alterations and perturbations of the nuclear envelope.

A mouse knock-out of the Zmpste24 metalloproteinase gene showed defective pre-lamin-A processing; homozygote mice show a phenotype resembling the clinical features observed in HPGS-patients (Mounkes et al.).




Amplified Length Forward primer /
reverse primer
Name Reference
p1 / p2 Machiels
p3 / p4 Machiels

Exonic sequences are in upper case, intronic and gene flanking sequences in lower case and added primer tails in italics. Amplified: region amplified (cDNA Reference Sequence). Length: length of PCR-product in basepairs. Reference: publication describing the primer(s). Forward primer: sequence of forward primer. Reverse primer: sequence of reverse primer. Name: name of the primers.

lamin A/C sequences

similar sequences

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