Table 3:
Mouse models of lamin-related disease.
| Mouse model [references] | Disease Relevance/Affected Tissues |
Model design | Model phenotype | |
|---|---|---|---|---|
| LMNASul/Sul[119,124,143,164,811] | DCM, EDMD, FPLD2/ Striated muscle, bone, liver, pancreas, adipose tissue | LMNA exons 8 through top of exon 11 deleted | Reduced growth from 2–3 weeks of age; abnormal gait and posture, muscular dystrophy, decreased bone mass, cardiomyopathy, reduced subcutaneous fat (lethal by 8 weeks of age) | |
| LMNAGT−/− [122] | DCM, EDMD, FPLD2/ Striated muscle, adipose tissue | Gene trap insertion in LMNA intron 2 | Reduced growth, abnormal gait, muscle weakness, cardiomyopathy, reduced subcutaneous fat, lethal by postembryonic day 16–18 (P16-P18) | |
| LMNAflx/flx CMV-Cre [121] | DCM, EDMD, FPLD2/ Striated muscle, adipose tissue | LoxP sites flanking LMNA exon 2, CMV-Cre drives whole-body LMNA deletion | Similar to LMNASul/Sul and LMNAGT−/− models; lethal by P16-P18 | |
| LMNAflx/flx; Zp3-Cre [125] | DCM, EDMD, FPLD2/ Striated muscle, adipose tissue | LoxP sites flanking LMNA exons 10–11, Zp3-Cre drives whole-body LMNA deletion | Phenotype not described; lethal between P13-P18 | |
| LMNAδ9/δ9 [129,145] | HGPS Skin, bone, adipose tissue |
LMNA L530P; alternative splicing generates truncated protein that remains farnesylated. | Subcutaneous fat loss, osteoporosis, abnormal dentition, thin skin, growth retardation, and shortened lifespan | |
| LMNAG609G/G609G [127] | HGPS Skin, bone, adipose tissue | LMNA G609G; cryptic splice site results in loss of Zmpste24 cleavage site and expression of progerin | Subcutaneous fat loss, alopecia, reduced bone density, kyphosis, thymic and splenic atrophy, reduced lifespan | |
| LMNAHG/+ [128] | HGPS Skin, bone, adipose tissue | LMNA introns 10–11, part of exon 11 removed; loss of Zmpste24 cleavage site and expression of progerin | Heterozygotes exhibited slow weight gain, rib fractures, loss of body fat, reduced lifespan | |
| LMNAnHG/+ [128] | HGPS Skin, bone, adipose tissue | Same as LMNAHG/+ except CAAX mutated to SAAX; non-farnesylated progerin expressed | Heterozygotes exhibited slow weight gain, rib fractures, loss of body fat, and shortened lifespan (less severe LMNAnHG/+) | |
| Zmpste24−/− (Pendas) [130] | HGPS Skin, bone, adipose tissue | Zmpste24−/− exons 2–3 deleted | Weight loss, kyphosis, muscle weakness, alopecia; average lifespan of 20 weeks | |
| Zmpste24−/− (Bergo) [19] | HGPS Skin, bone, adipose tissue | Zmpste24−/− exon 8 deleted | Spontaneous fractures, slow weight gain, alopecia, kyphosis, muscle weakness, average lifespan of 6–7 months | |
| LMNALCO/LCO [135] | HGPS | LMNA intron 11, part of exon 11 removed; lamin C but not prelamin A produced | Homozygotes similar to WT | |
| LMNALAO/LAO [134] | HGPS | LMNA introns 10–11, first 24 bp of exon 12 removed; mature lamin A expressed, not prelamin A or lamin C | Homozygotes similar to WT | |
| H222P LMNA [137,139,155,156] | DCM and EDMD Striated muscle | LMNA H222P (causes EDMD in humans) | Kyphosis, shallow breathing, dilated cardiomyopathy, reduced lifespan; no lipodystrophy | |
| N195K LMNA [138] | DCM Cardiac muscle | LMNA N195K (causes DCM in humans) | Cardiac muscle degeneration, dilated heart chambers, conduction defects; lethal by 12–14 weeks of age | |
| LMNAflx/flx; Villin-Cre [146] | Intestinal epithelium | LoxP sites flanking LMNA exons 10–11, Villin-Cre drives LMNA deletion in intestinal epithelial cells | Slight increase in number of intestinal polyps with ApcMin/+ background | |
| LMNAflx/flx; Alb-Cre [77] | FPLD2 and NAFLD Liver | LoxP sites flanking LMNA exons 10–11, Alb-Cre drives LMNA deletion in hepatocytes | Male-specific liver injury and steatosis, with steatohepatitis and fibrosis after high fat diet | |
| LMNAflx/flx; Cela1-CreERT2 [78] | Pancreas | LoxP sites flanking LMNA exons 10–11, Cela1-CreERT2 drives inducible LMNA deletion in acinar cells | ER stress, increased apoptosis and proliferation, chronic pancreatitis, fibrosis | |
| R482Q LMNA transgenic mice [160,161] | FPLD2 Adipose tissue | LMNA (human) R482Q transgene | Weight plateau at 41 weeks, fat pad loss, hepatic steatosis, thermogenesis defects, adipocyte differentiation defects [160]; TGF-β activation and fibrosis in adipose tissue [161] | |
| Lap2α−/− [24,S12–13] | DCM Striated muscle, epidermal/erythroid progenitor cells | Tmpo/Lap2 exon 4 deleted, eliminates Lap2α expression, preserves other isoforms | Systolic dysfunction, cardiac fibrosis in older mice, hyperproliferation of epidermal and erythroid progenitor cells | |
| Lmnb1−/− (Kim) [113] | Lung, diaphragm, brain | Lmnb1 exon 1 deleted | Delayed embryonic growth, lung/diaphragm defects, microencephaly, respiratory failure, perinatal lethality | |
| Lmnb1Δ/Δ [112,114] | Lung, bone, brain | Gene trap cassette in Lmnb1 intron 5; protein lacks NLS and CAAX motif | Abnormal lung development and bone ossification, microencephaly, respiratory failure, perinatal lethality | |
| Lmnb2−/− (Kim) [113] | Diaphragm, brain | Lmnb2 exon 1 deleted | Brain and diaphragm defects, respiratory failure, perinatal lethality | |
| Lmnb2−/− (Coffinier) [112] | Brain | Lmnb2 exon 1 replaced with lacZ reporter | Abnormal layering of cortical neurons in cerebral cortex, perinatal lethality | |
| Lmnb1−/−; Lmnb2−/− (Kim) [113] | Lung, diaphragm, brain | Lmnb1, Lmnb2 loci deleted | Thin diaphragm, microencephaly, delayed embryonic growth, perinatal lethality | |
| Lmnb1f Lmnb2flx/flx; Emx1-Cre [112] | Forebrain | LoxP sites flanking exon 2 of Lmnb1 and Lmnb2, Emx1-Cre drives forebrain-specific deletion | Cortical atrophy, loss of hippocampal structures, perinatal lethality | |
| Lmnb1flx/flx; Lmnb2flx/flx; K14-Cre [117] | Skin | LoxP sites flanking exon 2 of Lmnb1 and Lmnb2, K14-Cre drives keratinocyte-specific deletion | Normal skin and hair, normal keratinocyte proliferation | |
| Lmnb1flx/flx; Lmb2flx/flx; Alb-Cre [116] | Liver | LoxP sites flanking exon 2 of Lmnb1 and Lmnb2, Alb-Cre drives hepatocyte-specific deletion | Similar to WT; liver chemistries and histology normal | |
| Lmnb1B2/B2[115,S14] | Brain | Lmnb1 locus replaced with Lmnb2 | Cortical neuron layering defect, decreased body mass (less severe than Lmnb1−/−) | |
| Lmnb2B1/B1 [115,S14] | Brain | Lmnb2 locus replaced with Lmnb1 | Normal body mass, slightly decreased brain size, cortical neuron layering defect | |
| Lmnb1CS/CS [118] | Lung, brain | Lmnb1 CAAX motif replaced with SAAX | Cortical layering defect, microencephaly, lung defects, perinatal lethality | |
| Lmnb2CS/CS [118] | Brain | Lmnb2 CAAX motif replaced with SAAX | Similar to WT (normal growth, fertility, lifespan) | |