Disease relevance of LMNA

• A homozygous missense mutation, Arg527His, in the LMNA gene which encodes nuclear lamina proteins lamins A and C has been reported in patients with MAD and partial lipodystrophy [1].
• Nuclear envelope defects associated with LMNA mutations cause dilated cardiomyopathy and Emery-Dreifuss muscular dystrophy [2].
• Autosomal dominant Emery-Dreifuss muscular dystrophy is caused by mutations in the LMNA gene, which encodes lamin A and lamin C. Mutations in this gene also give rise to limb girdle muscular dystrophy type 1B, dilated cardiomyopathy with atrioventricular conduction defect and Dunnigan-type partial lipodystrophy [3].
• Familial partial lipodystrophy is an autosomal dominant disease caused by mutations of the LMNA gene encoding alternatively spliced lamins A and C. Abnormal distribution of body fat and insulin resistance characterize the clinical phenotype [4].
• This results in altered LMNA expression and subsequent impaired adipocyte differentiation, lipodystrophic body habitus, and metabolic disturbances in HIV infected patients receiving HAART [5].
• The prevalence of gestational diabetes and miscarriages was higher in lipodystrophic LMNA-mutated women than previously reported in PCOS women with similar body mass index [6].

High impact information on LMNA

• The protein product of LMNA is lamin A/C, which is a component of the nuclear envelope [7].
• Through a positional cloning approach we have identified five different missense mutations in LMNA among ten kindreds and three individuals with PLD [7].
• Heterozygous mutations in LMNA have recently been identified in kindreds with the variant form of muscular dystrophy (MD) known as autosomal dominant Emery-Dreifuss MD (EDMD-AD; ref. 7) and dilated cardiomyopathy and conduction-system disease (CMD1A) [7].
• This region contains the lamin A/C gene (LMNA), a candidate gene encoding two proteins of the nuclear lamina, lamins A and C, produced by alternative splicing [8].
• We carried out a genome-wide scan with a set of highly polymorphic short tandem-repeats (STR) in individuals from five well-characterized pedigrees and mapped the FPLD locus to chromosome 1q21-22 [9].

Chemical compound and disease context of LMNA

• We linked this phenotype to a novel heterozygous missense mutation in the LMNA, predicting a G602S amino acid substitution in lamin A. This mutation cosegregated with impaired glucose tolerance, insulin resistance, and acanthosis nigricans in the absence of clinical lipodystrophy in the family [10].
• CONCLUSION/INTERPRETATION: We conclude that the LMNA 3408C/T variant probably does not play a role in susceptibility to diabetes or obesity in Pima Indians [11].
• Multiple regression analysis showed that the LMNA 1908T allele tended to be associated with cerebral vascular disease, but was independent of age, hypertension, total cholesterol or triglyceride [odds ratio (OR) 7.03, P=0.0611] [12].
• Response to treatment with rosiglitazone in familial partial lipodystrophy due to a mutation in the LMNA gene [13].
• A competitive inhibitor of leukotriene slow-reacting substance of anaphylaxis, FPL 55712, blocked in a dose-response fashion LTB4-, C5a des arg-, and FMLP-triggered LAI [14].

Biological context of LMNA

• We identified four mutations in LMNA that co-segregate with the disease phenotype in the five families: one nonsense mutation and three missense mutations [8].
• In particular, the study of LMNA, its products and the phenotypes that result from its mutation have provided important insights into subjects ranging from transcriptional regulation, the cell biology of the nuclear lamina and mechanisms of ageing [15].
• Most mutations (7/11) were detected within the LMNA exons encoding the central rod domain common to both lamins A/C [16].
• Since LMNA is regulated by a retinoic acid responsive element (L-RARE) in the promoter region, we propose that indinavir impairs retinoic acid homeostasis and/or interact via the L-RARE within the LMNA promoter [5].
• Lack of mutations in LMNA, its promoter region, and the cellular retinoic acid binding protein II (CRABP II) in HIV associated lipodystrophy [5].

Anatomical context of LMNA

• Mutations in LMNA cause a spectrum of inherited diseases, including autosomal dominant Emery-Dreifuss muscular dystrophy and related striated muscle disorders, partial lipodystrophies, a peripheral neuropathy and progeria syndromes [17].
• Recently, missense mutations of LMNA encoding lamin A/C have been described in FPL providing evidence for a pivotal role of lamin A/C in the regulation of adipocytes [5].
• Patient skin fibroblasts showed nuclei that presented abnormal lamin A/C distribution and a dysmorphic envelope, thus demonstrating the pathogenic effect of the R527H LMNA mutation [18].
• The LMNA gene encoding two nuclear envelope proteins (lamins A and C [lamin A/C]) maps to chromosome 1q21 and has been associated with five distinct pathologies, including Dunnigan-type familial partial lipodystrophy, a condition that is characterized by subcutaneous fat loss and is invariably associated with insulin resistance and diabetes [18].
• Ultrastructural exploration of sciatic nerves of LMNA null (i.e., -/-) mice was performed and revealed a strong reduction of axon density, axonal enlargement, and the presence of nonmyelinated axons, all of which were highly similar to the phenotypes of human peripheral axonopathies [19].

Associations of LMNA with chemical compounds

• RESULTS: We found a homozygous nucleotide substitution, 1718C>T, in exon 11 of the LMNA gene, resulting in substitution of a well-conserved residue serine at position 573 with leucine (S573L) [20].
• CONCLUSIONS: We conclude that two homozygous missense LMNA mutations involving the arginine 527 and alanine 529 residues cause MAD with subtle variations in phenotype [21].
• RESULTS: We now report that both these patients have a novel homozygous missense mutation (c.1586C-->T; c refers to cDNA reference sequence) in LMNA that replaces a well-conserved residue alanine at position 529 to valine [21].
• In 971 participants from the Amish Family Diabetes Study, the H566H polymorphism of LMNA was associated with metabolic syndrome diagnosed according to National Cholesterol Education Program ATP III criteria and also higher mean fasting triglyceride and lower mean high-density lipoprotein-cholesterol concentrations [22].
• On the other hand, the R377L mutation, also located within the rod domain, is a novel mutation, although a histidine substitution instead of leucine (R377H) has been reported previously in an LGMD1B patient [23].

Regulatory relationships of LMNA

• Loss of lamin A/C expression revealed by immuno-electron microscopy in dilated cardiomyopathy with atrioventricular block caused by LMNA gene defects [24].

Other interactions of LMNA

• Few genes have generated as much recent interest as LMNA, LMNB1 and LMNB2, which encode the components of the nuclear lamina [15].
• Chromosomal assignment of human nuclear envelope protein genes LMNA, LMNB1, and LBR by fluorescence in situ hybridization [25].
• Similarly, diverse human progeroid syndromes are caused by mutations in ZMPSTE24 or LMNA genes [26].
• In humans, lamins are encoded by three genetic loci, LMNA, LMNB1 and LMNB2 [17].
• Mutations in the STA gene, encoding the nuclear envelope protein emerin, are responsible for X-linked EDMD, while mutations in the LMNA gene encoding lamins A and C by alternative splicing have been found in patients with autosomal dominant, autosomal recessive, and sporadic forms of EDMD [16].

Analytical, diagnostic and therapeutic context of LMNA

• BACKGROUND: A cohort of 49 nuclear families, 40 with familial DCM and 9 with sporadic DCM (269 subjects, 105 affected), was screened for mutations in LMNA using denaturing high-performance liquid chromatography and sequence analysis [27].
• The LMNA mutation carriers had a significantly poorer cumulative survival compared with non-carrier DCM patients: event-free survival at the age of 45 years was 31% versus 75% in non-carriers [27].
• Immunofluorescence microscopic analysis of the patient's cultured skin fibroblasts revealed nuclear disorganization and abnormal distribution of A-type lamins, similar to that observed in patients harboring other LMNA mutations [28].
• In radiation hybrid mapping LMNA was most significantly linked to SW270 on chromosome 4 (39 cR; LOD = 7.86) [29].
• To identify disease-specific transcripts for EDMD, we applied a leave-one-out (LOO) cross-validation approach using LMNA patient muscle as a test data set, with reverse transcription-polymerase chain reaction (RT-PCR) validations in both LMNA and emerin patient muscle [30].

References