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LMNA R482Q Mutation in Partial Lipodystrophy Associated with Reduced Plasma Leptin Concentration¹

John P. Robarts Research Institute, London, Ontario, Canada N6A 5K8

Address all correspondence and requests for reprints to: Dr. Robert A. Hegele, Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, 406–100 Perth Drive, London, Ontario, Canada N6A 5K8. E-mail: robert.hegele{at}rri.on.ca

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Mutations in LMNA, which encodes lamins A and C, have been found in patients with autosomal dominant Dunnigan-type familial partial lipodystrophy (FPLD). We analyzed the relationship between plasma leptin and the rare LMNA R482Q mutation in 23 adult FPLD subjects compared with 25 adult family controls with normal LMNA in an extended Canadian FPLD kindred. We found that the LMNA Q482/R482 genotype was a significant determinant of plasma leptin, the ratio of plasma leptin to body mass index (BMI), plasma insulin, and plasma C peptide (P = 0.015, P = 0.0007, P = 0.0004, and P < 0.0001, respectively), but not BMI (P = 0.67). Family members who were heterozygous for LMNA Q482/R482 had significantly lower plasma leptin and leptin:BMI ratio than unaffected R482/R482 homozygotes. Fasting plasma concentrations of insulin and C peptide were both significantly higher in LMNA Q482/R482 heterozygotes than in R482/R482 homozygotes. Multivariate regression analysis revealed that the LMNA R482Q genotype accounted for 40.9%, 48.2%, 86.9%, and 81.0%, respectively, of the attributable variation in log leptin, leptin:BMI ratio, log insulin, and log C peptide (P = 0.013, P = 0.0007, P = 0.0002 and P < 0.0001, respectively). The results indicate that a rare FPLD mutation in LMNA determines the plasma leptin concentration. It remains to be established whether the reduction in leptin results from the reduced adipose tissue mass in FPLD or from another subcellular effect of mutant LMNA. It also remains to be established whether the insulin resistance in FPLD is a consequence of the reduced plasma leptin or of another functional change resulting from mutant LMNA.

	Introduction

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PATIENTS WITH autosomal dominant Dunnigan-type familial partial lipodystrophy (FPLD; OMIM 151660) are born with normal adipocyte distribution, but after puberty experience adipocyte degeneration in their extremities, trunk, and gluteal region (1, 2, 3). Subjects with FPLD have insulin resistance preceding the development of diabetes, which is often associated with dyslipidemia and atherosclerosis. Recently, we discovered that mutant LMNA underlies FPLD in Canadian probands (4). The LMNA gene encodes the nuclear structural proteins lamins A and C (5). Rare mutations in LMNA have been shown to underlie autosomal dominant Emery-Dreifuss muscular dystrophy (EMD2; OMIM 181350), which is characterized by regional and progressive myocyte degeneration (6) and also an autosomal dominant form of dilated cardiomyopathy (CMD1A; OMIM 115200) (7). Our rationale to focus on LMNA as a candidate gene in FPLD was based upon deductive reasoning: FPLD had been mapped to chromosome 1q21-q22 (8), and there was analogy between the specificity of the adipocyte wasting in FPLD and the site-specific cellular degeneration in EMD2 and CMD1A. The relationship between specific LMNA mutations and the wasting of specific cell types in discrete anatomical locations leading to the development of particular neuromuscular, cardiovascular, and metabolic phenotypes is particularly intriguing. However, the mechanisms responsible for these complex interactions are unknown.

Leptin is a 167-amino acid protein that is secreted by adipocytes (9) that has multiple metabolic effects (10). Basal plasma concentrations of leptin are proportional to adipose tissue mass (9, 10, 11). Although plasma leptin has been shown to be significantly decreased in congenital and acquired syndromes of complete lipodystrophy (12, 13), there is surprisingly little information about plasma leptin concentrations in subjects with FPLD. The availability of an extended Canadian kindred with a large number of affected subjects with FPLD due to a specific mutation in LMNA provided a unique opportunity to evaluate plasma leptin in family members stratified according to LMNA genotype. We thus analyzed the relationship among plasma leptin, related quantitative traits, and the rare LMNA R482Q mutation in 23 nondiabetic adult FPLD subjects compared with 25 unaffected family controls with normal LMNA in an extended Canadian kindred.

	Subjects and Methods

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Study subjects

Forty-eight nondiabetic adult subjects, aged 18 yr and older, from an extended Canadian FPLD kindred (4) had sufficient clinical data and adequate plasma and cellular material available for all analyses. Body mass index [BMI; defined as weight (kilograms)/height(meters)²] was determined in all subjects. Each subject was fewer than 10 generations removed from a common ancestral husband-wife pair. Twenty-three subjects (17 females) were heterozygous for the mutant LMNA allele (Q482/R482), and 25 subjects (15 females), almost all of whom were within a second degree relationship of a carrier, were homozygous for the normal allele (R482/R482). Thus, there was an adequate number of genotypically normal adult subjects, LMNA R482/R482 homozygotes, within the family to serve as nonspousal controls for LMNA Q482/R482 heterozygotes in pairwise nonparametric comparisons. Each adult LMNA Q482/R482Q heterozygote had a clinical diagnosis of FPLD.

Biochemical analyses

Plasma samples were obtained after a 12-h fasting period, with informed consent. Exclusion criteria were an inadequate blood sample available for all biochemical and/or genetic determinations. Blood was centrifuged at 2000 rpm for 30 min, and the plasma was stored at -70 C. Concentrations of fasting plasma insulin were determined by RIA (Pharmacia Biotech, Mississauga, Canada). The insulin assay had a sensitivity of 0.4 ng/mL and intra- and interassay coefficients of variation of 5.2% and 8.7%, respectively. Concentrations of C peptide were determined using a RIA (Diagnostic Products, Los Angeles, CA), which has a minimal detection limit of 43 pmol/L and 0% cross-reactivity with insulin. Concentrations of fasting plasma leptin were determined by quantitative enzyme-linked immunoadsorbent assay (Quantikine Human Leptin, R&D Systems, Minneapolis, MN). The leptin assay had a minimal detectable concentration of 0.5 ng/mL, a limit of linearity of 100 ng/mL, and an interassay coefficient of variation 8.3%.

Genetic analysis

The LMNA R482Q genotype was determined as described previously (4). Briefly, genotyping involved amplification of a 1069-bp fragment that contained exon 8, using primers 5'-GCAAGATACACCCAAGAGCC-3' and 5'-ACACCTGGGTTCCCTGTTC-3'. This was followed by digestion of the amplification products with MspI and electrophoresis in 2% agarose. Digestion of the amplification product from the wild-type allele, R482 produced two variant fragments, 480 and 69 bp, in addition to invariant fragments of 381, 81, and 59 bp. Digestion of the product from the mutant allele, Q482, produced a single fragment of 549 bp in addition to the invariant fragments.

Statistical analysis

Statistical analyses were performed using SAS statistical software, version 6.12 (SAS Institute, Inc., Cary, NC). Between-sex differences in clinical traits were assessed using Bonferroni t tests. The association of LMNA genotype with quantitative traits was tested by ANOVA using a general linear model, with levels of significance computed from type III sums of squares, which is most appropriate for an unbalanced study design and reports significance after all covariates are taken into account. The LMNA R482Q genotype was introduced as a dichotomous variable in the analyses of the FPLD family members; subjects had either the Q482/R482 or R482/R482 genotype. Values for BMI and plasma concentrations of leptin, insulin, and C peptide were log transformed, which in each case produced a variable whose distribution was not significantly different from normal. One ANOVA was performed for log-transformed BMI, using LMNA genotype, age, and sex as the independent variables. One ANOVA was performed each for fasting plasma concentrations of leptin, insulin, and C peptide, using the transformed value for each as the dependent variable and using LMNA genotype, age, and sex as the independent variables. We also created a variable defined as the ratio of leptin to BMI (leptin:BMI ratio), as previously reported (14), to intrinsically correct for any variation in leptin that was related to variation in BMI. Confirmatory post-hoc analyses of between-genotype differences were conducted with the nonparametric Kruskal-Wallis ² approximation test of the Wilcoxon rank sums, as previously reported (15). Post-hoc parametric analyses for each sex separately were also conducted, using genotype and age as independent variables.

When LMNA genotype was found to be a significant source of variation for a biochemical trait, the general linear models procedure for least squares means was used to determine the level of significance of differences in pairwise comparisons between LMNA genotype classes. Least squares means, also called population marginal means, are the values for class means after adjustment for all covariates included in the model. Bonferroni adjustments were made to account for multiple pairwise comparisons. For all analyses, the nominal level of statistical significance was taken to be P < 0.05.

The percent contribution of the genotype to variations in the quantitative traits was estimated from partial regression coefficients obtained from multivariate regression analysis. A forward stepwise regression procedure was used to assist in the model building, with the P value for inclusion set at less than 0.15. The dependent variables in each regression analysis included transformed BMI; fasting plasma concentrations of leptin, insulin, and C peptide; and leptin:BMI ratio. The independent variables in the model for each analysis included LMNA genotype, age, and sex. The proportion of variation due to a specific variable was defined as the partial r² due to the variable divided by the total variation of the model accounted for by all variables in the regression analysis.

	Results

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Clinical and biochemical attributes

The clinical and biochemical attributes of the FPLD family members are shown in Table 1. None of the subjects had diabetes, muscular dystrophy, cardiomyopathy, or conduction system disease. None of the study subjects was taking oral hypoglycemic, antihypertensive, or antihyperlipidemic medications. We noted borderline between-sex differences in age and BMI. Women in this study had significantly higher mean concentrations of plasma leptin and leptin:BMI ratios than men. In contrast, mean plasma insulin and C peptide levels were not significantly different between the sexes.

In the 48 adult FPLD family members, ANOVA (Table 2) revealed highly significant associations between LMNA R482Q genotype and log leptin, leptin:BMI ratio, log insulin, and log C peptide (P = 0.015, P = 0.0007, P = 0.0004, and P < 0.0001, respectively). There was no significant association of genotype with log BMI (P = 0.67). These associations were confirmed in an independent post-hoc nonparametric analysis of variance (data not shown). Of the nongenetic covariates, age was not significantly associated with variation in any trait, but sex was significantly associated with log BMI, log leptin, and leptin:BMI ratio (P = 0.043, P = 0.0024, and P = 0.0006, respectively). BMI was significantly associated with log C peptide only (P = 0.0047). When males and females were examined separately, there was no difference in the associations of quantitative traits with LMNA genotype (data not shown).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

The most obvious explanation for the decreased plasma leptin in FPLD subjects with the LMNA Q482/R482 genotype is that it results directly from the deficiency of peripheral adipose tissue mass (9, 10, 11). Leptin has multiple metabolic effects and is a crucial signal for energy balance, adiposity, and reproduction (9, 10, 11). In addition, leptin might regulate the responses to chronic stress and starvation (9). In general, there is a direct correlation between adipose mass and plasma leptin concentration (10, 11). The substantial, but incomplete, adipose tissue loss in FPLD is compatible with the observed reduction of mean plasma leptin to approximately 40% of normal. In contrast, plasma leptin in congenital generalized lipodystrophy (CGL), a more severe phenotype unrelated to LMNA mutations (16), is reduced to about 10% of normal (12, 13). The secretion of leptin from nonadipose tissues, such as gastric epithelium and mammary epithelium (16), could explain the background detectable plasma leptin in CGL subjects. Interestingly, leptin was not reduced in two prepubertal children with FPLD (17), suggesting that low leptin is not an early feature of FPLD. This contrasts with the markedly reduced leptin in children with CGL (12, 13). Using the LMNA markers, we now have the ability to study young presymptomatic members of our Canadian FPLD kindreds. This might help in understanding the temporal relationship between the reduction in leptin and the development of the other clinical and biochemical features of FPLD.

The mechanism(s) underlying the relationship among mutant LMNA, peripheral adipose wasting, reduced leptin, and insulin resistance cannot be resolved by the results of the present study. A key question is whether the reduction in leptin is simply a marker of adipose tissue loss or whether it plays a direct role in the development of insulin resistance in FPLD. Adipose tissue appears to have antidiabetic effects through any of several possible endocrine and/or metabolic mechanisms. For example, adipose tissue can affect insulin sensitivity, including the secretion by adipose of leptin and/or tumor necrosis factor-, both of which affect insulin sensitivity (18, 19, 20). Also, adipose uptake of glucose, triglycerides, and/or free fatty acids (FFA) can affect insulin sensitivity (18, 19, 20, 21). Recently, surgical implantation of physiological amounts of adipose tissue was shown to improve insulin sensitivity in the A-ZIP/F-1 murine model of lipodystrophic diabetes through multiple mechanisms. These included both enhanced glucose uptake by the transplanted fat and increased glucose uptake into the skeletal muscle of transplanted animals (21).

It is possible that the relative deficiency of leptin in FPLD might play a pivotal role in the development of insulin resistance in lipodystrophy. An important proposed function of leptin is to direct the delivery of FFA to adipocytes for uptake and storage as triacylglycerols while limiting delivery of FFA to nonadipocytes, such as liver and skeletal muscle, for ß-oxidation, thereby protecting them from possible lipotoxicity (22). The deficiency of leptin in FPLD could thus increase the risk of exposure of insulin-sensitive nonadipocyte tissues, such as liver and/or skeletal muscle, to FFA. The FFA may be oxidized in preference to glucose by the skeletal muscle via the glucose-fatty acid cycle, resulting in muscle that is resistant to glucose-mediated insulin action (23, 24). Alternatively, the elevated FFA may create insulin resistance by affecting regulatory mechanisms (23, 24), such as transcription, by binding to transcription factors, including peroxisome proliferator-activated receptors (14).

A direct role for leptin deficiency in the pathogenesis of insulin resistance in lipodystrophy was suggested by observations in the aP2-SREBP-1c murine model of lipodystrophic diabetes, in which continuous infusion of low doses of leptin completely reversed the insulin resistance, but not the lipodystrophy (25). Those results provided support for the concept that leptin deficiency can directly result in insulin resistance. However, in a different murine model of lipodystrophic diabetes, the A-ZIP/F-1 mouse, leptin infusion was only minimally effective at reversing the diabetes and insulin resistance (21). Such disparity suggests that there is additional complexity underlying the relationship among adipose tissue mass, leptin, and the development of insulin resistance. The complexity might be related to the particular pathway that becomes deranged as a result of a specific monogenic defect. The role of relative leptin deficiency in contributing to insulin resistance in human FPLD could be resolved by testing whether administration of exogenous leptin, thereby increasing total plasma leptin and leptin:BMI ratio, would improve measures of insulin sensitivity.

It is also possible that the FPLD mutations in LMNA might have pleiotropic subcellular functional effects in other tissues. In addition to producing the peripheral adipose wasting, the FPLD mutations in LMNA might concurrently cause insulin resistance through an unrelated mechanism in the liver or muscle. The mechanism by which mutant LMNA in FPLD alters adipocyte biology, leading to site-specific wasting of adipose tissue, is unknown. It is of interest that two other FPLD mutations alter the same conserved residue in LMNA, namely, R482H and R482W (26), suggesting that there is a very precise relationship between the position of the LMNA mutation and the biological outcome. The LMNA mutations, by affecting charge or hydrophobicity, might destabilize lamin multimers, thereby disrupting the integrity of the nuclear lamina (27). Such disruption may be more pronounced in adipocytes because of tissue differences in the expression of redundant proteins, which might be able to subsume some of the functions of lamin A or C. Alternatively, there may be impaired interactions between mutant lamins and chromatin, nuclear inner membrane integral proteins, transcription factors, and/or other nuclear and cytoplasmic proteins (27). The potential cellular consequences would include impairment of proliferation of preadipocytes, differentiation of mature adipocytes, modulation of apoptosis, or other cellular or metabolic changes that would result in decreased adipose tissue mass (28). Furthermore, any of these functions could also be specifically impaired in insulin-sensitive nonadipocyte tissues, which might contribute to the FPLD phenotype.

In summary, we report a marked monogenic impact of LMNA R482Q on several quantitative metabolic traits, including a decrease in plasma leptin and leptin:BMI ratio, and an increase in plasma insulin and C peptide. Whether the leptin reduction plays a direct role in the pathogenesis of the insulin resistance or is merely a marker of reduced adipocyte mass requires further study. Monogenic disorders of adipocyte biology and insulin resistance, such as FPLD, can theoretically help to elucidate new metabolic pathways and mechanisms for the common forms of obesity and diabetes (16). However, certain aspects of FPLD due to mutant LMNA bespeak the underlying complexity of the pathogenesis of insulin resistance. For instance, in FPLD, the lack of fat is associated with insulin resistance and hyperglycemia, which is in striking contrast to the usual association of increased total body fat with these traits in common obesity. It is possible that the adipose tissue distribution is a crucial determinant of the clinical and metabolic consequences, such as insulin resistance. The findings in FPLD indicate that the components of human energy homeostasis are finely balanced and rigidly controlled. However, the relevance of the mechanism(s) at play in the metabolic derangements of FPLD to common obesity, insulin resistance, and diabetes remains to be established.

	Acknowledgments

 
We thank Drs. N. Forbath, T. J. McDonald, W. Dykeman, M. A. Carlos, and M. C. McSween for referring their patients. Pearl Campbell and Jane Edwards provided excellent technical assistance.

	Footnotes

 
¹ Novel concepts and materials derived from this work have been embodied in U.S. Patent 60/154825 (September 20, 1999). This work was supported by grants from the Medical Research Council of Canada (MT13430) and the Canadian Genetic Diseases Network.

² Career Investigator with the Heart and Stroke Foundation of Ontario.

Received March 14, 2000.

Revised May 15, 2000.

Accepted May 23, 2000.

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