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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 1 59-65
Copyright © 2001 by The Endocrine Society

From the Clinical Research Centers

Phenotypic Heterogeneity in Patients with Familial Partial Lipodystrophy (Dunnigan Variety) Related to the Site of Missense Mutations in Lamin A/C Gene1

Abhimanyu Garg, Maheswari Vinaitheerthan, Paul T. Weatherall and Anne M. Bowcock

Center for Human Nutrition (A.G., M.V.), Department of Internal Medicine (A.G.) and Radiology (P.T.W.), University of Texas Southwestern Medical Center, Dallas, Texas 75390; and Division of Human Genetics, Departments of Genetics and Pediatrics, Washington University School of Medicine (A.M.B.), St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: Dr. Abhimanyu Garg, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9052. E-mail: Abhimanyu.Garg{at}utsouthwestern.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The lamin A/C (LMNA) gene has recently been reported to be mutated in familial partial lipodystrophy, Dunnigan variety (FPLD). We found mutations within exon 8 of LMNA (R482Q, R482W, and G465D) in 12 families with typical FPLD and in exon 11 (R582H) in 1 atypical family. To investigate phenotypic heterogeneity, we compared body fat distribution, using anthropometry and whole body magnetic resonance imaging, and metabolic parameters in women with atypical and typical FPLD. Compared with women with typical FPLD, the two sisters with atypical FPLD had less severe loss of sc fat from all the extremities and trunk and particularly from the gluteal region and medial parts of proximal thighs. Both types had similar excess of fat deposition in the neck, face, intraabdominal, and intermuscular regions. Women with atypical FPLD tended to have lower serum triglyceride and higher high density lipoprotein cholesterol concentrations. As exon 11 of LMNA does not comprise part of the lamin C-coding region, the R582H mutation affects only lamin A protein. Therefore, a unique phenotype of atypical FPLD may result from disrupted interaction of lamin A with other proteins and chromatin compared with typical FPLD, in which interaction of both lamins A and C may be disrupted.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
FAMILIAL PARTIAL lipodystrophy, Dunnigan variety (FPLD; Mendelian Inheritance in Man no. 151660) is a rare autosomal dominant disorder characterized by gradual atrophy of sc adipose tissue from the extremities and trunk starting at puberty, but with excess fat accumulation on the face and neck (1). Affected subjects, particularly women, are predisposed to metabolic complications of insulin resistance such as glucose intolerance, diabetes mellitus, hypertriglyceridemia, reduced concentrations of high density lipoprotein (HDL) cholesterol, and atherosclerotic vascular disease (2). We had previously localized the gene for FPLD to human chromosome 1q21–22 (3). Recently, several missense mutations in the lamin A/C (LMNA) gene were reported in FPLD (4, 5, 6). All mutations except one reported to date (G465D, R482Q, R482W, R482L, and K486N) lie within exon 8 of the LMNA gene and affect both lamin A and C splice forms. However, one mutation, R582H, reported by us in pedigree F2700 was in exon 11 and affects only lamin A. We, hypothesized that mutations affecting both splice forms, lamins A and C, result in more severe phenotypic abnormalities than the mutation in exon 11 that affects only lamin A.

Physical examination of the 2 affected sisters in the F2700 family revealed some atypical features compared with the affected women belonging to pedigrees with mutations in exon 8 of LMNA gene (typical FPLD). To further investigate the phenotypic heterogeneity in FPLD, we compared physical features, body fat distribution as assessed by anthropometry and magnetic resonance imaging in the two sisters, and metabolic parameters related to insulin resistance among 3 females with atypical FPLD to those in 20 women with typical FPLD.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Informed written consent approved by appropriate institutional review board was obtained from all subjects. Prepubertal subjects were excluded from this comparison because phenotype is not fully expressed in them. All FPLD pedigrees (F200, F300, F500, F700, F1100, F1400, F2600, F2700, and F2900) have been previously published (3, 6). Of the 20 women with typical FPLD, 1 had the G465D mutation, 4 had the R482Q mutation, and 15 had the R482W mutation. Three affected women from the F2700 family had the R582H mutation. As F2700 had only 1 affected male subject, we did not compare his data with those for other men with typical FPLD. F100 and F600 have been excluded because we have not detected the LMNA mutation in those pedigrees (6). Other pedigrees (F900, F1000, F2500, and F3300) were excluded for lack of access to clinical and laboratory data from other investigators. Clinical data included history and physical examination, review of their medical records, responses to a written questionnaire, telephone interviews, and inspection of photographs when available as detailed previously (2, 3). Several subjects from F200, F300, F1100, F1400, F2600, and F2700 pedigrees were evaluated at the General Clinical Research Center of the University of Texas Southwestern Medical Center at Dallas; information and blood samples on others were obtained by mail as described previously (2).

Two affected females, F2700.7 and F2700.9, visited the General Clinical Research Center at Dallas. An affected female, F2700.2, and an affected male, F2700.9, were unable to visit Dallas, but responded to the written questionnaire, and their blood samples were collected by mail. The clinical features of these subjects with atypical FPLD were as follows.

F2700.2. The mother of the proband, a 60-yr-old woman, was asymptomatic and reported muscular arms and legs, but no prominent veins on the extremities. She attained menarche at age 13 yr and had irregular menstrual periods until hysterectomy at age 48 yr. She had smoked about two packs of cigarettes per day for the past 45 yr. She reported no acanthosis nigricans.

F2700.7. The proband, a 34-yr-old white woman first noted well defined muscles in the arms and legs after puberty. Her menstrual periods have been irregular since menarche at age 10 yr. After her first pregnancy at age 19 yr, she developed fatigue and generalized aches. The second pregnancy was complicated by toxemia. She underwent cholecystectomy at age 21 yr and surgery for left carpal tunnel syndrome at age 25 yr. She took estrogen therapy for irregular menstrual periods from age 27–31 yr. At age 32 yr, diabetes mellitus was diagnosed. She was also noted to have moon face and buffalo hump; however, investigation for Cushing’s syndrome revealed no hypercortisolemia. She was also noted to have a peptic ulcer, a benign thyroid adenoma, depression, and chronic headaches. Physical examination revealed reduced fat and prominent muscles on the upper and lower extremities. Excess fat was noted on the face, chin, neck, supraclavicular region, dorsocervical area, back of the trunk, and medial parts of the thighs (Figs. 1Go and 2Go). The liver was palpable 2 cm below the costal margin, and an umbilical hernia was present. She had no hirsutism, virilization, or acanthosis nigricans.



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  		Figure 1. The left panel shows an anterior view of the lower extremities and abdomen of a woman (F2700.7) with atypical FPLD, demonstrating a moderate lack of sc fat from the legs causing increased muscularity, but without prominent veins. Excess fat deposition is evident in the proximal thigh under the inguinal region extending medially. Labia majora are not prominent. The right panel shows a similar view of an affected woman, F300.7, with typical FPLD, demonstrating marked absence of sc fat causing prominence of muscles and veins in the legs and abdomen. Labia majora are prominent.

 


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  		Figure 2. The left panel shows a posterior view of the lower extremities and gluteal region of a woman (F2700.7) with atypical FPLD, demonstrating a moderate lack of sc fat from the legs causing increased muscularity. Fat deposition in the gluteal region appears normal. The right panel shows a similar view of an affected woman (F300.7) with typical FPLD, demonstrating a marked absence of sc fat from the legs and gluteal region.

 
F2700.9. This 33-yr-old brother of the proband was asymptomatic and reported having muscular arms and legs and prominent veins. He had smoked 1.5 packs of cigarette a day since age 13 yr. He consumed approximately 30 g ethanol/week. He reported no acanthosis nigricans. His fasting serum cholesterol, triglyceride, and HDL cholesterol concentrations were 5.51, 1.06, and 1.27 mmol/L, respectively. The fasting serum insulin concentration was 23 pmol/L, and blood hemoglobin A1c was 5.2%.

F2700.10. This 32-yr-old sister of the proband noticed muscular arms and legs when she was in high school, but was asymptomatic. She had normal menstrual periods since menarche at age 11 yr. Physical examination revealed lack of fat from both the upper and lower extremities, but excess fat in the chin, supraclavicular fosse, and medial thigh. Some sc fat was noted in the gluteal region and upper arm. The fat distribution was similar to that of the proband. She had no acanthosis nigricans, virilization, or hirsutism, but had acne vulgaris on the posterior-superior area of chest.

Anthropometric measurements

In the subjects evaluated in Dallas, height and body weight were measured using standard procedures. Skinfold thickness was measured with a Lange caliper (Cambridge Scientific Industries, Cambridge, MD) at five truncal (chest, midaxillary, abdominal, subscapular, and suprailiac) and six peripheral (biceps, triceps, forearm, hip, thigh, and calf) sites on the right side of the body and at the chin. The mean of three repeat measurements at each site was calculated.

Magnetic resonance imaging (MRI) technique

MRI studies in the two affected women with atypical FPLD belonging to F2700 and the three affected women with typical FPLD belonging to F1400 and F2600 were performed using a 1.5 Tesla imaging device (Philips Medical Systems, Best, The Netherlands) using 5.2-2 software. The patients were evaluated using 10-mm thick T1 imaging techniques with TR of 580 ms, a TE of 8 ms, and a 384 x 512 matrix combined with a 45-cm field of view. In three other affected women with typical FPLD belonging to pedigrees F200 and F300, MRI studies were performed using a 0.35 Tesla imaging device (Toshiba America MRI, Inc., South San Francisco, CA) as described previously (7). The comparison images in these three women were also 10 mm T1 weighted (TR/TE = 600/17 ms), but with a lower spatial resolution of approximately 2-mm pixel size. The images of two affected women with atypical FPLD were compared visually with those of women with typical FPLD. The qualitative visual assessment of relative thickness of adipose tissue is not significantly affected by the different imaging devices.

Biochemical analyses

Fasting serum samples were analyzed for cholesterol, triglycerides, HDL cholesterol, and insulin and for other parameters as described previously (2). Blood hemoglobin A1C was measured using ion exchange high performance liquid chromatography (Bio-Rad Laboratories, Inc., Hercules, CA).

Statistical analyses

Because of the limited sample size of affected women with atypical FPLD, descriptive statistics are shown.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The general characteristics of the subjects are given in Table 1Go. Women with atypical FPLD had similar age, weight, height, and body mass index as those with typical FPLD. Historical information and physical examination, which was limited to the two sisters with atypical FPLD, revealed many unique features. First, females with atypical FPLD had less severe loss of sc fat from the extremities and more notably from the trunk and gluteal region compared with those with typical FPLD (Figs. 1Go and 2Go). There was sparing of fat in the most proximal part of the thighs extending medially (Fig. 2Go). Prominence of the labia majora, a characteristic feature in typical FPLD, was not observed in atypical FPLD. Furthermore, all three affected women with atypical FPLD had no acanthosis nigricans or hirsutism. In contrast, one third of affected women with typical FPLD have acanthosis nigricans and two fifths have hirsutism (2). Similar to patients with typical FPLD, both sisters with atypical FPLD had excess sc fat deposition in the face, chin, and supraclavicular region, and the proband also had a buffalo hump.


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  		Table 1. General characteristics and biochemical parameters of female patients with familial partial lipodystrophy, Dunnigan variety (FPLD)

 
Skinfold thickness was measured in the two sisters with atypical FPLD and seven women with typical FPLD. Compared with the normal age-matched women (8), women with atypical and typical FPLD had similar, markedly reduced peripheral skinfold thickness in the biceps, triceps, forearm, anterior thigh, and calf (Fig. 3Go). However, the skinfold thickness of the hips in women with atypical FPLD was markedly increased. Furthermore, compared with the anterior thigh skinfold thickness, the medial thigh skinfold thickness was also markedly increased by 15 and 21 mm in the proband and her sister, respectively, with atypical FPLD. Since making this observation in patients with atypical FPLD, we measured the medial thigh skinfold thickness in one woman with typical FPLD (F300.7) and found it to be similar to her anterior thigh skinfold (Fig. 3Go). Furthermore, because normal values for medial thigh skinfold thickness were not available, we measured the anterior and medial thigh skinfold thicknesses in nine normal, healthy women (age, 21–41 yr) and found those to be similar (mean ± SD, 27 ± 8 and 25 ± 8 mm, respectively; 95% confidence interval of difference, -2 to 5 mm).



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  		Figure 3. Skinfold thickness at various anatomical sites in two women [F2700.7 (triangles) and F2700.9 (squares)] with atypical FPLD. The median values and the range of skinfold thickness from seven women with typical FPLD are shown as circles with whiskers, respectively. The bars represent the median and 10th and 90th percentile values of skinfold thickness for the normal women, aged 18–55 yr (8 ). Patients with atypical FPLD had considerably reduced peripheral skinfold thickness, similar to the women with typical FPLD. However, patients with atypical FPLD had a less profound lack of fat from the medial thigh, gluteal, and truncal regions.

 
Whole body MRI studies revealed only mild to moderate loss of sc adipose tissue in all the extremities in women with atypical FPLD compared with the extreme lack of adipose tissue noted in those with typical FPLD (Fig. 4Go). Women with atypical FPLD had excess sc adipose tissue in the medial aspects of the thighs as well as in the gluteal region. In contrast, patients with typical FPLD had only scant sc adipose tissue in the medial and posterior aspects of the thigh. Patients with both types of FPLD had well preserved intermuscular adipose tissue and moderate degrees of bone marrow fat within normal limits. MRI also revealed fat accumulation in the labia majora and perirectal region in both types of FPLD.



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  		Figure 4. Transaxial T1 (TR/TE = 580 ms/8 ms) MR images at the levels of the thigh (A), calf (B), and arm (C) in a woman (F2700.7) with atypical FPLD demonstrate only slight loss of sc fat from these areas and preservation of intermuscular adipose tissue and moderate bone marrow fat. There is a propensity for excess sc adipose tissue in the medial aspects of the thigh (arrow). Similar T1 (TR/TE = 600/17 ms) images at the level of thigh (D), calf (E), and arm (F) from a woman (F300.7) with typical FPLD show the near-complete absence of sc fat, but the preservation of intermuscular adipose tissue and bone marrow fat. Only scant sc adipose tissue can be seen in the medial and posterior aspects of the thigh.

 
Transaxial abdominal MR images revealed normal amounts of sc and intraabdominal fat in women with atypical FPLD whereas in patients with typical FPLD, marked reduction in sc fat was observed, particularly in the anterior region (Fig. 5Go). As reported previously (7), variable amounts of intraabdominal fat were present in patients with typical FPLD. MRI studies further revealed excess adipose tissue in the face, neck, and chin in both types of FPLD. The proband with atypical FPLD also had excess sc adipose tissue in the dorsocervical region in the midline, causing a buffalo hump. This feature has been noted only in one patient with typical FPLD.



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  		Figure 5. A, A transaxial T1 (TR/TE = 580/8 ms) MR image of the abdomen at the level of kidneys in a woman (F2700.7) with atypical FPLD shows normal amounts of sc and intraabdominal fat. B, A similar T1 (600/17 ms) image from a woman (F300.7) with typical FPLD demonstrates marked reduction in sc abdominal fat to the point of near absence anteriorly. Intraabdominal fat is reduced.

 
Compared with women with typical FPLD, the three women with atypical FPLD tended to have lower levels of serum triglycerides (median, 3.78 and 2.37 mmol/L, respectively) and higher levels of HDL cholesterol (median, 0.83 and 1.02 mmol/L, respectively; Fig. 6Go). Serum cholesterol, glucose, insulin, and uric acid and blood hemoglobin A1c concentrations were similar among women with typical and atypical FPLD.



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  		Figure 6. Fasting serum triglyceride (A) and HDL cholesterol concentrations (B) in patients with typical and atypical FPLD. Each circle is the value for a patient with FPLD. The horizontal bars represent the median values.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We have previously reported a peculiar and unique adipose tissue distribution pattern in three women and one man affected with FPLD using MRI (7). Besides near-total absence of sc fat from all extremities, a variable reduction in sc adipose tissue was noted from the truncal area, more prominent anteriorly than posteriorly. However, intermuscular adipose tissue in the extremities and pelvic region was increased. Another characteristic finding in patients with FPLD was the presence of excess fat in the neck and face. Intraabdominal adipose tissue was present in excess in some patients. Subsequently, we studied three more women with typical FPLD belonging to other pedigrees, and similar findings were noted among them.

We report phenotypic heterogeneity in FPLD patients. Our detailed evaluation of body fat distribution with anthropometry and MRI demonstrates a unique pattern of loss of adipose tissue in patients with atypical FPLD. The medial parts of the proximal thighs and the gluteal region seem to be spared from adipocyte loss, and, in fact, a characteristic fat accumulation was noted in the medial parts of the proximal thighs under the inguinal ligament. The MRI studies revealed that even in the distal extremities, the sc fat loss in patients with atypical FPLD was not as severe as in those with typical FPLD. Furthermore, in contrast to variable sc fat loss from the truncal region in patients with typical FPLD, there was no evidence of sc fat loss in patients with atypical FPLD.

Besides differences in body fat distribution in women with typical and atypical FPLD, MRI studies revealed common features, such as excess of fat in the face, neck, intraabdominal region, and intermuscular areas. As our findings of atypical body fat distribution are limited to one pedigree, F2700, whether other patients with the same mutation, R582H, in LMNA or other mutations mainly in exons 11 and 12, which affect lamin A only, will have a similar phenotype remains to be investigated. Furthermore, whether men affected with atypical FPLD also have a unique adipose tissue distribution requires further study.

Interestingly, we observed a similar excess of fat deposition under the inguinal ligament extending from lateral to medial thigh in two women with multiple symmetric lipomatosis who consumed large quantities of ethanol (9). Patients with multiple symmetric lipomatosis also tend to develop excess fat around the neck, even causing buffalo hump formation. Patients infected with human immunodeficiency virus (HIV) and who develop HIV-1 protease inhibitor-induced lipodystrophy also accumulate excess fat in the neck region, and some of them develop a buffalo hump (10). However, sparing of fat from the proximal thigh region has not been reported among women with HIV-1 protease inhibitor-induced lipodystrophy. Whether these three disorders, namely, atypical FPLD, multiple symmetric lipomatosis, and HIV-1 protease inhibitor-induced lipodystrophy, have any common underlying pathogenetic mechanisms remains to be elucidated.

Compared with patients with typical FPLD, those with atypical FPLD tended to have less severe metabolic complications; their fasting serum triglyceride concentrations were lower and HDL cholesterol concentrations were higher. However, because we studied only a limited number of affected subjects with atypical FPLD, it is not clear whether they have reduced prevalence of impaired glucose tolerance, diabetes mellitus, hyperinsulinemia, hyperuricemia, acanthosis nigricans, hirsutism, and polycystic ovarian syndrome compared with patients with typical FPLD.

The underlying mechanisms by which LMNA mutations result in loss of adipose tissue and a unique body fat distribution in patients with typical or atypical FPLD are not known. LMNA produces lamin A and C through alternative splicing (11). Lamins A and C belong to the intermediate filament protein family and possess a nonhelical N-terminal head followed by central {alpha}-helical coiled coil rod and nonhelical C-terminal tail domains. Lamins A and C dimerize at the rod domains and interact with nuclear chromatin and other proteins of the inner nuclear membrane (12, 13, 14, 15, 16). As mutations in LMNA also cause Emery-Dreifuss muscular dystrophy and idiopathic conduction system disease and cardiomyopathy (17, 18, 19), it seems that specific mutations may cause tissue-specific alterations. Thus, the missense mutations in patients with FPLD may result in adipocyte apoptosis and degeneration by affecting interaction of the mutated lamins with other proteins or by affecting their posttranslational modifications.

Whether the unique pattern of loss of adipose tissue in those subjects with typical and atypical FPLD is related to heterogeneity in expression of various lamins in adipocytes from different anatomical locations remains unclear. Different splice variants of lamin A may be expressed at different levels depending on the cell types (20, 21). Furthermore, studies have shown distinct differences in the nuclear assembly pathways of lamins A and C (21). Thus, it is possible that adipocytes in the medial part of the thigh and gluteal region are spared in atypical FPLD because these adipocytes express more lamin C than lamin A.

We conclude that in typical FPLD, interruption of the interaction of both lamins A and C with other proteins and nuclear chromatin causes a more severe phenotype than that seen in atypical FPLD, in which only lamin A is altered. We conclude further that phenotypic heterogeneity in FPLD may be related to the site of mutations in the lamin A/C gene. Those with mutations in exon 11 of the LMNA gene have mild lipodystrophy with a unique and atypical adipose tissue distribution compared with others with mutations in exon 8.


   Acknowledgments
 
We thank the members of the families studied for their invaluable contribution to this project: Drs. David C. Robbins, Robert A. Kreisberg, Andrea Dunaif, Richard Legro, Irene Sills, Margo Denke, Steven Aronoff, Noralane M. Lindor, Tu T. Nguyen, and Evelyn Cintron for referring their families for investigation; Angela Osborn and Rebecca Cochran for technical help; Beverley Adams-Huet for statistical analyses; and the nursing and dietetic services of the General Clinical Research Center for patient care support.


   Footnotes
 
1 This work was supported in part by the grants from the NIH (R01-DK-54387 and M01-RR-00633), the Moss Heart Foundation, and the Southwest Medical Foundation. Back

Received March 29, 2000.

Revised July 17, 2000.

Accepted September 20, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Dunnigan MG, Cochrane MA, Kelly A, Scott JW 1974 Familial lipoatrophic diabetes with dominant transmission: a new syndrome. Q J Med. 49:33–48.
  2. Garg A 2000 Gender differences in the prevalence of metabolic complications in familial partial lipodystrophy (Dunnigan variety). J Clin Endocrinol Metab. 85:1776–1782.[Abstract/Free Full Text]
  3. Peters JM, Barnes R, Bennett L, Gitomer WM, Bowcock AM, Garg A 1998 Localization of the gene for familial partial lipodystrophy (Dunnigan variety) to chromosome 1q21–22. Nat Genet. 18:292–295.[CrossRef][Medline]
  4. Cao H, Hegele RA 2000 Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet. 9:109–112.[Abstract/Free Full Text]
  5. Shackelton S, Llyod DJ, Jackson SN, Evans R, Niermeijer MF, Singh BM, et al. 2000 LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat Genet. 24:153–156.[CrossRef][Medline]
  6. Speckman RA, Garg A, Du F, Bennett L, Veile R, Arioglu E, et al. 2000 Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A/C. Am J Hum Genet. 66:1192–1198. [Erratum published in Am J Hum Genet 2000; 67:775.][CrossRef][Medline]
  7. Garg A, Peshock RM, Fleckenstein JL 1999 Adipose tissue distribution pattern in patients with familial partial lipodystrophy (Dunnigan variety). J Clin Endocrinol Metab. 84:170–4.[Abstract/Free Full Text]
  8. Jackson AS, Pollock ML, Ward A 1980 Generalized equations for predicting body density of women. Med Sci Sports Ex. 12:175–182.
  9. Chen D, Garg A Regional adipose tissue distribution in multiple symmetric lipomatosis (MSL). 81st Annual Meet of The Endocrine Soc. 1999; 452.
  10. Carr A, Samaras K, Burton S, Law M, Freund J, Chisholm DJ, et al. 1998 A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS. 12:F51—F58.
  11. Lin F, Worman HJ 1993 Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C. J Biol Chem. 268.:16321–16326.
  12. Fisher DZ, Chaudhary N, Blobel G 1986 cDNA sequencing of nuclear lamins A and C reveals primary and secondary structural homology to intermediate filament proteins. Proc Natl Acad Sci USA. 83:6450–6454.[Abstract/Free Full Text]
  13. Foisner R, Gerace L 1993 Integral membrane proteins of the nuclear envelope interact with lamins and chromosomes, and binding is modulated by mitotic phosphorylation. Cell. 73:1267–1279.[CrossRef][Medline]
  14. McKeon FD, Kirschner MW, Caput D 1986 Homologies in both primary and secondary structure between nuclear envelope and intermediate filament proteins. Nature. 319:463–469.[CrossRef][Medline]
  15. Squarzoni S 1998 Immunocytochemical detection of emerin within the nuclear matrix. Neuromuscul Dis. 8:338–344.
  16. Worman HJ, Evans CD, Blobel G 1990 The lamin B receptor of the nuclear envelope inner membrane: a polytopic protein with eight potential transmembrane domains. J Cell Biol. 111:1535–1542.[Abstract/Free Full Text]
  17. Bonne G, Di Barletta MR, Varnous S, et al. 1999 Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy. Nat Genet. 21:285–288.[CrossRef][Medline]
  18. Fatkin D, MacRae C, Sasaki T, et al. 1999 Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J Med. 341:1715–1724.[Abstract/Free Full Text]
  19. di Barletta MR, Ricci E, Galluzzi G, et al. 2000 Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery- Dreifuss muscular dystrophy. Am J Hum Genet. 66:1407–1412.[CrossRef][Medline]
  20. Machiels BM, Zorene AHG, Endet JM, et al. 1996 An alternative splicing product of the lamin A/C gene lacks exon 10. J Biol Chem. 271:9249–9253.[Abstract/Free Full Text]
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A Homozygous Mutation in the Lamin A/C Gene Associated with a Novel Syndrome of Arthropathy, Tendinous Calcinosis, and Progeroid Features
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K. N. Jacob, F. Baptista, H. G. dos Santos, J. Oshima, A. K. Agarwal, and A. Garg
Phenotypic Heterogeneity in Body Fat Distribution in Patients with Atypical Werner's Syndrome Due to Heterozygous Arg133Leu Lamin A/C Mutation
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Peroxisome Proliferator-Activated Receptor-{alpha} Deficiency Does Not Alter Insulin Sensitivity in Mice Maintained on Regular or High-Fat Diet: Hyperinsulinemic-Euglycemic Clamp Studies
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Acquired and Inherited Lipodystrophies
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V. Simha, A. K. Agarwal, E. A. Oral, J.-P. Fryns, and A. Garg
Genetic and Phenotypic Heterogeneity in Patients with Mandibuloacral Dysplasia-Associated Lipodystrophy
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W. A. Haque, E. A. Oral, K. Dietz, A. M. Bowcock, A. K. Agarwal, and A. Garg
Risk Factors for Diabetes in Familial Partial Lipodystrophy, Dunnigan Variety
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I. K. Aronson and V. C. Fiedler
Of Mice and Men: The Road to Understanding the Complex Nature of Adipose Tissue and Lipoatrophy
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C. J. Lelliott, L. Logie, C. P. Sewter, D. Berger, P. Jani, F. Blows, S. O'Rahilly, and A. Vidal-Puig
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