help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Schmidt, H. H.-J.
Right arrow Articles by Brabant, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Schmidt, H. H.-J.
Right arrow Articles by Brabant, G.
The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 5 2289-2295
Copyright © 2001 by The Endocrine Society

Original Studies

Dyslipemia in Familial Partial Lipodystrophy Caused by an R482W Mutation in the LMNA Gene

Hartmut H.-J. Schmidt, Janine Genschel, Peter Baier, Martina Schmidt, Johann Ockenga, Uwe J. F. Tietge, Marcus Pröpsting, Carsten Büttner, Michael P. Manns, Herbert Lochs and Georg Brabant

Charité Campus Mitte, Medizinische Klinik Gastroenterologie, Hepatologie und Endokrinologie (H.H.-J.S., J.G., P.B., M.P., C.B., H.L.), 10098 Berlin, Germany; Abteilung Klinische Endokrinologie (M.S., G.B.) und Abteilung Gastroenterologie und Hepatologie (J.O., U.J.F.T., M.P.M.), Medizinische Hochschule Hannover, 30623 Hannover, Germany

Address all correspondence and requests for reprints to: Dr. Hartmut Schmidt, Med. Klinik Gastroenterologie, Hepatologie, und Endokrinologie, Humboldt Universität, Charité Campus Mitte, 10098 Berlin, Germany. E-mail: hartmut.schmidt{at}charite.de


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Lipatrophic diabetes, also referred to as familial partial lipodystrophy, is a rare disease that is metabolically characterized by hypertriglyceridemia and insulin resistance. Affected patients typically present with regional loss of body fat and muscular hypertrophic appearance. Variable symptoms may comprise pancreatitis and/or eruptive xanthomas due to severe hypertriglyceridemia, acanthosis nigricans, polycystic ovaria, and carpal tunnel syndrome. Mutations within the LMNA gene on chromosome 1q21.2 were recently reported to result in the phenotype of familial partial lipodystrophy. The genetic trait is autosomal dominant. We identified a family with partial lipodystrophy carrying the R482W (Arg482Trp) missense mutation within LMNA. Here we present the lipoprotein characteristics in this family in detail. Clinically, the loss of sc fat and muscular hypertrophy especially of the lower extremities started as early as in childhood. Acanthosis and severe hypertriglyceridemia developed later in life, followed by diabetes. The characterization of the lipoprotein subfractions revealed that affected children present with hyperlipidemia. The presence and severity of hyperlipidemia seem to be influenced by age, apolipoprotein E genotype, and the coexistence of diabetes mellitus. In conclusion, dyslipemia is an early and prominent feature in the presented lipodystrophic family carrying the R482W mutation within LMNA.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
DUNNIGAN AND Köbberling initially reported on patients with familial partial lipodystrophy (FPL) (1, 2). Among the typical features of regional loss of sc fat and muscular hypertrophy, affected patients present with insulin resistance and hyperlipidemia. As affected female subjects usually have more prominent clinical features of disease, it was initially thought to be an X-chromosomal dominant genetic trait. Later, FPL was identified as an autosomal dominant inherited disease linked to chromosome 1q21-q23. Linkage analysis of affected families and direct analysis of candidate genes revealed the LMNA gene as the underlying locus (OMIM 151660) (3, 4). LMNA encodes for the nucleophilic proteins lamin A and lamin C, which are splice variants. It is 24 kb in size and is composed of 12 exons encoding for an intermediate filament protein. Nuclear lamins possess a central {alpha}-helical coiled-coil rod domain, flanked by globular amino-terminal head and carboxyl-terminal tail domains. Hydrophobic repeats within the central rod domain promote formation of the {alpha}-helical coiled-coil dimer, and charged residues along the surface of the coiled-coil dimer promote interactions between rod dimers, thereby producing complex assembly of the filaments (5, 6, 7). Lamin A/C expression appears to be related to the state of the cellular differentiation. In general, well differentiated cells express A-type lamins, whereas undifferentiated cells synthesize low or undetectable levels of A-type lamins (8, 9, 10). Their functional roles have yet to be elucidated in more detail.

Interestingly, missense mutations of the LMNA gene have been reported to cause Emery-Dreifuss muscular dystrophy (OMIM 310100, 181350, and 604929) (11) and dilated cardiomyopathy with conduction system disease (OMIM 115200) (12). Very recently, mutations within LMNA were also shown to cause limb girdle muscular dystrophy with atrioventricular conduction disturbances (OMIM 159001) (13). The mutations causing FPL reported to date are localized within exon 8 at codons 465, 482, and 486. The only reported additional mutation causing partial lipodystrophy is R582H in exon 11, which affects lamin A, but not lamin C (14). The site-specific mutations within the LMNA gene result in various types of diseases, presumably reflecting different functional roles of this gene product.

Hypertriglyceridemia has been reported to be present to a variable degree in some, but not all, patients with FPL (15, 16). The underlying cause has not been elucidated to date. Commonly, hypertriglyceridemia results from secondary causes such as hyperalimentation, alcohol consumption, and diabetes mellitus (17, 18). Inherited forms of severe hypertriglyceridemia can result from defects of the lipoprotein lipase activity, mutations within apolipoprotein (apo) C2, and antibodies against apoC2 (19, 20, 21, 22). However, no additional candidate gene has been identified for inherited forms of combined hyperlipidemia apart from apoE phenotypes (23, 24).

Here we report on a family with hereditary partial lipodystrophy carrying the R482W mutation and describe the age-dependent abnormalities of lipoprotein parameters. These data clearly demonstrate that the R482W mutation of the LMNA gene results in early disturbances in lipoprotein parameters.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Case report

We identified a 36-yr-old white female propositus, who was first admitted to our department for diagnostics of hypertriglyceridemia. The clinical features of this propositus were muscle hypertrophy, especially of the lower legs, generalized lipodystrophy sparing the face and neck, severe myalgia of the lower extremities on exercise and at rest, acanthosis nigricans involving the axillar region, severe hypertriglyceridemia with episodes of eruptive xanthoma, and insulin-resistant diabetes mellitus (Fig. 1Go). Her family history is illustrated in Fig. 2Go (propositus = III-2). Her mother II-2 died at the age of 49 yr due to a myocardial infarction. From her medical records, in addition to severe hypertriglyceridemia, diabetes mellitus, and acanthosis nigricans, myalgia and muscle hypertrophy were reported. The 11-yr-old daughter of the propositus (IV-2) presented with muscle hypertrophy of the lower legs and myalgia without any sign of axillary acanthosis nigricans, hyperinsulinemia, or diabetes mellitus. The brother of the propositus (33 yr old, III-3) had a similar lipodystrophic phenotype, with hypertriglyceridemia, acanthosis nigricans, myalgia, muscle hypertrophy, and insulin-resistant diabetes. His 7-yr-old daughter (IV-4) had a muscle hypertrophic appearance of the lower legs without any other obvious abnormality. The remaining illustrated members of this pedigree are currently under more detailed clinical investigation.



View larger version (145K):
[in this window]
[in a new window]
  		Figure 1. The physical examination of the 36-yr-old propositus revealed muscle hypertrophy and loss of sc fat especially of the lower extremities, acanthosis nigricans of the axilla, and fat accumulation of face and neck.

 


View larger version (9K):
[in this window]
[in a new window]
  		Figure 2. Pedigree of the presented family with inherited partial lipodystrophy carrying the R482W mutation. The propositus is shown as subject III-2. Squares, Males; circles, females; diagonal slash, deceased; blackened square or circle, genetically affected subjects; gray square or circle, clinical diagnosis of partial lipodystrophy.

 
Analytical methods

Plasma cholesterol and triglycerides were quantitated using an enzymatic assay (Roche, Mannheim, Germany). High density lipoprotein (HDL) cholesterol was determined in plasma after precipitation. Classification of type of hyperlipoproteinemia according to the method described by Fredrickson was based on agarose gel electrophoresis (25). In addition, the 90th percentile for triglyceride and low density lipoprotein (LDL) cholesterol serum concentrations were used as criteria according to the results of the Lipid Research Prevalence Study (26). ApoA-I, apoB, and lipoprotein(a) were quantitated by nephelometric assays (Behringwerke, Marburg, Germany) (27).

ApoE genotyping

Depending on point mutations at codons 112 and 158, three alleles of apoE usually occur in humans. We extracted DNA from the studied subjects using a commercially available purification kit (QIAGEN, Hilden, Germany). The relevant region within apoE was amplified by PCR using the sense primer 5'-TAAGCTTGGCACGGCTGTCCAAGGA-3' and the antisense primer 5'-ACAGAATTCGCCCCGGCCTGGTACAC-3'. Subsequently, the product was digested with the restriction enzyme HhaI for 4 h at 37 C. Fragments were analyzed on agarose gels (28).

ApoB 3500 and apoB 3531 mutation

The presence of R3500Q and R3531C mutations was investigated by PCR, followed by digestion with the restriction enzymes MspI and NsiI, respectively (29, 30).

Sequencing of LMNA

Genomic DNA was extracted from whole blood collected in ethylenediamine tetraacetate tubes. The coding regions of lamin A/C were amplified as previously described (12). The sequences used for exons 8 and 9 were: sense primer, 5'-TCA ATT GCA GGC AGG CAG AG-3'; and antisense primer, 5'-CCT CCG ATG TTG GCC ATC AG-3'. DNA sequencing of the amplified exons was performed by cycle sequencing with fluorescent dye terminators on an ABI 310 automatic sequencer (PE Applied Biosystems, Weiterstadt, Germany). The analysis was confirmed by sequencing in both directions.

LDL receptor sequencing and single strand conformation polymorphism (SSCP) analysis

The exons of the LDL receptor gene were amplified using primers described previously (31, 32). For exons 12, 17, and 18, the primers used were described by Nissen et al. (33). SSCP analysis was performed according to the method described by Hobbs et al. (32).

LMNA R482W mutation

The identified R482W mutation of the LMNA gene generates loss of a restriction site for HpaII after PCR amplification of exon 8 (4). The sequence for the forward primer was 5'-TCA ATT GCA GGC AGG CAG AG-3', and that for the reversed primer was 5'-GCT CCC ATC GAC ACC CAA GG-3'. In the absence of the R482W mutation there is a restriction site for HpaII resulting in the fragments of 67 and 98 bp after digestion. In the presence of a heterozygote R482W mutation there is an additional undigested 167-bp fragment.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
We identified a family with lipodystrophy sparing face and neck. Therefore, the description of the propositus and the family is consistent with the Dunnigan and Köbberling variety of familial partial lipodystrophy. Physical examination of the index patient (Fig. 1Go) and her brother revealed masculine-appearing muscle hypertrophy of all extremities and trunk, acanthosis nigricans of the axillae, eruptive xanthomas, spleen and liver enlargement, and carpal tunnel syndrome. There were no signs of muscle weakness of the hypertrophic muscles. The affected adult patients of this family (Fig. 2Go) characteristically present in the sequence of appearance with loss of sc fat of the extremities, muscular hypertrophy especially of the lower legs, acanthosis nigricans, severe hypertriglyceridemia, and insulin-resistant diabetes mellitus. Remarkably, affected members of this family present with severe myalgia, especially after exercise. No sc fat, except mammae, was visible in an abdominal and thoracic magnetic resonance investigation, and there was marked left ventricular myocardial muscle with normal pericardial fat. In addition, axillary fat tissue was detectable as well as near-normal retroperitoneal and mesenterial fat tissues. Neurophysiological investigation confirmed symmetric sensoric carpal tunnel syndrome.

Laboratory tests in propositus III-2 revealed normal white and red blood cell counts; serum parameters showed mild elevations of liver enzymes (GOT, 20 U/L; GPT, 17 U/L; GlDH, 12 U/L; {gamma}-GT, 45 U/L; cholinesterase, 10.2 kU/L) and were otherwise unremarkable, including creatinine kinase and lactate dehydrogenase. Autoantibodies and serological determinations for hepatitis A, B, and C were negative; complement analysis was normal. Lipoprotein lipase and hepatic lipase activities were normal. ApoC-II was qualitatively and quantitatively normal. The patient was euthyroid, and levels of somatotropin, insulin-like growth factor I, 17{alpha}-hydroxyprogesterone, LH, FSH, androgens, sex hormone-binding globulin, basal estradiol, androstenedione, dehydroepiandrosterone sulfate, and catecholamines (serum and urine) were within the normal range as well. The serum lipid profile revealed hyperlipoproteinemia type V combined with decreased levels of HDL cholesterol: serum total cholesterol, 603 mg/dL; triglycerides, 3141 mg/dL; LDL cholesterol, 227 mg/dL; very low density lipoprotein (VLDL) cholesterol, 349 mg/dL; and HDL cholesterol, 27 mg/dL (Table 1Go). On another visit the lipid composition was quantitated after ultracentrifugation. This analysis showed that free and total cholesterol, triglycerides, and phospholipids were dramatically increased within the VLDL fraction. The apoE genotype was 2/3, and lipoprotein(a) was within the normal range. Fasting serum glucose was 6.5 mmol/L (normal, 3.9–5.6 mmol/L), and fasting insulin was 76 µU/mL (normal, <20 µU/mL), Hemoglobin A1c (HbA1c) was increased at 6.9% (normal, 3.5–4.7%). An oral glucose tolerance test showed a hyperglycemic response, with a maximum glucose of 14.2 mmol/L and insulin of 339 µU/mL, both after 120 min. The fasting C peptide level was elevated (4.8 ng/dL; normal range, 1.0–3.0 ng/dL).


View this table:
[in this window]
[in a new window]
  		Table 1. Lipoprotein characteristics in the studied subjects

 
The lipoprotein characteristics of the studied family members are illustrated in Table 1Go. The adult FPL subjects with coexistence of diabetes mellitus (II-2, III-2, III-3, III-15, and III-17) all presented with hypertriglyceridemia; four of these five patients had severe hypertriglyceridemia. Subjects II-2, III-2, and III-3 in addition had decreased HDL cholesterol serum concentrations, which are commonly observed in the hypertriglyceridemic state. The husband of the propositus (subject III-1) had a combined elevation of VLDL and LDL cholesterol, which can be partially explained by the apoE genotype 3/4. Interestingly, among the remaining analyzed R482W gene carriers there was a high frequency of dyslipemia. Subject III-5 presented with pronounced elevation of total and LDL cholesterol, III-10 had markedly elevated triglycerides and VLDL cholesterol; IV-2 had elevated total and LDL cholesterol, triglycerides, and VLDL cholesterol; IV-4 presented with increased LDL cholesterol; and IV-9 had elevated VLDL cholesterol and triglycerides levels. The cut-off points for elevated lipid values were above the 90th percentile according to the Lipid Research Prevalence data based on sex and age (26). We were able to obtain lipid values from 11 subjects carrying the R482W mutation. With the exception of subject IV-7, all of the affected patients studied had dyslipemia. Figure 3Go summarizes the presence of dyslipemia in 10 of 11 R482W gene carriers, whereas 3 of 9 healthy relatives were hyperlipemic. The same figure also illustrates that 5 of 11 R482W gene carriers developed diabetes mellitus, whereas none of the healthy relatives was diabetic.



View larger version (37K):
[in this window]
[in a new window]
  		Figure 3. The numbers of dyslipemic and diabetic subjects with or without the R482W mutation within LMNA in the presented family are illustrated.

 
To extend the lipid analysis, we also studied the lipoprotein(a) serum concentration in these subjects. The affected subjects III-5 and IV-9 as well as the unaffected subject III-16 had elevated lipoprotein(a). Table 1Go also summarizes the type of hyperlipidemia observed in the subjects studied according to the Fredrickson classification (25). The presence of variable types of hyperlipidemia within this pedigree fits the criteria of familial combined hyperlipidemia. As the apolipoprotein E isoform is known to influence lipoprotein serum concentrations, we determined its genotype. These data show that especially the IV generation seems to have a predisposition for dyslipemia in the apoE 2/3 gene carrier. The presence of diabetes is also known to be an additional factor exacerbating hyperlipidemia. The adult subjects II-2, III-2, III-3, III-15, and III-17 carrying the R482W mutation within LMNA and presenting with diabetes mellitus suffered from pronounced hypertriglyceridemia. Therefore, besides the presence of diabetes, age and apoE genotype may play roles in the onset and severity of dyslipemia in subjects carrying the R482W mutation.

Increased cholesterol levels can be due to defects in the LDL receptor gene and the apoB gene. To exclude an abnormality of the LDL receptor in the hypercholesterolemic R482W gene carriers we screened this gene by SSCP and direct sequencing of all exons including the exon/intron boundaries. We observed no abnormalities in the patients studied. In addition, we excluded the presence of apoB 3500 and apoB 3531 mutations in these subjects.

The autosomal dominant inherited partial lipodystrophy in this family is caused by a substitution of arginine to tryptophan within codon 482 (R482W) on exon 8 within LMNA, which has been recently identified (4). Figure 4Go illustrates the direct sequencing results of this region. All family members were subsequently screened for this mutation, confirming the heterozygous mutation in the described patients using direct sequencing and PCR amplification with subsequent restriction digest analysis (Fig. 5Go). These data are reflected in the pedigree depicted in Fig. 2Go.



View larger version (22K):
[in this window]
[in a new window]
  		Figure 4. Sequence analysis of the LMNA gene in the propositus is demonstrated. The upper panel shows the presence of a homozygous arginine at codon 482 in a healthy subject. The lower panel illustrates a heterozygous C->T mutation at codon 482 resulting in a substitution of arginine to tryptophan. A, C, G, and T are the different nucleotides. Y indicates nonrecognizable nucleotides due to a heterozygous mutation.

 


View larger version (60K):
[in this window]
[in a new window]
  		Figure 5. Restriction enzyme analysis in subjects of the pedigree illustrated in Fig. 2Go was performed after agarose gel electrophoresis. Subjects IV-2, III-2, III-5, III-3, IV-4, IV-9, IV-7, III-10, IV-10, III-17, III-15, III-19, and III-7 have an additional 167-bp fragment reflecting the presence of a heterozygote R482W mutation within LMNA.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We report on the lipoprotein characteristics of a family with autosomal dominant inherited partial lipodystrophy (FPL) carrying the R482W mutation within LMNA. The sequence of symptoms starts with loss of sc fat combined with muscular hypertrophy, followed by myalgia and dyslipemia and later by axillary acanthosis nigricans, insulin-resistant diabetes mellitus, and hepatosplenomegaly. In this family the phenotype of the affected subjects is more pronounced in females than in males, which is consistent with previous reports (34).

Several candidate genes have been excluded in FPL (35, 36, 37). Linkage analysis in affected families revealed 1q21 as the genetic locus for FPL. Using the candidate gene approach in this region, Hegele et al. and Trembath et al. identified mutations in the LMNA gene on chromosome 1 in region 1q21.2 to 1q21.3 causing FPL (3). LMNA is encoding lamin A/C. Alternative splicing within exon 10 generates two different messenger ribonucleic acids that code for the human proteins lamin A and lamin C. The A-type (including lamin A and lamin C) and B-type lamins are major components of the nuclear lamina, which are members of the intermediate filament protein family. To date 7 mutations at 4 different sites of 30 unrelated affected subjects have been identified in this gene (3, 4, 14). Interestingly, the mutations are localized within exon 8 at codons 465, 482, and 486. The only additional mutation reported to date that causes partial lipodystrophy is R582H in exon 11, which affects lamin A, but not lamin C (14). All reported mutations present single nucleotide missense mutations. FPL in this reported family is caused by a R482W mutation on exon 8 within LMNA, which is shown by direct sequencing. The subsequent specific restriction enzyme analysis confirmed this mutation and revealed a total of 13 living R482W gene carriers in this family.

Interestingly, the mutations within the LMNA gene can result in familial dilated cardiomyopathy with conduction system disease, Emery-Dreifuss muscular dystrophy, and limb girdle muscular dystrophy (11, 12, 13). The dystrophy of the peripheral and/or cardiac muscle is the striking feature in affected subjects. In contrast to FPL the characteristic presence of dyslipemia and insulin-resistant diabetes mellitus, respectively, has not been reported in these disease entities.

Although dyslipemia is a common feature reported in FPL, there is no report on a detailed lipoprotein characterization including apoE genotyping in an extended family. We identified a family with partial lipodystrophy carrying the R482W mutation within LMNA. The screening of this mutation in 121 living relatives revealed affected subjects without any overt clinical symptoms of FPL. The informative pedigree of this screening is illustrated in Fig. 2Go. Interestingly, our results showed that dyslipemia was present in 10 of 11 tested R482W carriers. Thus, dyslipemia is a common feature in this family. Our data show for the first time that children with FPL develop dyslipemia. The general causes of the inherited dyslipemia were excluded in the patients studied using direct sequencing and SSCP of the LDL receptor gene, PCR analysis of apoB mutants, and analysis of lipoprotein lipase and hepatic lipase activities and apoC2. The severity of the increased levels of cholesterol and triglycerides seems to be dependent on the age of the subjects. In addition, the presence of diabetes in five FPL subjects was associated with hypertriglyceridemia; four of them developed severe hypertriglyceridemia despite good glucose control. All five subjects received antidiabetic treatment resulting in HbA1c within the normal range. Diabetes mellitus was excluded in all other analyzed subjects by the determination of HbA1c and fasting glucose serum concentration. We also determined the apoE genotype in the family members. Depending on the apoE genotype, variable forms of hyperlipoproteinemias may occur. The data suggest that the apoE 2/3 genotype is associated with an earlier onset and a more pronounced form of dyslipemia than that in R482W carriers with an apoE 3/3 genotype. The presence of variable hyperlipoproteinemic phenotypes in the R482W gene carriers is intriguing, because it fits the criteria of familial combined hyperlipidemia. Interestingly, genetic mapping using families with familial combined hyperlipidemia have been shown to be linked with 1q21-q23 (38, 39), which is also supported by studies in mice (40). Combining the findings that the lipoprotein pattern in FPL subjects carrying the R482W mutation within the LMNA gene resembles the definition of familial combined hyperlipidemia, that familial combined hyperlipidemia has been linked to 1q21-q23, and that the LMNA gene causing FPL is also located on 1q21-q23 suggests that lamin A/C may play a role in familial combined hyperlipidemia.

The mechanism by which LMNA may influence the lipoprotein metabolism is very speculative, especially as functional aspects of lamin A/C have not been elucidated in detail. In this respect it is of interest that the LMNA promotor contains a retinol acid-responsive element (41). Retinoids, such as retinol acid, belong to the group of lipophilic hormones (metabolites of vitamin A) that have pleiotropic effects mediated via specific nuclear receptors (42, 43). They have been reported to influence lipoprotein metabolism (44, 45, 46, 47). Thus, the intracellularly interaction of retinoids, their receptors, and their binding proteins with the lamin promotor may be a link. On the other hand, A-type lamins have been shown to bind to specific DNA sequences (48, 49, 50, 51). Therefore, gene expression may be influenced by lamin A/C, which, in turn, may interfere with the regulation of lipoprotein metabolism.

In summary, this reported kindred with autosomal dominant inherited partial lipodystrophy carrying the R482W mutation within LMNA on chromosome 1q21-q23 typically present with regional lipodystrophy, muscular hypertrophy, dyslipemia, and insulin-resistant diabetes. Besides additional features, such as eruptive xanthomata and acanthosis nigricans, the affected subjects of this family complained of significant myalgia. The striking finding is the early onset of dyslipemia in these subjects. Variable forms of dyslipemia exist within this family. The pattern of dyslipemia present in this family is similar to familial combined hyperlipidemia, which has been recently linked to chromosome 1q21-q23. Therefore, LMNA encoding lamin A/C may play a role in the genesis of familial combined hyperlipidemia. As other affected subjects with the same or a similar defect have been reported in the literature, their corresponding phenotype in detail will help to extend our observations. A better understanding of this rare disease may also have broad clinical implications for the pathomechanism of common diseases such as dyslipemia and insulin-resistant diabetes mellitus.


   Acknowledgments
 
We are very thankful for the excellent help of Regina Haas, Regina Tomm, Monika Seifert, Susanne Herschel, Bettina Bochow, and Renita Weltrich with patient care and generating laboratory data. In addition, we greatly appreciate the determination of the lipoprotein and hepatic lipase activity by Ulrike Beisiegel (Medical University, Hamburg, Germany).

Received September 11, 2000.

Revised January 26, 2001.

Accepted January 28, 2001.


   References
Top
 Abstract
 Introduction
 Materials 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. 43:33–48.[Abstract/Free Full Text]
  2. Köbberling J, Willms B, Kattermann R, Creutzfeldt W. 1975 Lipodystrophy of the extremities. A dominantly inherited syndrome associated with lipatrophic diabetes. Humangenetik. 29:111–120.[CrossRef][Medline]
  3. 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]
  4. Shackleton S, Lloyd DJ, Jackson SN, et al. 2000 LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat Genet. 24:153–156.[CrossRef][Medline]
  5. 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]
  6. Herrmann H, Aebi U. 1998 Intermediate filament assembly: fibrillogenesis is driven by decisive dimer-dimer interactions. Curr Opin Struct Biol. 8:177–185.[CrossRef][Medline]
  7. Stuurman N, Heins S, Aebi U. 1998 Nuclear lamins: their structure, assembly, and interactions. J Struct Biol. 122:42–66.[CrossRef][Medline]
  8. Broers JL, Raymond Y, Rot MK, Kuijpers H, Wagenaar SS, Ramaekers FC. 1993 Nuclear A-type lamins are differentially expressed in human lung cancer subtypes. Am J Pathol. 143:211–220.[Abstract]
  9. Gerace L, Burke B. 1988 Functional organization of the nuclear envelope. Annu Rev Cell Biol. 4:335–374.[CrossRef]
  10. Krohne G, Benavente R. 1986 The nuclear lamins. A multigene family of proteins in evolution and differentiation. Exp Cell Res. 162:1–10.[CrossRef][Medline]
  11. 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]
  12. 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]
  13. Muchir A, Bonne G, van der Kooi AJ, et al. 2000 Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B). Hum Mol Genet. 9:1453–1459.[Abstract/Free Full Text]
  14. Speckman RA, Garg A, Du F, 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.[CrossRef][Medline]
  15. Kobberling J, Dunnigan MG. 1986 Familial partial lipodystrophy: two types of an X linked dominant syndrome, lethal in the hemizygous state. J Med Genet. 23:120–127.[Abstract/Free Full Text]
  16. Jackson SN, Howlett TA, McNally PG, O’Rahilly S, Trembath RC. 1997 Dunnigan-Kobberling syndrome: an autosomal dominant form of partial lipodystrophy. Q J Med. 90:27–36.[Abstract/Free Full Text]
  17. Chait A, Brunzell JD. 1990 Acquired hyperlipidemia (secondary dyslipoproteinemias). Endocrinol Metab Clin North Am. 19:259–278.[Medline]
  18. Grundy SM. 1999 Hypertriglyceridemia, insulin resistance, and the metabolic syndrome. Am J Cardiol. 83:25F–29F.
  19. Gotoda T, Yamada N, Kawamura M, et al. 1991 Heterogeneous mutations in the human lipoprotein lipase gene in patients with familial lipoprotein lipase deficiency. J Clin Invest. 88:1856–1864.
  20. Yamamura T, Sudo H, Ishikawa K, Yamamoto A. 1979 Familial type I hyperlipoproteinemia caused by apolipoprotein C-II deficiency. Atherosclerosis. 34:53–65.[CrossRef][Medline]
  21. Breckenridge WC, Little JA, Steiner G, Chow A, Poapst M. 1978 Hypertriglyceridemia associated with deficiency of apolipoprotein C-II. N Engl J Med. 298:1265–1273.[Abstract]
  22. Reckless JP, Stocks J, Holdsworth G, Galton DJ, Suggett AJ, Walton KW. 1982 Studies of a variant very-low-density lipoprotein with an acquired deficiency of apolipoprotein C-II. Clin Sci. 62:93–100.[Medline]
  23. Utermann G, Kindermann I, Kaffarnik H, Steinmetz A. 1984 Apolipoprotein E phenotypes and hyperlipidemia. Hum Genet. 65:232–236.[CrossRef][Medline]
  24. Mamotte CD, Sturm M, Foo JI, van Bockxmeer FM, Taylor RR. 1999 Comparison of the LDL-receptor binding of VLDL and LDL from apoE4 and apoE3 homozygotes. Am J Physiol. 276:E553—E557.
  25. Fredrickson DS. 1971 An international classification of hyperlipidemias and hyperlipoproteinemias. Ann Intern Med. 75:471–472.
  26. Lipid Research Clinics Program Epidemiology Committee. 1979 Plasma lipid distributions in selected North American populations: the Lipid Research Clinics Program Prevalence Study. Circulation. 60:427–439.[Abstract/Free Full Text]
  27. Schmidt HH, Genschel JC, Wagner S, Manns MP. 1996 Quantification of lipoprotein(a): comparison of an automated latex-enhanced nephelometric assay with an immunoenzymometric method. Eur J Clin Chem Clin Biochem. 34:119–124.[Medline]
  28. Hixson J, Vernier D. 1990 Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res. 31:545–548.[Abstract]
  29. Pullinger CR, Hennessy LK, Chatterton JE, et al. 1995 Familial ligand-defective apolipoprotein B. Identification of a new mutation that decreases LDL receptor binding affinity. J Clin Invest. 95:1225–1234.
  30. Hansen PS, Rudiger N, Tybjaerg-Hansen A, Faergeman O, Gregersen N. 1991 Detection of the apoB-3500 mutation (glutamine for arginine) by gene amplification and cleavage with MspI. J Lipid Res. 32:1229–1233.[Abstract]
  31. Ebhardt M, Schmidt H, Doerk T, et al. 1999 Mutation analysis in 46 German families with familial hypercholesterolemia: identification of 8 new mutations. Mutations in brief no. 226. Online Hum Mutat. 13:257.
  32. Hobbs HH, Brown MS, Goldstein JL. 1992 Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat. 1:445–466.[CrossRef][Medline]
  33. Nissen H, Guldberg P, Hansen AB, Petersen NE, Horder M. 1996 Clinically applicable mutation screening in familial hypercholesterolemia. Genome Res. 10:652–658. Hum Mutat. 8:168–177.[Abstract/Free Full Text]
  34. Hegele RA, Anderson CM, Wang J, Jones DC, Cao H. 2000 Association between nuclear lamin A/C R482Q mutation and partial lipodystrophy with hyperinsulinemia, dyslipidemia, hypertension, and diabetes. Genome Res. 10:652–658.
  35. Desbois-Mouthon C, Magre J, Amselem S, et al. 1995 Lipoatrophic diabetes: genetic exclusion of the insulin receptor gene. J Clin Endocrinol Metab. 80:314–319.[Abstract]
  36. Chait A, Janus E, Mason AS, Lewis B. 1979 Lipodystrophy with hyperlipidaemia: the role of insulin in very low density lipoprotein over-synthesis. Clin Endocrinol (Oxf). 10:173–178.[Medline]
  37. Robbins DC, Horton ES, Tulp O, Sims EA. 1982 Familial partial lipodystrophy: complications of obesity in the non-obese? Metabolism. 31:445–452.[CrossRef][Medline]
  38. Pajukanta P, Nuotio I, Terwilliger JD, et al. 1998 Linkage of familial combined hyperlipidaemia to chromosome 1q21–q23. Nat Genet. 18:369–373.[CrossRef][Medline]
  39. Pei W, Baron H, Muller-Myhsok B, et al. 2000 Support for linkage of familial combined hyperlipidemia to chromosome 1q21–q23 in Chinese and German families. Clin Genet. 57:29–34.[CrossRef][Medline]
  40. Castellani LW, Weinreb A, Bodnar J, et al. 1998 Mapping a gene for combined hyperlipidaemia in a mutant mouse strain. Nat Genet. 18:374–377.[CrossRef][Medline]
  41. Okumura K, Nakamachi K, Hosoe Y, Nakajima N. 2000 Identification of a novel retinoic acid-responsive element within the lamin A/C promoter. Biochem Biophys Res Commun. 269:197–202.[CrossRef][Medline]
  42. Napoli JL. 1999 Interactions of retinoid binding proteins and enzymes in retinoid metabolism. Biochim Biophys Acta. 1440:139–162.[Medline]
  43. Egea PF, Klaholz BP, Moras D. 2000 Ligand-protein interactions in nuclear receptors of hormones. FEBS Lett. 476:62–67.[CrossRef][Medline]
  44. Henkin Y, Como JA, Oberman A. 1992 Secondary dyslipidemia. Inadvertent effects of drugs in clinical practise. JAMA. 267:961–968.[Abstract/Free Full Text]
  45. Ribalta J, Girono J, Vallve JC, La Ville AE, Heras M, Masana L. 1999 Vitamin A is linked to the expression of the AI-CIII-AIV gene cluster in familial combined hyperlipidemia. J Lipid Res. 40:426–431.[Abstract/Free Full Text]
  46. Solomon LW, Erdman Jr JW. 1980 Vitamin A induced hypertriglyceridemia in cholesterol-fed rats. Lipids. 15:157–162.[Medline]
  47. Nagasaki A, Kikuchi T, Kurata K, Masushige S, Hasegawa T, Kato S. 1994 Vitamin A regulates the expression of the apolipoprotein AI and CIII genes in the rat. Biochem Biophys Res Commun. 205:1510–1571.[CrossRef][Medline]
  48. Glass CA, Glass JR, Taniura H, Hasel KW, Blevitt JM, Gerace L. 1993 The alpha-helical rod domain of human lamins A and C contains a chromatin binding site. EMBO J. 12:4413–4424.[Medline]
  49. Gampe Jr RT, Montana VG, Lambert MH, et al. Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors. Mol Cell. 5:545–555.
  50. Mancini MA, Shan B, Nickerson JA, Penman S, Lee WH. 1994 The retinoblastoma gene product is a cell cycle-dependent, nuclear matrix-associated protein. Proc Natl Acad Sci USA. 91:418–422.[Abstract/Free Full Text]
  51. Spann TP, Moir RD, Goldman AE, Stick R, Goldman RD. 1997 Disruption of nuclear lamin organization alters the distribution of replication factors and inhibits DNA synthesis. J Cell Biol. 136:1201–1212.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J. Med. Genet.Home page
A. Ludtke, J. Buettner, H. H-J Schmidt, and H. J Worman
New PPARG mutation leads to lipodystrophy and loss of protein function that is partially restored by a synthetic ligand
J. Med. Genet., September 1, 2007; 44(9): e88 - e88.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
A. Ludtke, J. Buettner, W. Wu, A. Muchir, A. Schroeter, S. Zinn-Justin, S. Spuler, H. H.-J. Schmidt, and H. J. Worman
Peroxisome Proliferator-Activated Receptor-{gamma} C190S Mutation Causes Partial Lipodystrophy
J. Clin. Endocrinol. Metab., June 1, 2007; 92(6): 2248 - 2255.
[Abstract] [Full Text] [PDF]

Home page
 NeurologyHome page
S. Spuler, T. Kalbhenn, J. Zabojszcza, F.K.H. van Landeghem, A. Ludtke, K. Wenzel, M. Koehnlein, M. Schuelke, L. Ludemann, and H. H. Schmidt
Muscle and nerve pathology in Dunnigan familial partial lipodystrophy
Neurology, February 27, 2007; 68(9): 677 - 683.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
I. Lemieux
Energy Partitioning in Gluteal-Femoral Fat: Does the Metabolic Fate of Triglycerides Affect Coronary Heart Disease Risk?
Arterioscler Thromb Vasc Biol, May 1, 2004; 24(5): 795 - 797.
[Full Text]

Home page
 Diabetes CareHome page
K. L. Herbst, L. R. Tannock, S. S. Deeb, J. Q. Purnell, J. D. Brunzell, and A. Chait
Kobberling Type of Familial Partial Lipodystrophy: An underrecognized syndrome
Diabetes Care, June 1, 2003; 26(6): 1819 - 1824.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
H. H.-J. Schmidt and R. A. Hegele
Consider Cardiomyopathy in Subjects With Familial Partial Lipodystrophy Response
Circulation, January 15, 2002; 105 (2): e7 - e7.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Schmidt, H. H.-J.
Right arrow Articles by Brabant, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Schmidt, H. H.-J.
Right arrow Articles by Brabant, G.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals