Human Molecular Genetics, 2000, Vol. 9, No. 1 109-112
© 2000 Oxford University Press
Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy
Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, 406-100 Perth Drive, London, Ontario, Canada N6A 5K8
Received 15 September 1999; Revised and Accepted 15 October 1999.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Patients with Dunnigan-type familial partial lipodystrophy (FPLD) are born with normal fat distribution, but after puberty experience regional and progressive adipocyte degeneration, often associated with profound insulin resistance and diabetes. Recently, the FPLD gene was mapped to chromosome 1q21–22, which harbours the LMNA gene encoding nuclear lamins A and C. Mutations in LMNA were shown to underlie autosomal dominant Emery–Dreifuss muscular dystrophy (EDMD-AD), which is characterized by regional and progressive skeletal muscle wasting and cardiac effects. We hypothesized that the analogy between the regional muscle wasting in EDMD-AD and the regional adipocyte degeneration in FPLD, in addition to its chromosomal localization, made LMNA a good candidate gene for FPLD. DNA sequencing of LMNA in five Canadian FPLD probands indicated that each had a novel missense mutation, R482Q, which co-segregated with the FPLD phenotype and was absent from 2000 normal alleles (P = 1.1 x 10–13). This is the first report of a mutation underlying a degenerative disorder of adipose tissue and suggests that LMNA mutations could underlie other diseases characterized by tissue type- and anatomical site-specific cellular degeneration.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Dunnigan-type familial partial lipodystrophy (FPLD; OMIM 151660) is a rare autosomal dominant disease, which is part of a heterogeneous group of disorders characterized by complete or partial absence of adipose tissue (1,2). Patients with FPLD are born with normal fat distribution, but then lose subcutaneous fat from their extremities, trunk and gluteal region after the onset of puberty (1–3). Also, excess fat may become deposited within the face, neck, back and labia majora (1–3). Furthermore, patients with FPLD have normal stores of intermuscular, intra-abdominal, intrathoracic and bone marrow fat (1–3). Acanthosis nigricans, hirsutism, menstrual abnormalities and polycystic ovarian disease can also occur (1,2). Profound insulin resistance with diabetes can develop later in life, and FPLD subjects can also have dyslipidaemia and coronary heart disease, which is secondary to the metabolic disturbances (1,2).
Recently, three groups have independently mapped the FPLD gene to chromosome 1q21–22 (4–6). Included among >100 known genes within this region is the lamin A/C gene (LMNA), which undergoes alternative splicing to produce two nuclear laminar proteins: lamin A and lamin C (7). Nuclear lamins are part of the intermediate filament multigene family, and lamins A and C are present in most differentiated mammalian cells (7). Lamins participate in DNA replication, chromatin organization, spatial arrangement of nuclear pores, nuclear growth and anchorage of nuclear membranes (7). Four mutations in LMNA were found in families with autosomal dominant Emery–Dreifuss muscular dystrophy (EDMD-AD), which is characterized by regional and progressive skeletal muscle wasting and cardiac effects (8). We hypothesized that mutations in LMNA might lead to the analogous regional and progressive degeneration of adipocytes that is characteristic of patients with FPLD.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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We evaluated five probands from five Canadian kindreds with FPLD (Fig. 1). DNA sequencing revealed that all probands with FPLD were heterozygous for a G
A change at codon 482 in exon 8, which predicted the replacement of arginine (CGG) by glutamine (CAG) (Fig. 2). The control subject in the screening experiment was homozygous for the wild-type sequence (Fig. 2). There were no other coding sequence or flanking region abnormalities in LMNA detected in any subject. Sequencing of the coding and flanking sequences of 11 other genes on chromosome 1q21 revealed no DNA variants that both altered the coding sequence and were unique to FPLD probands (data not shown). Genotyping confirmed that all FPLD probands were LMNA Q482/R482 heterozygotes (Fig. 1). In sharp contrast, all 1000 normal control subjects were LMNA R482/R482 homozygotes (
2 = 1005, P = 1.1 x 10–13). Furthermore, the mutation completely co-segregated with either a definite or probable diagnosis of FPLD (Fig. 1). One male subject, OFPLD-1-13, had an uncertain phenotype based on clinical criteria, but was clearly not a carrier of the LMNA R482 mutation by genotyping.
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Complete clinical data were available from 22 LMNA Q482/R482 heterozygotes and 23 R482/R482 homozygotes from the FPLD families, and are shown in Table 1. The genotype classes did not differ with respect to age, gender and body mass index (BMI). Compared with LMNA R482/R482 homozygotes, there were significantly more Q482/R482 heterozygotes who had definite FPLD and frank diabetes (Table 1). Also, compared with LMNA R482/R482 homozygotes, Q482/R482 heterozygotes had significantly higher serum insulin and C-peptide (data not shown). The LMNA Q482/R482 heterozygotes with diabetes were significantly older than heterozygotes without diabetes (51.4 ± 11.3 versus 34.4 ± 15.8 years, P = 0.02), but were not different with respect to BMI (data not shown).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Our results indicate that the LMNA R482Q mutation is the molecular basis for the FPLD phenotype in these Canadian kindreds. The LMNA R482Q mutation had an extremely strong statistical association with FPLD, since it was absent from 2000 normal alleles and was present only in FPLD families. Moreover, within FPLD families, LMNA R482Q was found only within subjects with definite or probable FPLD, and not within those family members who were definitely unaffected. Carriers of LMNA R482Q had significantly more diabetes, with elevated serum concentrations of insulin and C-peptide, which is consistent with the conspicuous insulin resistance that is pathognomonic for FPLD. Finally, phenotype in LMNA Q482/R482 homozygotes was variably penetrant, and the development of diabetes in LMNA Q482/R482 heterozygotes was age dependent.
The results indicate that different mutations in LMNA can underlie the disparate clinical entities of EDMD-AD and FPLD, analogous to the relationship between different mutations in the RET proto-oncogene and the disparate clinical entities of multiple endocrine neoplasia type 2, related sporadic tumours and Hirschsprung disease (9). The LMNA Q6X, R453W, R527P and L530P mutations underlie muscle wasting in EDMD-AD (7). The LMNA R482Q mutation underlies site-specific degeneration of adipocytes in FPLD. The position of the mutant residue within LMNA appears to be a crucial determinant of both the affected cell type and the anatomical distribution of the affected cells. This suggests a high degree of functional specificity for particular lamin A/C residues and raises the possibility that LMNA mutations could underlie other diseases characterized by degeneration of specific cell types in particular anatomical distributions.
Lamins A and C are members of the intermediate filament multigene family. Both are absent from early embryos and undifferentiated cells, but are present in most terminally differentiated cells. Lamins A and C polymerize to form part of the nuclear lamina, a structural meshwork of 10 nm filaments on the nucleoplasmic side of the inner nuclear membrane (7). Lamins A and C form dimers through their rod domains and interact with chromatin and integral proteins of the inner nuclear membrane through binding sites located both in the rod domain and in the C-terminal globular tail. The non-conservative ArgGln change at LMNA codon 482 occurs within the C-terminal tail sequence that is common to both lamins A and C (7). The evolutionary conservation of R482 in human lamin A/C, mouse lamin A/C, rat lamin A and chicken lamin A suggests that this residue is important for the normal function of lamin A/C (7). We also cannot discount the very unlikely possibility that this mutation is in linkage disequilibrium with another causative functional variant.
Although LMNA R482 is conserved in lamin A/C across species, it is not conserved among other members of the lamin multigene family. In contrast, the mutated residues in EDMD-AD are each conserved not just in lamin A/C across species, but also among other members of the lamin multigene family (8). This might explain why LMNA R482 underlies a different phenotype than the EDMD-AD mutations. In addition, there are tissue-specific differences in the distribution of the other nuclear lamina proteins, such as lamin B1, which has been suggested to be another determinant of the specificity of the impact of particular LMNA mutations (10). A complicating attribute in the case of FPLD is that puberty is clearly related to the onset of adipocyte degeneration. This suggests that changes in the hormonal or metabolic milieu trigger the expression of the specific histological and anatomical changes in carriers of the LMNA R482Q mutation. Such complexity might overwhelm the capacity of current in vitro functional assays of lamin interactions with other lamina proteins to explain fully the phenotypic changes observed in FPLD; other in vitro models of lamin A/C function might be required.
The presence of the LMNA Q482 mutation in five probands suggests the possibility of a founder effect for this mutation in Canadian FPLD kindreds. Haplotype analysis strongly suggests that there is a common chromosomal haplotype for all subjects with LMNA (data not shown). In addition, there is likely to be a common ancestor for OFPLD-1, OFPLD-2 and NBFPLD-1, who would be nine generations removed from the most recent generations in these kindreds. If this common ancestry can be confirmed, then it may be possible to extend these kindreds in order to perform a large multigenerational family study and to evaluate such attributes as epistasis or gene–environment interactions that could affect penetrance of the FPLD phenotype in LMNA Q482 carriers.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Patients
After informed consent was obtained, we performed clinical evaluations and drew blood samples from five probands and members of their families, shown in Figure 1. We studied: 29 members of a three-generation Ontario family (OFPLD-1), of whom 13 were definitely or probably affected; six members of a two-generation Ontario family (OFPLD-2), of whom three were definitely or probably affected; seven members of a three-generation New Brunswick family (NBFPLD-1), of whom four were definitely or probably affected; a definitely affected mother–daughter pair from New Brunswick (NBFPLD-2); and a single definitely affected New Brunswick proband (NBFPLD-3). All families were of Northern European descent and had lived in Canada for several generations. Each family member was assessed for characteristic physical attributes of FPLD and provided a fasting serum sample for biochemical determinations.
The phenotype was classified as ‘definitely affected’, ‘probably affected’ or ‘definitely unaffected’ based on clinical and biochemical criteria. The absence of subcutaneous fat tissue from upper and lower extremities and an extremely muscular appearance commencing in adolescence was the essential criterion for a definitive diagnosis of FPLD. Other important phenotypic criteria included the presence of excess adipose tissue in the face and neck, giving a pseudo-Cushingoid appearance. Additional supportive criteria included the presence of acanthosis nigricans, hirsutism, menstrual abnormalities and laboratory data confirming the presence of diabetes, hypertension, elevated insulin, elevated C-peptide and/or abnormal lipoproteins. Control DNA was obtained from 1000 unaffected normal subjects representing six ethnic groups (276 Caucasians, 243 South Asians, 169 Africans, 160 Chinese, 76 Oji-Cree and 76 Inuit). Statistical comparisons were made using SAS software (11).
DNA analysis
DNA was extracted from all family members; it was sequenced in subjects with a certain diagnosis of FPLD, and in an unrelated, unaffected normal control subject. Primers for DNA amplification and sequencing were derived using published sequence information for all 12 exons, all intron–exon boundaries and the 5'- and 3'-untranslated regions of LMNA (12). After the LMNA R482Q mutation was identified, a rapid genotyping assay was developed, which 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 of size 480 and 69 bp, in addition to invariant fragments with sizes 381, 80 and 59 bp. Digestion of the product from the mutant allele, Q482, produced a single fragment of size 549 bp, in addition to the invariant fragments.
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ACKNOWLEDGEMENTS |
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We thank Drs N. Forbath, T.J. McDonald and M.C. McSween for referring their patients. Dr Jian Wang, Carol Anderson, Doreen Jones and Pearl Campbell provided excellent technical assistance. Novel concepts and materials derived from this work have been embodied in US patent application no. 60/154825 (filed on 20 September 1999). This work was supported by grants from MRC Canada (MT13430) and the Canadian Genetic Diseases Network. R.A.H. is a Career Investigator of the Heart and Stroke Foundation of Ontario.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +1 519 663 3461; Fax: +1 519 663 3789; Email: robert.hegele@rri.on.ca
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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1 Kobberling, J. and Dunnigan, M.F. (1986) Familial partial lipodystrophy. J. Med. Genet., 23, 120–127.
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J. L.V. Broers, E. A.G. Peeters, H. J.H. Kuijpers, J. Endert, C. V.C. Bouten, C. W.J. Oomens, F. P.T. Baaijens, and F. C.S. Ramaekers Decreased mechanical stiffness in LMNA-/- cells is caused by defective nucleo-cytoskeletal integrity: implications for the development of laminopathies Hum. Mol. Genet., November 1, 2004; 13(21): 2567 - 2580. [Abstract] [Full Text] [PDF]
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J. Phan, M. Peterfy, and K. Reue Lipin Expression Preceding Peroxisome Proliferator-activated Receptor-{gamma} Is Critical for Adipogenesis in Vivo and in Vitro J. Biol. Chem., July 9, 2004; 279(28): 29558 - 29564. [Abstract] [Full Text] [PDF]
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M. Fu, R. Kazlauskaite, M. d. F. Paiva Baracho, M. G. D. Nascimento Santos, J. Brandao-Neto, S. Villares, F. S. Celi, B. L. Wajchenberg, and A. R. Shuldiner Mutations in Gng3lg and AGPAT2 in Berardinelli-Seip Congenital Lipodystrophy and Brunzell Syndrome: Phenotype Variability Suggests Important Modifier Effects J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2916 - 2922. [Abstract] [Full Text] [PDF]
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A B Csoka, H Cao, P J Sammak, D Constantinescu, G P Schatten, and R A Hegele Novel lamin A/C gene (LMNA) mutations in atypical progeroid syndromes J. Med. Genet., April 1, 2004; 41(4): 304 - 308. [Full Text] [PDF]
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M. Alsheimer, B. Liebe, L. Sewell, C. L. Stewart, H. Scherthan, and R. Benavente Disruption of spermatogenesis in mice lacking A-type lamins J. Cell Sci., March 1, 2004; 117(7): 1173 - 1178. [Abstract] [Full Text] [PDF]
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H. Cao, E. van der Veer, M. R. Ban, A. J. G. Hanley, B. Zinman, S. B. Harris, T. K. Young, J. G. Pickering, and R. A. Hegele Promoter Polymorphism in PCK1 (Phosphoenolpyruvate Carboxykinase Gene) Associated with Type 2 Diabetes Mellitus J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 898 - 903. [Abstract] [Full Text] [PDF]
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M. Tazir, H. Azzedine, S. Assami, P. Sindou, S. Nouioua, R. Zemmouri, T. Hamadouche, M. Chaouch, J. Feingold, J. M. Vallat, et al. Phenotypic variability in autosomal recessive axonal Charcot-Marie-Tooth disease due to the R298C mutation in lamin A/C Brain, January 1, 2004; 127(1): 154 - 163. [Abstract] [Full Text] [PDF]
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J J Shen, C A Brown, J R Lupski, and L Potocki Mandibuloacral dysplasia caused by homozygosity for the R527H mutation in lamin A/C J. Med. Genet., November 1, 2003; 40(11): 854 - 857. [Full Text] [PDF]
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A Todorova, B Halliger-Keller, M C Walter, M-C Dabauvalle, H Lochmuller, and C R Muller A synonymous codon change in the LMNA gene alters mRNA splicing and causes limb girdle muscular dystrophy type 1B J. Med. Genet., October 1, 2003; 40(10): e115 - 115. [Full Text] [PDF]
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I. Holt, C. Ostlund, C. L. Stewart, N. t. Man, H. J. Worman, and G. E. Morris Effect of pathogenic mis-sense mutations in lamin A on its interaction with emerin in vivo J. Cell Sci., July 15, 2003; 116(14): 3027 - 3035. [Abstract] [Full Text] [PDF]
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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 J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2821 - 2824. [Abstract] [Full Text] [PDF]
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M. K. S. Leow, C. L. Addy, and C. S. Mantzoros Human Immunodeficiency Virus/Highly Active Antiretroviral Therapy-Associated Metabolic Syndrome: Clinical Presentation, Pathophysiology, and Therapeutic Strategies J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 1961 - 1976. [Full Text] [PDF]
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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 Diabetes Care, May 1, 2003; 26(5): 1350 - 1355. [Abstract] [Full Text] [PDF]
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M. R. G. Taylor, P. R. Fain, G. Sinagra, M. L. Robinson, A. D. Robertson, E. Carniel, A. Di Lenarda, T. J. Bohlmeyer, D. A. Ferguson, G. L. Brodsky, et al. Natural history of dilated cardiomyopathy due to lamin A/C gene mutations J. Am. Coll. Cardiol., March 5, 2003; 41(5): 771 - 780. [Abstract] [Full Text] [PDF]
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F. Caux, E. Dubosclard, O. Lascols, B. Buendia, O. Chazouilleres, A. Cohen, J.-C. Courvalin, L. Laroche, J. Capeau, C. Vigouroux, et al. A New Clinical Condition Linked to a Novel Mutation in Lamins A and C with Generalized Lipoatrophy, Insulin-Resistant Diabetes, Disseminated Leukomelanodermic Papules, Liver Steatosis, and Cardiomyopathy J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1006 - 1013. [Abstract] [Full Text] [PDF]
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W.-C. Hsueh, P. L. St. Jean, B. D. Mitchell, T. I. Pollin, W. C. Knowler, M. G. Ehm, C. J. Bell, H. Sakul, M. J. Wagner, D. K. Burns, et al. Genome-Wide and Fine-Mapping Linkage Studies of Type 2 Diabetes and Glucose Traits in the Old Order Amish: Evidence for a New Diabetes Locus on Chromosome 14q11 and Confirmation of a Locus on Chromosome 1q21-q24 Diabetes, February 1, 2003; 52(2): 550 - 557. [Abstract] [Full Text] [PDF]
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R. A. Hegele, M. E. Kraw, M. R. Ban, B. A. Miskie, M. W. Huff, and H. Cao Elevated Serum C-Reactive Protein and Free Fatty Acids Among Nondiabetic Carriers of Missense Mutations in the Gene Encoding Lamin A/C (LMNA) With Partial Lipodystrophy Arterioscler Thromb Vasc Biol, January 1, 2003; 23(1): 111 - 116. [Abstract] [Full Text] [PDF]
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R. I. Kumaran, B. Muralikrishna, and V. K. Parnaik Lamin A/C speckles mediate spatial organization of splicing factor compartments and RNA polymerase II transcription J. Cell Biol., December 9, 2002; 159(5): 783 - 793. [Abstract] [Full Text] [PDF]
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R. A. Hegele, H. Cao, C. Frankowski, S. T. Mathews, and T. Leff PPARG F388L, a Transactivation-Deficient Mutant, in Familial Partial Lipodystrophy Diabetes, December 1, 2002; 51(12): 3586 - 3590. [Abstract] [Full Text] [PDF]
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Y. Tange, A. Hirata, and O. Niwa An evolutionarily conserved fission yeast protein, Ned1, implicated in normal nuclear morphology and chromosome stability, interacts with Dis3, Pim1/RCC1 and an essential nucleoporin J. Cell Sci., November 15, 2002; 115(22): 4375 - 4385. [Abstract] [Full Text] [PDF]
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D. Chen, A. Misra, and A. Garg Lipodystrophy in Human Immunodeficiency Virus-Infected Patients J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 4845 - 4856. [Abstract] [Full Text] [PDF]
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D. Fatkin and R. M. Graham Molecular Mechanisms of Inherited Cardiomyopathies Physiol Rev, October 1, 2002; 82(4): 945 - 980. [Abstract] [Full Text] [PDF]
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A. J. van der Kooi, G. Bonne, B. Eymard, D. Duboc, B. Talim, M. Van der Valk, P. Reiss, P. Richard, L. Demay, L. Merlini, et al. Lamin A/C mutations with lipodystrophy, cardiac abnormalities, and muscular dystrophy Neurology, August 27, 2002; 59(4): 620 - 623. [Abstract] [Full Text] [PDF]
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A. Garg and A. Misra Hepatic Steatosis, Insulin Resistance, and Adipose Tissue Disorders J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3019 - 3022. [Full Text] [PDF]
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E. A. Oral, E. Ruiz, A. Andewelt, N. Sebring, A. J. Wagner, A. M. Depaoli, and P. Gorden Effect of Leptin Replacement on Pituitary Hormone Regulation in Patients with Severe Lipodystrophy J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3110 - 3117. [Abstract] [Full Text] [PDF]
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S. Dhe-Paganon, E. D. Werner, Y.-I. Chi, and S. E. Shoelson Structure of the Globular Tail of Nuclear Lamin J. Biol. Chem., May 10, 2002; 277(20): 17381 - 17384. [Abstract] [Full Text] [PDF]
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D. J. Lloyd, R. C. Trembath, and S. Shackleton A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies Hum. Mol. Genet., April 1, 2002; 11(7): 769 - 777. [Abstract] [Full Text] [PDF]
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E. Arbustini, A. Pilotto, A. Repetto, M. Grasso, A. Negri, M. Diegoli, C. Campana, L. Scelsi, E. Baldini, A. Gavazzi, et al. Autosomal dominant dilated cardiomyopathy with atrioventricular block: a lamin A/C defect-related disease J. Am. Coll. Cardiol., March 20, 2002; 39(6): 981 - 990. [Abstract] [Full Text] [PDF]
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C. Ostlund, G. Bonne, K. Schwartz, and H. J. Worman Properties of lamin A mutants found in Emery-Dreifuss muscular dystrophy, cardiomyopathy and Dunnigan-type partial lipodystrophy J. Cell Sci., March 14, 2002; 114(24): 4435 - 4445. [Abstract] [Full Text] [PDF]
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W. H. Raharjo, P. Enarson, T. Sullivan, C. L. Stewart, and B. Burke Nuclear envelope defects associated with LMNA mutations cause dilated cardiomyopathy and Emery-Dreifuss muscular dystrophy J. Cell Sci., March 14, 2002; 114(24): 4447 - 4457. [Abstract] [Full Text] [PDF]
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C. Vigouroux, M. Auclair, E. Dubosclard, M. Pouchelet, J. Capeau, J.-C. Courvalin, and B. Buendia Nuclear envelope disorganization in fibroblasts from lipodystrophic patients with heterozygous R482Q/W mutations in the lamin A/C gene J. Cell Sci., March 14, 2002; 114(24): 4459 - 4468. [Abstract] [Full Text] [PDF]
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Q. Zhang, J. N. Skepper, F. Yang, J. D. Davies, L. Hegyi, R. G. Roberts, P. L. Weissberg, J. A. Ellis, and C. M. Shanahan Nesprins: a novel family of spectrin-repeat-containing proteins that localize to the nuclear membrane in multiple tissues J. Cell Sci., March 14, 2002; 114(24): 4485 - 4498. [Abstract] [Full Text] [PDF]
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T. Haraguchi, T. Koujin, M. Segura-Totten, K. K. Lee, Y. Matsuoka, Y. Yoneda, K. L. Wilson, and Y. Hiraoka BAF is required for emerin assembly into the reforming nuclear envelope J. Cell Sci., March 14, 2002; 114(24): 4575 - 4585. [Abstract] [Full Text] [PDF]
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Bh. Muralikrishna, J. Dhawan, N. Rangaraj, and V. K. Parnaik Distinct changes in intranuclear lamin A/C organization during myoblast differentiation J. Cell Sci., March 13, 2002; 114(22): 4001 - 4011. [Abstract] [Full Text] [PDF]
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E. Nili, G. S. Cojocaru, Y. Kalma, D. Ginsberg, N. G. Copeland, D. J. Gilbert, N. A. Jenkins, R. Berger, S. Shaklai, N. Amariglio, et al. Nuclear membrane protein LAP2{beta} mediates transcriptional repression alone and together with its binding partner GCL (germ-cell-less) J. Cell Sci., March 11, 2002; 114(18): 3297 - 3307. [Abstract] [Full Text] [PDF]
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E. A. Oral, V. Simha, E. Ruiz, A. Andewelt, A. Premkumar, P. Snell, A. J. Wagner, A. M. DePaoli, M. L. Reitman, S. I. Taylor, et al. Leptin-Replacement Therapy for Lipodystrophy N. Engl. J. Med., February 21, 2002; 346(8): 570 - 578. [Abstract] [Full Text] [PDF]
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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 Lamin Expression in Human Adipose Cells in Relation to Anatomical Site and Differentiation State J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 728 - 734. [Abstract] [Full Text] [PDF]
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W. Wu, F. Lin, and H. J. Worman Intracellular trafficking of MAN1, an integral protein of the nuclear envelope inner membrane J. Cell Sci., January 4, 2002; 115(7): 1361 - 1371. [Abstract] [Full Text] [PDF]
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J. M. K. Mislow, M. S. Kim, D. B. Davis, and E. M. McNally Myne-1, a spectrin repeat transmembrane protein of the myocyte inner nuclear membrane, interacts with lamin A/C J. Cell Sci., January 1, 2002; 115(1): 61 - 70. [Abstract] [Full Text] [PDF]
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R. A. Hegele, M. W. Huff, and T. K. Young Common Genomic Variation in LMNA Modulates Indexes of Obesity in Inuit J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2747 - 2751. [Abstract] [Full Text] [PDF]
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K. Ebihara, Y. Ogawa, H. Masuzaki, M. Shintani, F. Miyanaga, M. Aizawa-Abe, T. Hayashi, K. Hosoda, G. Inoue, Y. Yoshimasa, et al. Transgenic Overexpression of Leptin Rescues Insulin Resistance and Diabetes in a Mouse Model of Lipoatrophic Diabetes Diabetes, June 1, 2001; 50(6): 1440 - 1448. [Abstract] [Full Text]
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N.-O. Ku, R. Gish, T. L. Wright, and M. B. Omary Keratin 8 Mutations in Patients with Cryptogenic Liver Disease N. Engl. J. Med., May 24, 2001; 344(21): 1580 - 1587. [Abstract] [Full Text] [PDF]
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R. A. Hegele Premature Atherosclerosis Associated With Monogenic Insulin Resistance Circulation, May 8, 2001; 103(18): 2225 - 2229. [Abstract] [Full Text] [PDF]
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H. H.-J. Schmidt, J. Genschel, P. Baier, M. Schmidt, J. Ockenga, U. J. F. Tietge, M. Pröpsting, C. Büttner, M. P. Manns, H. Lochs, et al. Dyslipemia in Familial Partial Lipodystrophy Caused by an R482W Mutation in the LMNA Gene J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 2289 - 2295. [Abstract] [Full Text]
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E. C. Schirmer, T. Guan, and L. Gerace Involvement of the Lamin Rod Domain in Heterotypic Lamin Interactions Important for Nuclear Organization J. Cell Biol., April 30, 2001; 153(3): 479 - 490. [Abstract] [Full Text] [PDF]
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H. H.-J. Schmidt, H. Lochs, G. L. Brodsky, L. Mestroni, F. Muntoni, C. Sewry, S. Miocic, and G. Sinagra Lamin A/C Gene Mutation Associated With Dilated Cardiomyopathy With Variable Skeletal Muscle Involvement Response Circulation, January 30, 2001; 103 (4): e20 - e20. [Full Text] [PDF]
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A. Garg, M. Vinaitheerthan, P. T. Weatherall, and A. M. Bowcock Phenotypic Heterogeneity in Patients with Familial Partial Lipodystrophy (Dunnigan Variety) Related to the Site of Missense Mutations in Lamin A/C Gene J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 59 - 65. [Abstract] [Full Text]
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C. Hutchison, M Alvarez-Reyes, and O. Vaughan Lamins in disease: why do ubiquitously expressed nuclear envelope proteins give rise to tissue-specific disease phenotypes? J. Cell Sci., January 1, 2001; 114(1): 9 - 19. [Abstract] [PDF]
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R. L. Steen, S. B. Martins, K. Tasken, and P. Collas Recruitment of Protein Phosphatase 1 to the Nuclear Envelope by a-Kinase Anchoring Protein Akap149 Is a Prerequisite for Nuclear Lamina Assembly J. Cell Biol., September 18, 2000; 150(6): 1251 - 1262. [Abstract] [Full Text] [PDF]
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R. A. Hegele, H. Cao, C. M. Anderson, and I. M. Hramiak Heterogeneity of Nuclear Lamin A Mutations in Dunnigan-Type Familial Partial Lipodystrophy J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3431 - 3435. [Abstract] [Full Text]
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K. K. Lee, Y. Gruenbaum, P. Spann, J. Liu, and K. L. Wilson C. elegans Nuclear Envelope Proteins Emerin, MAN1, Lamin, and Nucleoporins Reveal Unique Timing of Nuclear Envelope Breakdown during Mitosis Mol. Biol. Cell, September 1, 2000; 11(9): 3089 - 3099. [Abstract] [Full Text]
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