Literature
Home医源资料库在线期刊动脉硬化血栓血管生物学杂志2004年第24卷第9期

Laminopathies and Atherosclerosis

来源:动脉硬化血栓血管生物学杂志
摘要:ABSTRACTLaminopathiesaregeneticdiseasesthatencompassawidespectrumofphenotypeswithdiversetissuepathologiesandresultmainlyfrommutationsintheLMNAgeneencodingnuclearlaminA/C。Somelaminopathiesaffectthecardiovascularsystem,andafew(namely,Dunnigan-typefamilialpar......

点击显示 收起

From the Robarts Research Institute and University of Western Ontario, London, Canada.

ABSTRACT

Laminopathies are genetic diseases that encompass a wide spectrum of phenotypes with diverse tissue pathologies and result mainly from mutations in the LMNA gene encoding nuclear lamin A/C. Some laminopathies affect the cardiovascular system, and a few (namely, Dunnigan-type familial partial lipodystrophy  and Hutchinson-Gilford progeria syndrome ) feature atherosclerosis as a key component. The premature atherosclerosis of FPLD2 is probably related to characteristic proatherogenic metabolic disturbances such as dyslipidemia, hyperinsulinemia, hypertension, and diabetes. In contrast, the premature atherosclerosis of HGPS occurs with less exposure to metabolic proatherogenic traits and probably reflects the generalized process of accelerated aging in HGPS. Although some common polymorphisms of LMNA have been associated with traits related to atherosclerosis, the monogenic diseases FPLD2 and HGPS are more likely to provide clues about new pathways for the general process of atherosclerosis.

Dunnigan-type familial partial lipodystrophy and Hutchinson-Gilford progeria syndrome are laminopathies caused by mutation in LMNA that feature atherosclerosis, which is related to proatherogenic metabolic disturbances and to the generalized process of accelerated aging, respectively. These monogenic diseases may provide clues about new pathways for atherogenesis.

Key Words: nuclear envelope ? insulin resistance ? aging ? vascular disease ? progeria

Introduction

The nuclear lamina is a 20-nm filamentous meshwork that underlies the inner nuclear membrane and plays a central role in defining interphase nuclear architecture, DNA replication, and chromatin organization.1 Nuclear lamins are type V intermediate filaments that are the major components of the nuclear lamina.1 Mutations in the genes encoding lamins have been discovered in a staggering variety of inherited diseases called "laminopathies," which at least superficially seem to share little with one another. Causative genes for some diseases encode lamina-associated proteins, such as EMD encoding emerin (MIM 300384), which causes X-linked Emery-Dreifuss muscular dystrophy (MIM 301300),2,3 and LBR encoding the lamin B receptor (MIM 600024), which causes both Pelger-Huet anomaly (MIM 169400) and Greenberg skeletal dysplasia (MIM 215140).4,5 However, the "pure" laminopathies are so far associated only with mutations in LMNA (MIM 150330) on chromosome 1q21 encoding lamin A/C.

To date, at least 10 different human diseases result from LMNA mutations (see Table). The position of the mutation within LMNA appears to be a key determinant of affected cell type and anatomic distribution. For instance, in >90% of subjects with Dunnigan-type familial partial lipodystrophy (FPLD2; MIM 151660), the mutation in LMNA involves codon 482, and each mutation affects the sequence encoding the lamin A isoform.6 Genetically modified mice have provided insights into the possible pathogenic mechanisms of LMNA mutations. For instance, monocytes from Lmna-deficient mice showed displaced fragmented heterochromatin and disorganized, detached desmin filaments.7 Also, mechanical strain applied to fibroblasts from Lmna-deficient mice was associated with increased nuclear fragility and altered gene transcription.8 A 2-step disease model for LMNA mutations is favored presently: (1) mutations cause mechanical abnormalities of the nucleus, followed by (2) perturbed interactions with transcription factors and abnormal regulation of gene expression.9 However, our understanding of how LMNA mutations cause such a wide spectrum of diseases is still very rudimentary.

Laminopathies Listed According to Mode of Inheritance

Some laminopathies involve the cardiovascular system. For instance, cardiac conduction is abnormal in inherited early onset atrial fibrillation, dilated cardiomyopathy, and Emery-Dreifuss muscular dystrophy (Table). Other laminopathies, particularly FPLD2 and Hutchinson-Gilford progeria syndrome (HGPS; MIM 176670), are associated with premature atherosclerosis. As with other monogenic diseases, such as familial hypercholesterolemia (FH), FPLD2 and HGPS might help illuminate key atherogenic mechanisms. Atherosclerosis in FPLD2 is probably related to insulin resistance, whereas in HGPS, atherosclerosis occurs at a chronologically young age but seems to be commensurate with the generalized accelerated aging that affects all tissues and organs.

FPLD2: A Monogenic Form of Metabolic Syndrome With Early Atherosclerosis

The National Cholesterol Education Program Adult Treatment Panel has defined the common metabolic syndrome (MetS) according to deviation from threshold values for any 3 or more of 5 clinical quantitative traits, namely blood pressure, waist circumference, and plasma concentrations of glucose, high-density lipoprotein (HDL) cholesterol, and triglyceride (TG).10 The common MetS phenotype results from interaction between environment and genes and has been associated prospectively with development of type 2 diabetes mellitus (T2DM)11 and all-cause and cardiovascular mortality.12 Because FPLD2 patients have insulin resistance that progresses to T2DM, they are considered to represent a human monogenic model system for the common MetS.13

Heterozygosity for germline LMNA mutations causes FPLD2, but a very similar phenotype (FPLD3) can result from mutation in PPARG (MIM 601487), which encodes peroxisomal proliferator activated receptor-.13 Prevalence of FPLD2 may be as high as 1:200 000 in some populations. FPLD2 subjects begin life with normal fat distribution, but around puberty, they begin to lose adipocytes in specific depots, such as subcutaneous fat on limbs and in the gluteal region, with sparing of facial, truncal, visceral, and bone marrow fat stores.14 As in the common MetS, FPLD2 subjects have an increased ratio of central to peripheral fat, almost an infinite ratio in some cases. Insulin resistance is the biochemical hallmark of FPLD2, and other features include acanthosis nigricans, hirsutism, menstrual abnormalities, and polycystic ovaries.14

Careful phenotypic or "phenomic" studies performed in extended FPLD2 kindreds have shown metabolic changes that were similar to those seen in the common MetS.15,16 In young adulthood, the characteristic biochemical profile seen in FPLD2 carriers of mutant LMNA included elevated plasma concentrations of free fatty acids, insulin and C-peptide, TG, and C-reactive protein (CRP), with depressed plasma concentrations of HDL cholesterol, leptin, and adiponectin.15,16 Depressed adiponectin in particular could be a potent atherosclerosis risk factor in lipodystrophy syndromes. Hypertension usually presents next, followed by T2DM that causes profound changes in the metabolic intermediate traits. However, the extended biochemical profile in FPLD2 was distinct from that seen in MetS because plasma fibrinolytic variables were unchanged, whereas both serum leptin and adiponectin were depressed.16

Early coronary heart disease (CHD) has been observed in FPLD2,17 especially in women.18 Compared with normal family controls, FPLD2 subjects with heterozygous LMNA mutations in codon 482 had an odds ratio of 6 for having a CHD end point <age 55.18 Furthermore, female LMNA codon 482 mutation carriers <55 years old were >100-fold more likely to be hospitalized for coronary artery bypass surgery than women in the general Canadian population.18 Subjects with mutant LMNA with CHD also had T2DM, suggesting that extensive metabolic progression is necessary for expression of vascular disease.18 It has been proposed that further careful evaluation of subphenotypes in LMNA mutation carriers at younger ages might identify other biomarkers associated with atherosclerosis susceptibility.13

Atherosclerosis in Laminopathies With a Lipodystrophy Component

Some LMNA mutations produce complex conditions that feature lipodystrophy as but 1 component. For instance, mandibuloacral dysplasia (MAD; MIM 248370) is a rare recessive disorder characterized by postnatal growth retardation, mandibular and clavicular hypoplasia, acro-osteolysis, delayed closure of cranial sutures, joint contractures, and mottled cutaneous pigmentation.19 Lipodystrophy and metabolic complications associated with insulin resistance have also been reported in subjects with MAD, but there is no clear documentation of vascular complications in affected subjects. Other LMNA mutations cause syndromes with overlapping phenotypes, such as the syndrome lipodystrophy, insulin-resistant diabetes, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy (MIM 608056)20 and an overlap syndrome characterized by lipodystrophy, muscular dystrophy, and cardiac conduction anomalies.21,22 However, again, there is no clear association between atherosclerosis and these particular laminopathies.

Atherosclerosis in HGPS

Subjects with HGPS may appear normal at birth but display severe growth retardation by the first year of life.23–25 Additional features include growth failure of the facial bones and mandible, prominent eyes, alopecia, prominent scalp veins, loss of subcutaneous fat, stiff, enlarged joints, thin limbs, thin, wrinkled and dry skin, dystrophic nails, delayed dentition, a high-pitched voice, and absent sexual maturation.26 Recently, de novo point mutations in LMNA have been found in most subjects with HGPS, with the most common mutation at codon 608.27–29 This mutation creates a cryptic splice site within exon 11, which results in deletion of a proteolytic cleavage site within the expressed mutant lamin A.27

HGPS subjects have a median life span of <14 years, and death is most frequently from cardiovascular causes, with atherosclerosis being the predominant pathology.25,26 The coronary arteries are frequently stenosed or occluded by atherosclerotic plaques.24–26,30–36 Most reported necropsies of HGPS subjects have documented aortic atherosclerosis, ranging from small fatty plaques to complicated, calcified lesions.30–36 Most reported necropsies of HGPS subjects have also documented significant myocardial changes, which included healed and recent myocardial infarction (MI), diffuse interstitial fibrosis, and ventricular hypertrophy and dilation.30–41 MI in HGPS is associated strongly with severe coronary atherosclerosis30–41 but occasionally also with narrowing of the small intramural arteries.30 A few HGPS subjects had diffuse myocardial fibrosis without significant coronary atherosclerosis.40,41

Atherosclerosis may also affect the cerebrovasculature in HGPS. Angiographic evidence of atherosclerosis affecting both the carotid and vertebral systems42,43 and MRI evidence of cerebral infarction42–45 has been documented in HGPS children with localizing neurological findings. Mandera et al46 reported epidural hematomas in a 10-year-old HGPS boy after mild head injury and suggested that these resulted in part from advanced atherosclerosis of the intracranial vessels.

The mechanisms underlying the atherosclerosis in HGPS remain unclear. Although the general aging process extracts a toll on the vasculature, it is possible that vascular deterioration might in turn contribute to tissue changes associated with aging, in effect setting up a vicious cycle. Importantly, the vascular changes in HGPS are similar to those seen in the general aging process and differ from other forms of precocious atherosclerosis in children. For instance, Stehbens et al suggested that the xanthomatous vascular lesions that are typical for homozygous FH are not seen in the atherosclerosis of HGPS.47,48 Furthermore, serum lipoproteins in HGPS are relatively normal, except for occasional reports of depressed HDL cholesterol.38 Exposure to risk factors such as poor diet, smoking, or hypertension is an unlikely proatherogenic mechanism in HGPS. Similarly, the variable association with insulin resistance does not fully explain atherosclerosis in HGPS.49,50 Marked reduction in insulin receptor gene expression was observed in lymphoblasts from a 15-year-old girl with HGPS and severe insulin resistance;51 however, insulin resistance to that degree is atypical for HGPS. Furthermore, insulin resistance alone would not be expected to cause expression of CHD end points within the first 2 decades of life.

It is more likely that the same mechanism(s) by which mutant LMNA produces accelerated aging in tissues, such as replicative senescence,52 telomere shortening,53 decreased capacity to propogate in subculture,54 and decreased repair capacity,55 may also affect vascular wall components. For instance, endothelial cells with mutant LMNA might not regenerate fully to restore intimal integrity after injury.30 Also, vascular smooth muscle cells in HGPS were susceptible to hemodynamic and ischemic stress injury47 and were depleted from arterial media.48 An alternative proposed mechanism for atherosclerosis in HGPS is hyperhyaluronic acidemia and aciduria,56,57 which are suggested to cause vascular calcification58 despite the fact that these biochemical abnormalities are not specific for either HGPS or atherosclerosis.59 Other cardiovascular changes in HGPS, such as calcification of cardiac valves,24,30–33,37–40 are similar to those seen in the general aging process.60,61

Association Studies of LMNA SNPs With Metabolic Traits

A few studies report association of common LMNA single nucleotide polymorphisms (SNPs) with metabolic and cardiovascular traits. The results of these studies are subject to the usual limitations of association studies.62 The most commonly evaluated LMNA SNP is the synonymous 1908C/T polymorphism in exon 10, wobbling the third base of codon 566, which is the last codon shared in common between lamin A and C before alternative splicing gives rise to the 2 distinct proteins.63 In nondiabetic Canadian aboriginal subjects, those with the 1908T/1908T genotype had significantly higher plasma leptin than the subjects with either the 1908C/1908T or 1908C/1908C genotypes, after adjustment for age and sex. Physical indices of obesity, such as body mass index, percent body fat, and ratio of waist-to-hip circumference, were also higher among subjects with the LMNA 1908T/1908T genotype than the subjects with either the 1908C/1908T or 1908C/1908C homozygotes. This was later replicated in an independent, genetically distinct Canadian aboriginal sample.64 In a Japanese study, there was a nonsignificant trend to an association of diabetes with the 1908T allele, and both diabetic and nondiabetic carriers of the 1908T allele showed significantly higher fasting insulin, TG, total cholesterol, and lower HDL cholesterol levels than 1908C/C subjects.65 An analysis in Pima Indians indicated that the 1908T allele was associated with reduced age-, sex-, and body fat-adjusted mean abdominal adipocyte size.66 Finally, a report in the current issue provides evidence that the 1908T allele was associated with elevated TG, lower HDL cholesterol, and a higher frequency of the MetS in the Old Order Amish.67 Thus, although the phenotypes varied, the association studies have generally tended to agree that the 1908T allele was associated with more deleterious metabolic traits.

Conclusions

The recent characterization of numerous rare inherited disorders that result from mutations in the LMNA gene has been an interesting chapter in human molecular genetics. The laminopathies encompass a wide range of phenotypes with diverse tissue pathologies. Thus, it is not surprising that some laminopathies affect the cardiovascular system and that a few feature atherosclerosis as a key component. The atherosclerosis of FPLD2 is premature, with end points occurring in midadulthood, and is very likely to be related to the wide range of proatherogenic metabolic disturbances (such as dyslipidemia, elevated CRP, hyperinsulinemia, hypertension, and diabetes) that are characteristic of that condition. In contrast, the very premature atherosclerosis of HGPS occurs with less exposure to metabolic proatherogenic traits. The generalized process of accelerated aging in HGPS appears to affect the vascular system with the same intensity as other tissues. These monogenic diseases that result from defective structure and function of a nuclear membrane component may provide clues to new pathways for the general process of atherosclerosis.

Acknowledgments

R.A.H. is supported by a Canada Research Chair (Tier I) in Human Genetics and a Career Investigator award from the Heart and Stroke Foundation of Ontario. Support has come from the Canadian Institutes for Health Research, the Canadian Genetic Diseases Network, the Canadian Diabetes Association, and the Blackburn Group.

References

Gerace L, Burke B. Functional organization of the nuclear envelope. Annu Rev Cell Biol. 1988; 4: 335–374.

Bione S, Maestrini E, Rivella S, Mancini M, Regis S, Romeo G, Toniolo D. Identification of a novel X-linked gene responsible for Emery-Dreifuss muscular dystrophy. Nat Genet. 1994; 8: 323–327.

Fairley EA, Kendrick-Jones J, Ellis JA. The Emery-Dreifuss muscular dystrophy phenotype arises from aberrant targeting and binding of emerin at the inner nuclear membrane. J Cell Sci. 1999; 112: 2571–2582.

Hoffmann K, Dreger CK, Olins AL, Olins DE, Shultz LD, Lucke B, Karl H, Kaps R, Muller D, Vaya A, Aznar J, Ware RE, Sotelo Cruz N, Lindner TH, Herrmann H, Reis A, Sperling K. Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huet anomaly). Nat Genet. 2002; 31: 410–414.

Waterham HR, Koster J, Mooyer P, Noort Gv G, Kelley RI, Wilcox WR, Wanders RJ, Hennekam RC, Oosterwijk JC. Autosomal recessive HEM/Greenberg skeletal dysplasia is caused by 3 ?-hydroxysterol  14-reductase deficiency due to mutations in the lamin B receptor gene. Am J Hum Genet. 2003; 72: 1013–1017.

Bhayana S, Hegele RA. The molecular basis of genetic lipodystrophies. Clin Biochem. 2002; 35: 171–177.

Nikolova V, Leimena C, McMahon AC, Tan JC, Chandar S, Jogia D, Kesteven SH, Michalicek J, Otway R, Verheyen F, Rainer S, Stewart CL, Martin D, Feneley MP, Fatkin D. Defects in nuclear structure and function promote dilated cardiomyopathy in lamin A/C-deficient mice. J Clin Invest. 2004; 113: 357–369.

Lammerding J, Schulze PC, Takahashi T, Kozlov S, Sullivan T, Kamm RD, Stewart CL, Lee RT. Lamin A/C deficiency causes defective nuclear mechanics and mechanotransduction. J Clin Invest. 2004; 113: 370–378.

Worman HJ, Courvalin JC. How do mutations in lamins A and C cause disease? J Clin Invest. 2004; 113: 349–351.

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. J Am Med Assoc. 2001; 285: 2486–2497.

Laaksonen DE, Lakka HM, Niskanen LK, Kaplan GA, Salonen JT, Lakka TA. Metabolic syndrome and development of diabetes mellitus: application and validation of recently suggested definitions of the metabolic syndrome in a prospective cohort study. Am J Epidemiol. 2002; 156: 1070–1077.

Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. J Am Med Assoc. 2002; 288: 2709–2716.

Hegele RA. Monogenic forms of insulin resistance: apertures that expose the common metabolic syndrome. Trends Endocrinol Metab. 2003; 14: 371–377.

Kobberling J, Dunnigan MG. Familial partial lipodystrophy: two types of an X linked dominant syndrome, lethal in the hemizygous state. J Med Genet. 1986; 23: 120–127.

Hegele RA, Anderson CM, Wang J, Jones DC, Cao H. Association between nuclear lamin A/C R482Q mutation and partial lipodystrophy with hyperinsulinemia, dyslipidemia, hypertension, and diabetes. Genome Res. 2000; 10: 652–658.

Hegele RA, Kraw ME, Ban MR, Miskie BA, Huff MW, Cao H. 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. 2003; 23: 111–116.

Burn J, Baraitser M. Partial lipoatrophy with insulin-resistant diabetes and hyperlipidaemia (Dunnigan syndrome). J Med Genet. 1986; 23: 128–130.

Hegele RA. Premature atherosclerosis associated with monogenic insulin resistance. Circulation. 2001; 103: 2225–2229.

Novelli G, Muchir A, Sangiuolo F, Helbling-Leclerc A, D’Apice MR, Massart C, Capon F, Sbraccia P, Federici M, Lauro R, Tudisco C, Pallotta R, Scarano G, Dallapiccola B, Merlini L, Bonne G. Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C. Am J Hum Genet. 2002; 71: 426–431.

Caux F, Dubosclard E, Lascols O, Buendia B, Chazouilleres O, Cohen A, Courvalin JC, Laroche L, Capeau J, Vigouroux C, Christin-Maitre S. 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. 2003; 88: 1006–1013.

Garg A, Speckman RA, Bowcock AM. Multisystem dystrophy syndrome due to novel missense mutations in the amino-terminal head and -helical rod domains of the lamin A/C gene. Am J Med. 2002; 112: 549–555.

van der Kooi AJ, Bonne G, Eymard B, Duboc D, Talim B, Van der Valk M, Reiss P, Richard P, Demay L, Merlini L, Schwartz K, Busch HF, de Visser M. Lamin A/C mutations with lipodystrophy, cardiac abnormalities, and muscular dystrophy. Neurology. 2002; 59: 620–623.

Hutchinson J. Congenital absence of hair and mammary glands with atrophic condition of the skin and its appendages in a boy whose mother had been almost totally bald from alopecia areata from the age of six. Medicochirurgical Transactions. 1886; 69: 473–477.

Gilford H. Progeria: a form of senilism. Practitioner. 1904; 73: 188–217.

Brown WT. Progeria: a human-disease model of accelerated aging. Am J Clin Nutr. 1992; 55: 1222S–1224S.

DeBusk FL. The Hutchinson-Gilford progeria syndrome. Report of 4 cases and review of the literature. J Pediatr. 1972; 80: 697–724.

Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW. Collins FS. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 2003; 423: 293–298.

De Sandre-Giovannoli A, Chaouch M, Kozlov S, Vallat JM, Tazir M, Kassouri N, Szepetowski P, Hammadouche T, Vandenberghe A, Stewart CL, Grid D, Levy N. Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse. Am J Hum Genet. 2002; 70: 726–736.

Cao H, Hegele RA. LMNA is mutated in Hutchinson-Gilford progeria (MIM 176670) but not in Wiedemann-Rautenstrauch progeroid syndrome (MIM 264090). J Hum Genet. 2003; 48: 271–274.

Baker PB, Baba N, Boesel CP. Cardiovascular abnormalities in progeria. Case report and review of the literature. Arch Pathol Lab Med. 1981; 105: 384–386.

Manschot W. A case of progeronanism (progeria of Gilford). Acta Paediatr Scand. 1950; 39: 158–164.

Atkins L. Progeria: report of a case with post-mortem findings. N Engl J Med. 1954; 250: 1065–1069.

Makous N, Friedman S, Yakovac W, Maris EP. Cardiovascular manifestations in progeria. Report of clinical and pathologic findings in a patient with severe arteriosclerotic heart disease and aortic stenosis. Am Heart J. 1962; 64: 334–346.

Grossman HJ, Pruzansky S, Rosenthal IM. Progeroid syndrome; report of a case of pseudo-senilism. Pediatrics. 1955; 15: 413–423.

Bronstein IP, Dallenbach FD, Pruzansky S, Rosenthal IM, Rosenwald AK. Progeria; report of a case with cephalometric roentgenograms and abnormally high concentrations of lipoproteins in the serum. Pediatrics. 1956; 18: 565–577.

Orrico J, Stroda F. Etude anatomo-clinique sur un cas de nanisme senile (progerie). Arch Med Enfant. 1927; 30: 385–398.

Talbot N, Butler A, Pratt E. Progeria: clinical, metabolic and pathologic studies on a patient. Am J Dis Child. 1945; 69: 267–279.

Macnamara BG, Farn KT, Mitra AK, Lloyd JK, Fosbrooke AS. Progeria. Case report with long-term studies of serum lipids. Arch Dis Child. 1970; 45: 553–560.

Reichel W, Garcia-Bunuel R. Pathologic findings in progeria: myocardial fibrosis and lipofuscin pigment. Am J Clin Pathol. 1970; 53: 243–253.

Gabr M, Hashem N, Hashem M, Fahmi A, Safouh M. Progeria, a pathologic study. J Pediatr. 1960; 57: 70–77.

Dyck JD, David TE, Burke B, Webb GD, Henderson MA, Fowler RS. Management of coronary artery disease in Hutchinson-Gilford syndrome. J Pediatr. 1987; 111: 407–410.

Rosman NP, Anselm I, Bhadelia RA. Progressive intracranial vascular disease with strokes and seizures in a boy with progeria. J Child Neurol. 2001; 16: 212–215.

Naganuma Y, Konishi T, Hongou K, Murakami M, Yamatani M, Okada T. A case of progeria syndrome with cerebral infarction. No To Hattatsu. 1990; 22: 71–76.

Wagle WA, Haller JS, Cousins JP. Cerebral infarction in progeria. Pediatr Neurol. 1992; 8: 476–477.

Smith AS, Wiznitzer M, Karaman BA, Horwitz SJ, Lanzieri CF. MRA detection of vascular occlusion in a child with progeria. Am J Neuroradiol. 1993; 14: 441–443.

Mandera M, Larysz D, Pajak J, Klimczak A. Epidural hematomas in a child with Hutchinson-Gilford progeria syndrome. Childs Nerv Syst. 2003; 19: 63–65.

Stehbens WE, Wakefield SJ, Gilbert-Barness E, Olson RE, Ackerman J. Histological and ultrastructural features of atherosclerosis in progeria. Cardiovasc Pathol. 1999; 8: 29–39.

Stehbens WE, Delahunt B, Shozawa T, Gilbert-Barness E. Smooth muscle cell depletion and collagen types in progeric arteries. Cardiovasc Pathol. 2001; 10: 133–136.

Rosenbloom AL, Kappy MS, DeBusk FL, Francis GL, Philpot TJ, Maclaren NK. Progeria: insulin resistance and hyperglycemia. J Pediatr. 1983; 102: 400–402.

Folsom AR. "New" risk factors for atherosclerotic diseases. Exp Gerontol. 1999; 34: 483–490.

Briata P, Bellini C, Vignolo M, Gherzi R. Insulin receptor gene expression is reduced in cells from a progeric patient. Mol Cell Endocrinol. 1991; 75: 9–14.

Goyns MH, Lavery WL. Telomerase and mammalian ageing: a critical appraisal. Mech Ageing Dev. 2000; 114: 69–77.

Allsopp RC, Vaziri H, Patterson C, Goldstein S, Younglai EV, Futcher AB, Greider CW, Harley CB. Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci U S A. 1992; 89: 10114–10118.

Danes BS. Progeria: a cell culture study on aging. J Clin Invest. 1971; 50: 2000–2003.

Brown WT, Little JB, Epstein J, Williams JR. DNA repair defect in progeric cells. Birth Defects Orig Artic Ser. 1978; 14: 417–430.

Tokunaga M, Wakamatsu E, Sato K, Satake S, Aoyama K, Saito K, Sugawara M, Yosizawa Z. Hyaluronuria in a case of progeria (Hutchinson-Gilford syndrome). J Am Geriatr Soc. 1978; 26: 296–302.

Zebrower M, Kieras FJ, Brown WT. Urinary hyaluronic acid elevation in Hutchinson-Guilford progeria. Mech Ageing Dev. 1986; 35: 39–46.

Sweeney KJ, Weiss AS. Hyaluronic acid in progeria and the aged phenotype? Gerontology. 1992; 38: 139–152.

Laurent TC, Laurent UB, Fraser JR. Serum hyaluronan as a disease marker. Ann Med. 1996; 28: 241–253.

Pomerance A. Ageing changes in human heart valves. Br Heart J. 1967; 29: 222–231.

Sell S, Scully RE. Aging changes in the aortic and mitral valves. Am J Pathol. 1965; 46: 345–365.

Hegele RA. SNP judgments and freedom of association. Arterioscler Thromb Vasc Biol. 2002; 22: 1058–1061.

Hegele RA, Cao H, Harris SB, Zinman B, Hanley AJ, Anderson CM. Genetic variation in LMNA modulates plasma leptin and indices of obesity in aboriginal Canadians. Physiol Genomics. 2000; 3: 39–44.

Hegele RA, Huff MW, Young TK. Common genomic variation in LMNA modulates indexes of obesity in Inuit. J Clin Endocrinol Metab. 2001; 86: 2747–2751.

Murase Y, Yagi K, Katsuda Y, Asano A, Koizumi J, Mabuchi H. An. LMNA variant is associated with dyslipidemia and insulin resistance in the Japanese. Metabolism. 2002; 51: 1017–1021.

Weyer C, Wolford JK, Hanson RL, Foley JE, Tataranni PA, Bogardus C, Pratley RE. Subcutaneous abdominal adipocyte size, a predictor of type 2 diabetes, is linked to chromosome 1q21–q23 and is associated with a common polymorphism in LMNA in Pima Indians. Mol Genet Metab. 2001; 72: 231–238.

Steinle NI, Kazlauskaite R, Imumorin IG, Hsueh WC, Pollin TI, O’Connell JR, Mitchell BD, Shuldiner AR. Variation in the lamin A/C (LMNA) gene: associations with metabolic syndrome. Arterioscler Thromb Vasc Biol. 2004; 24: 1709–1714.

 

作者: Khalid Z. Al-Shali; Robert A. Hegele 2007-5-18
医学百科App—中西医基础知识学习工具
  • 相关内容
  • 近期更新
  • 热文榜
  • 医学百科App—健康测试工具