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Service de Dermatologie, Hôpital Avicenne (F.C., L.L.), 93000 Bobigny; Département de Biologie Cellulaire, Institut Jacques Monod, UMR 7592 (B.B., J.-C.C.), 75005 Paris; and UPRES EA-3408, Université Paris XIII (F.C., L.L.); INSERM, U-402, Faculté de Médecine Saint-Antoine (E.D., O.L., C.V.), Laboratoire de Biologie Moléculaire, Fédération de Biochimie (O.L.), Service d’Hépatologie (O.C.), Service de Cardiologie (A.C.), Service d’Endocrinologie, EA 1533 Génétique de la Reproduction Humaine (S.C.-M.), Hôpital Saint-Antoine, 75012 Paris, France
Address all correspondence and requests for reprints to: Dr. Sophie Christin-Maitre, Service d’Endocrinologie, Hôpital Saint-Antoine, 184 rue du Fbg Saint-Antoine, 75571 Paris Cedex 12, France. E-mail: sophie.christin-maitre{at}sat.ap-hop-paris.fr.
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Abstract |
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We report a new condition in a 30-yr-old man exhibiting a previously undescribed heterozygous R133L LMNA mutation. His phenotype associated generalized acquired lipoatrophy with insulin-resistant diabetes, hypertriglyceridemia, hepatic steatosis, hypertrophic cardiomyopathy with valvular involvement, and disseminated whitish papules. Immunofluorescence microscopic analysis of the patient’s cultured skin fibroblasts revealed nuclear disorganization and abnormal distribution of A-type lamins, similar to that observed in patients harboring other LMNA mutations.
This observation broadens the clinical spectrum of laminopathies, pointing out the clinical variability of lipodystrophy and the unreported possibility of hypertrophic cardiomyopathy and skin involvement. It emphasizes the fact that the diagnosis of genetic alterations in A-type lamins requires careful and complete clinical and morphological investigations in patients regardless of the presenting signs.
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Introduction |
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-helical dimerization domain flanked by amino-terminal (head) and carboxyl-terminal (tail) regions (3). Naturally occurring mutations in LMNA have been shown to be responsible for six distinct diseases, called laminopathies: autosomal dominant and recessive Emery-Dreifuss muscular dystrophy (EDMD) (4, 5), limb-girdle muscular dystrophy type 1B (LGMD1B) (6), dilated cardiomyopathy with conduction defects (DCM-CD) (7), autosomal recessive Charcot-Marie-Tooth disease type 2 (CMT2B1) (8), familial partial lipodystrophy of the Dunnigan-type (FPLD) (9, 10, 11, 12), and mandibuloacral dysplasia (MAD) (13). The skeletal and/or cardiac muscular phenotypes (EDMD, LGMD1B, and DCM-CD), of variable expressivity, are due to heterozygous or, more rarely, homozygous mutations highly dispersed throughout the LMNA gene. In contrast, adipose tissue seems to be the main target of the disease in FPLD, characterized by partial lipodystrophy, insulin resistance, and hypertriglyceridemia. FPLD is caused by a few specific heterozygous amino acid changes in the carboxyl-terminal domain of lamin A/C; more than 90% of the mutations affect the 482nd codon of the gene (9, 10, 11, 12). The axonal neuropathy CMT2B1 has been related to homozygous R298C LMNA substitution (8). Finally, the more complex phenotype of MAD, associating craniofacial dysmorphy, skeletal malformations, and lipodystrophy, has recently been shown to be caused by a homozygous R527H LMNA mutation in five consanguineous families (13). The pathophysiology of laminopathies remains elusive.
Here we report a new phenotype, characterized by acquired generalized lipoatrophy with metabolic alterations, massive liver steatosis, distinctive cutaneous manifestations, and cardiac abnormalities involving both endocardium and myocardium, in a man harboring a novel heterozygous substitution, R133L, in the -helical rod domain of lamin A/C.
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Materials and Methods |
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The patient, both parents, his brother, and his sister gave their informed consent for this study.
Molecular analyses
DNA was prepared from peripheral white blood cells using standard procedures (14). LMNA exons 1–12 and the surrounding intronic sequences from the patient were amplified by PCR using primers and conditions previously described (12). After purification on QIAGEN columns (Chatsworth, CA), the PCR products were directly sequenced using the ABI Big Dye terminator mix and forward primers (PE Applied Biosystems, Foster City, CA) used for amplification. Reactions were run on an ABI 3100 automated sequencing analyzer (PE Applied Biosystems). Data were analyzed using Sequence Navigator software (PE Applied Biosystems). We used a rapid genotyping assay to screen for the R133L LMNA mutation in exon 2 in the patient’s relatives. After amplification with specific primers (2F, 5'-CAGACTCCTTCTCTTAAATCTAC-3'; 2R, 5'-CCTAGGTAGAAGAGTGAGTGTAC-3'), PCR products (25 µl) were digested with 10 U of the restriction enzyme AlwNI (New England Biolabs, Inc., Beverly, MA). After a 2-h incubation at 37 C, the fragments were separated on a 3% agarose gel and visualized after staining with ethidium bromide. The G to T transversion at codon 133 created a unique restriction site for AlwNI in the exon 2 PCR product (268 bp), generating two DNA fragments of 74 and 194 bp.
Tissue and cell studies
Histopathological studies were performed using liver and lesional skin samples from the proband. They were obtained by biopsy and snap-frozen. Liver control samples were obtained from patients who underwent liver surgery, in agreement with the current French legislation. They were taken at a distance from pathological areas and did not display any histological abnormalities. Skin control samples were obtained during breast reduction surgery. Frozen blocks were embedded in Tissue-Tek compound (Sakura Finetek, Zoeterwoude, The Netherlands). Cryostat sections of 6 µm were fixed in 75% acetone-25% methanol or in 100% acetone at 4 C for 10 min and then stored at -80 C. Before use, they were removed from the freezer, thawed rapidly, and incubated with 5% BSA and 0.2% Triton in PBS for 1 h to block nonspecific protein binding. For immunofluorescence analysis, incubations with primary and secondary antibodies were performed at room temperature for 1 h in a humidified environment, followed by three 7-min washes in PBS. After adding the secondary antibody and before washing, tissues were incubated for 5 min with 1 µg/ml 4',6-diamidine-2'-phenylindole- dihydrochloride (DAPI), which specifically stains DNA. Specimens were then mounted in Mowiol (Calbiochem, La Jolla, CA).
Cutaneous fibroblasts obtained by biopsy of lesional skin from the patient’s back and from control individuals were cultured in DMEM containing 20% fetal calf serum and 1% penicillin/streptomycin. These human fibroblasts were grown on glass coverslips, fixed in methanol at -20 C, then processed for immunofluorescence analysis as previously described (15).
For immunofluorescence and immunoblotting experiments, lamins were detected with mouse monoclonal antibodies (mab) IgM anti-lamin A/C 346 (sc-7293) purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA), and rabbit antibodies directed against peptides from the carboxyl-terminal ends of A- and B-type lamins, which have been previously described (16). Emerin was detected with the mab antiemerin (NCL-emerin clone 4G5, Novocastra Laboratories, Newcastle upon Tyne, UK). Affinity-purified fluorescein isothiocyanate-conjugated goat antirabbit antibodies and Texas Red-conjugated goat antimouse antibodies were purchased from Jackson ImmunoResearch Laboratories, Inc. (West Grove, PA).
Immunoblotting analysis of cell extracts was performed as previously described (15).
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Results |
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A 27-yr-old man was referred to Saint-Antoine University Hospital for diabetes. He had been diagnosed with hepatic steatosis at the age of 21 yr, hypertriglyceridemia (5.10 mmol/liter; normal range, 0.65–1.55) at the age of 22 yr, and diabetes at the age of 25 yr. Furthermore, he had suffered twice from gout. The patient had been advised to follow a low fat, diabetic diet.
On physical examination, the patient presented a peculiar appearance with square jaw, thin lips, high forehead, marked thinning of the eyebrows, pectus excavatum, and narrow shoulders (Fig. 1
). His weight was 62 kg, and his height was 1.78 m (body mass index, 19.6). A generalized atrophy of the sc fat was noticed, resulting in sunken cheeks and muscular pseudohypertrophy of the four limbs (Fig. 1). Multiple whitish papules on pigmented skin were present on the neck, trunk, and upper limbs and to a lesser extent on the lower limbs (Fig. 2). The skin of the back of the feet and hands was thin and atrophic, with very prominent sc veins. The patient mentioned that his sc body fat progressively disappeared from the age of 14 yr, after the onset of puberty. The development of the skin lesions occurred simultaneously. No acanthosis nigricans was present. Examination of the oral cavity revealed labial mucosa set just under the neck of teeth; however, both the number and distribution of teeth were normal. Gray hair had been present since the age of 17 yr. No skin hyperelasticity or joint hypermobility was found. The abdominal examination showed smooth hepatomegaly. Blood pressure was 140/90 mm Hg. The rest of the physical examination was unremarkable. Of note, muscular strength was normal, and no neurological defects were detected.
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A standard 75-g WHO oral glucose tolerance test was performed with determination of glucose and insulin at 0, 60, 90, and 120 min. Glucose levels reached 4.8, 15.1, 18.9, and 16.1 mM and insulin levels reached 85, 335, 735, and 670 pM at 0, 60, 90, and 120 min, respectively, thus defining diabetes. Hemoglobin A1C was 6.6% (normal range, 4–6). An iv insulin tolerance test was performed, using 6 U insulin (0.1 U insulin/kg). The blood glucose level remained stable throughout the test, from 6.9 mM before administration to 7, 6.5, and 6.4 mM at 5, 10, and 15 min, respectively. Therefore, a status of insulin resistance was identified according to insulin levels during the oral glucose tolerance test as well as glucose values during the insulin tolerance test. Treatment with metformin (850 mg, twice daily) was begun. No diabetic retinopathy or cataract was present upon eye examination, and 24-h microalbuminuria was less than 20 mg (normal range, <30 mg).
To evaluate the patient’s fat reserve, dual energy x-ray absorptiometry was performed. It showed 8.63% body fat (normal range, 14–23) corresponding to a total fat mass of 5242 g. The percentage of fat was lower in his legs (left leg, 6.6%; right leg, 7.1%) and his trunk (7.3%) than in his arms (left and right arms, 13.1% and 16.2%, respectively). The plasma leptin concentration was low at 1.5 ng/ml (normal range, 1.4–9.8 ng/ml). Abdominal magnetic resonance imaging revealed an absence of body fat at both sc and visceral levels. For example, the perirenal region was free of fat (Fig. 3). Therefore, the patient presented acquired generalized lipoatrophy. Although his leptin level was low, he did not present increased appetite, as his daily intake was 1850 kcal, with 17% proteins, 33% lipids, and 54% carbohydrates.
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-glutamyl transpeptidase, and total bilirubin concentrations. Hepatitis A, B, and C serologies were negative, as well as antibody testing for antinuclear, smooth muscle, and liver-kidney microsomal antibodies. Serum total hemolytic complement, C4, C3, rheumatoid factor, iron, and ceruloplasmin levels were normal. Urinary copper excretion was not increased. Abdominal ultrasound revealed hepatic hypertrophy and suggested liver steatosis. The liver measured 115 mm in front of the aorta and 180 mm in front of the right kidney. No focal liver lesion or signs of portal hypertension could be identified. The gallbladder contained two 5- and 10-mm stones. Liver biopsy revealed severe macrovesicular steatosis (60% of hepatocytes) without fibrosis and no inflammation or necrosis. The liver copper concentration was normal. Skin biopsies were performed at several sites (back, thigh, and axillae). Histological examination demonstrated mild fibrosis in the deep dermis. Special staining techniques, including orcein, Alcian Blue, Congo Red, and periodic acid-Schiff stains, were unremarkable. Electron microscopy study showed thick, fragmented, and coarse collagen fibers in the lower dermis. The epidermis, adnexae, and elastic fibers were normal, and no abnormal dermal or intracellular deposits were observed.
The family of the patient consisted of both parents, one sister, and one brother. No consanguinity was reported. These four individuals were clinically examined, and none presented with lipodystrophy, hepatomegaly, or dermatological alterations. Laboratory measurements, including fasting glycemia, insulinemia, triglycerides, total cholesterol, and hepatic enzymes, were normal.
As the patient presented with lipodystrophy and insulin resistance, molecular analysis of seipin and insulin receptor genes was first performed. No variation in sequence was identified in any of these genes. We then decided to screen for mutations in the LMNA gene.
Molecular analyses of the LMNA gene
In the patient we found a heterozygous CGG to CTG transversion at LMNA codon 133 (exon 2; Fig. 4A), leading to an arginine to leucine substitution (R133L). This DNA variation, which has not been previously reported, was absent in 100 unrelated control individuals. Therefore, it represents a new LMNA point mutation. This genetic alteration was searched in the 4 family members using the AlwNI enzyme (see Materials and Methods). None was found in any of them (Fig. 4B), and the absence of a mutation in LMNA exon 2 was confirmed using direct sequencing.
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As a lamin A/C mutation was identified in our patient, we searched for other phenotypic manifestations previously described in LMNA-related diseases. An electromyogram was performed on the four limbs. No sign of neuropathy or myopathy was identified. The serum creatine kinase level was normal. A muscular biopsy performed on deltoid muscle revealed normal histological findings.
Two-dimensional echocardiography identified an unusual aspect for a 30-yr-old man with concentric left ventricular (LV) hypertrophy, elevated LV filling pressures, and thickened valves. The LV mass index was 145 g/m2 (normal, <125 g/m2), and the relative wall thickness (h/R, where h is wall thickness, and R is LV cavity radius) ratio was 0.42. Aortic cusps were thickened (>3 mm), and marked fibrotic nodules were present. Central aortic regurgitation was quantified as moderate using the Doppler approach. An extensive calcification was inserted on the posterior annulus; mitral regurgitation was moderate. LV filling pressures and systolic pulmonary pressure (38 mm Hg) were increased. Doppler echocardiographic findings were similar to those described in aged patients. A 24-h electrocardiogram monitoring revealed sinus rhythm averaging 82 beats/min. Three episodes of sinus bradycardia reaching 40 beats/min during 26, 16, and 13 sec, respectively, occurred during the daytime. Sixty supraventricular extrasystoles were measured during the 24-h recording. No sino-atrial or atrio-ventricular conduction defect could be identified. A careful follow-up was planned, including Doppler echocardiography and Holter monitoring.
Neither osteopoikilosis, acroosteolysis, hypoplastic clavicles, wide sutures, nor mandibular hypoplasia, previously described in MAD, were identified by bone x-rays (hands, chest, skull, pelvis, and tibia).
Tissue and cell studies
As the lamina has been shown to be essential for nuclear structure and organization (17), we studied the nuclei in tissues and cells affected by the disease in our patient. We used immunofluorescence microscopy to localize A-type lamins and their main partners at the nuclear envelope: B-type lamins and emerin.
In liver and skin biopsies from the patient, no abnormality in the shape of the nuclei was noticed. Lamin A/C, lamin B, and emerin were present at the whole nuclear periphery of the cells, and their staining was homogeneous, as in control nuclei (Fig. 5A).
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). In abnormal nuclei, B-type lamin staining was often weaker than in control nuclei, particularly in the buds presenting a honeycomb aspect of the lamin A/C meshwork (Fig. 5B). In these particular nuclear areas, B-type lamins were sometimes absent, as judged from the negative immunostaining, but emerin labeling was conserved, although disturbed as the lamin A/C network with which it always colocalized (data not shown). DAPI staining was weaker in the herniations of dysmorphic nuclei, suggesting that chromatin was decondensed in these regions (Fig. 5B).
Protein expression of lamin A/C, lamin B, and emerin was analyzed by Western blot in whole fibroblast extracts from patient and controls. The three proteins were revealed at the expected size and were present in similar amounts in both cellular extracts (Fig. 5C).
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Discussion |
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Arginine 133 is located in a charged peptide stretch, which is highly conserved in lamins A and C and lamins B1 and B2 of vertebrates (Fig. 6). The switch from positively charged arginine to hydrophobic leucin in the lamin A/C dimerization domain may severely impair lamin polymerization and further filament assembly. Accordingly, nuclear abnormalities were observed in primary cultures of patient’s fibroblasts. In a subset of cells, we observed alterations in the localization of A- and B-type lamins and emerin and defects in chromatin condensation. These abnormalities were reminiscent of that observed in fibroblasts from patients presenting with typical FPLD, EDMD, and MAD (13, 15, 20). Thus, they are not specific for a particular pathological phenotype and were also generated in lmna-/- mice (21). In contrast with the defects observed in cultured cells, lamin A/C staining in skin and liver tissue from our patient was normal, as previously reported in skeletal or cardiac muscle from patients with LMNA-linked EDMD (4, 22). Abnormalities observed in fibroblast nuclei may have been revealed by the ex vivo conditions of cell proliferation. Besides their ubiquitous structural function, lamins may have more specific functions due to their putative interactions with nuclear proteins that play a role in tissue-specific gene expression (17). Impairment of such interactions by mutations in lamins A and C could lead to pathological consequences. Accordingly, it has recently been shown that the C-terminal domain of lamin A/C can interact with sterol regulatory element-binding protein 1, a transcription factor involved in adipocyte differentiation (23).
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In conclusion, we describe a new phenotype in a patient affected by a novel R133L heterozygous substitution in lamin A/C. As the genotype-phenotype relations are particularly complex in LMNA-related diseases, the discovery of a mutation in this gene requires extensive clinical and morphological investigations.
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Acknowledgments |
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Footnotes |
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Abbreviations: CMT2B1, Autosomal recessive Charcot-Marie-Tooth disease type 2; DAPI, 4',6-diamidine-2'-phenylindole-dihydrochloride; DCM-CD, dilated cardiomyopathy with conduction defects; EDMD, Emery-Dreifuss muscular dystrophy; FPLD, familial partial lipodystrophy of the Dunnigan type; LGMD1B, limb-girdle muscular dystrophy type 1B; LV, left ventricular; mab, monoclonal antibody; MAD, mandibuloacral dysplasia.
Received September 25, 2002.
Accepted December 11, 2002.
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-helical rod domains of the lamin A/C gene. Am J Med 112:549–555[CrossRef][Medline]
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T substitution at position 398 in the proband. B, Search for the R133L LMNA mutation in patient’s relatives. The G
