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Phenotypic Heterogeneity in Body Fat Distribution in Patients with Atypical Werner’s Syndrome Due to Heterozygous Arg133Leu Lamin A/C Mutation

Division of Nutrition and Metabolic Diseases (K.N.J., A.K.A., A.G.), Department of Internal Medicine, and the Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas 75390; Medical Genetics Service (H.G.d.S.) and Endocrinology Unit (F.B.), Santa Maria Hospital, 1649-035 Lisbon, Portugal; and Department of Pathology (J.O.), University of Washington, Seattle, Washington 98195

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

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Context: A heterozygous missense mutation substituting arginine at position 133 to leucine in the lamin A/C protein has been reported in two young women with clinical features of short stature, bird-like faces, and early onset of aging processes.

Objective: The objective of the study was to carry out detailed phenotyping of these two women by evaluating the pattern of fat loss using anthropometry, dual-energy x-ray absorptiometry (DEXA), and magnetic resonance imaging (MRI) and study metabolic abnormalities in glucose and lipid metabolism.

Design: The study consisted of descriptive case reports.

Setting: The study was conducted at a referral center.

Patients: Patient 1 was a 23-yr-old African-American female with progeroid features. Patient 2 was a 24-yr-old Caucasian female with generalized lipodystrophy, hypertriglyceridemia, and severe insulin resistance diabetes who required more than 200 U of insulin daily.

Interventions: There were no interventions.

Main Outcome Measures: Body fat distribution to characterize pattern of lipodystrophy and nuclear morphology abnormalities in skin fibroblasts were studied.

Results: Patient 1 had normal body fat (27%) by DEXA. However, MRI revealed relative paucity of sc fat in the distal extremities, with preservation of sc truncal fat. She had impaired glucose tolerance and elevated postprandial serum insulin levels. Patient 2, in contrast, had only 11.6% body fat as determined by DEXA and had generalized loss of sc and intraabdominal fat on MRI. Skin fibroblasts from patient 2 showed marked abnormal nuclear morphology, compared with those from patient 1. Despite the deranged nuclear morphology, the lamin A/C remained localized to the nuclear envelope, and the nuclear DNA remained within the nucleus.

Conclusions: Atypical Werner’s syndrome associated with Arg133Leu mutation in the LMNA gene presents with a phenotypically heterogeneous disorder. Furthermore, the severity of metabolic complications seems to correlate with the extent of lipodystrophy.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
WERNER’S SYNDROME (OMIM no. 277700) and Hutchinson-Gilford progeria syndrome (HGPS, OMIM no. 176670) are two well-characterized disorders that present with many features of early aging. Werner’s syndrome is a rare, autosomal recessive disorder caused by mutations in the Werner syndrome gene (WRN), which encodes a RecQ-type DNA/RNA helicase (1). HGPS interestingly results from specific synonymous heterozygous de novo mutations affecting the codon 608 of the lamin A/C (LMNA) gene, which normally encodes for glycine residue (2, 3, 4). The mutations generate an alternative splicing site in exon 11, resulting in a truncated lamin A protein. Both disorders have unique phenotypes with a few overlapping features. For example, Werner’s syndrome is characterized by short stature, bird-like appearance of the face, and early onset of aging processes such as graying of hair and osteoporosis (5, 6). The clinical features of Werner’s syndrome manifest during the third or fourth decade, and patients die prematurely during the fourth or fifth decade (6). In contrast, HGPS manifests as early as during the first year of life with severe alopecia, graying of hair, micrognathia, beaked nose, shrill voice, and extensive wrinkling of the skin. Later the patients develop lipodystrophy, joint contractures, severe atherosclerosis, and short stature (7). Many of them die before the age of 13 yr.

The University of Washington International Registry of Werner’s syndrome has been collecting patients with presumed diagnosis of Werner’s syndrome for several years. Of the 129 such patients, 26 carried no mutations in the coding region and the splicing sites of the WRN gene (8). Four of these 26 patients were recently discovered to harbor heterozygous missense mutations in the LMNA gene. These mutations were distinct from those reported in patients with typical HGPS, and thus, these patients were referred to as having atypical Werner’s syndrome (8). However, considering that they had heterozygous LMNA mutations similar to HGPS patients rather than compound heterozygous or homozygous WRN mutations as seen in patients with Werner’s syndrome, these patients may also be referred to as having atypical progeroid syndrome.

In recent years, LMNA mutations have been implicated in a variety of other rare disorders besides HGPS, including those that affect the adipose tissue (lipodystrophies), cardiac muscle (cardiomyopathy), skeletal muscle (muscular dystrophies), nervous system (Charcot-Marie Tooth neuropathy, type 2), skeletal tissue (mandibuloacral dysplasia), and cutaneous tissue (restrictive dermopathy) (7, 9, 10, 11). Among those with LMNA mutations, lipodystrophy has been reported in patients with familial partial lipodystrophy of the Dunnigan variety (12) and mandibuloacral dysplasia (13) and in a 27-yr-old French male with insulin resistance diabetes, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy who harbored an R133L heterozygous mutation in the LMNA gene (14). Interestingly, two of the four patients with atypical Werner’s syndrome reported by Chen et al. (8) also harbored the same R133L heterozygous LMNA mutation. These patients had short stature, scleroderma-like skin, graying and thinning of the hair, and diabetes mellitus. However, whether these patients had any peculiar type of lipodystrophy and associated metabolic abnormalities like the French patient is not known (15). Therefore, we studied the pattern of body fat distribution and metabolic abnormalities in these two patients with atypical Werner’s syndrome harboring the R133L heterozygous LMNA mutation.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Both patients were evaluated at the General Clinical Research Center of the University of Texas Southwestern Medical Center at Dallas. The research protocol was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center. All of the patients and the control subjects gave written consent to participate in the study. Limited data on these patients have been published previously (8). Clinical data included history, physical examination, review of their medical records, and responses to a written questionnaire.

Clinical features of the patients

A comparison of the clinical features of our patients with the previously reported French male has been presented in Table 1. Other salient features of each patient are described below:

This patient [previously referred to as ATLAN1010 by Chen et al. (8)] is a 23-yr-old African-American female who was diagnosed as having Werner’s syndrome at a very young age, as was her father. She reported thinning and graying of the hair at the age of 17 yr. She had a beaked nose and sclerodermatous, atrophic skin over the hands and feet (Fig. 1). She reported a peculiar skin discoloration over her body since childhood. She attained menarche at the age of 10 yr, followed by irregular heavy menstrual periods until the age of 18 yr. Subsequently, her menstrual cycles became more regular. At the same time, she was found to have an elevated fasting serum insulin level; however, fasting serum glucose concentration was normal. Her father had diabetes mellitus, hypertension, congestive heart failure, and peripheral vascular disease and developed end-stage renal disease before dying at the age of 49 yr.

View larger version (60K): [in this window] [in a new window]   FIG. 1. Anterior and right lateral views of patient 1 are shown in A and B, respectively. The patient appears older than her chronological age. Note the graying and thinning of hair, sparse eyebrows, beaked nose, and thin lips. C–E, Close-up of her axillary region, hand, and foot, respectively. Note loss of fat and atrophic-appearing skin over the hand and foot. The axillary region shows the lack of hair and the prominent skin pigmentation but no acanthosis nigricans.

Patient 2

This patient [previously referred to as PORTU8010 by Chen et al. (8)] is a 24-yr-old Caucasian female who was born at full term with a birth weight of 2.50 kg and a length of 47 cm. She attained menarche at the age of 14 yr, followed by regular menstruation with heavy bleeding. She started having graying and thinning of scalp hair at the age of 15 yr. She developed diabetes mellitus at the age of 18 yr. Insulin therapy was initiated; however, she has had poor glycemic control despite injecting more than 200 U of insulin a day. Serum aminotransferase levels have been persistently elevated since the age of 19 yr (Table 1).

On examination, she appeared much older than her stated age. She also had the bird-like face with a beaked nose; her lips were thin with exaggerated radial furrows resembling those seen in patients with scleroderma (Fig. 2, A and B). She had small mandible and a small mouth (Fig. 2A, B). Her eyes were deep set with sunken cheeks, and she had grooves over the temporal areas (Fig. 2). There were multiple white papules over hyperpigmented skin covering the neck, trunk, and upper extremities. The skin over the hands and feet was atrophic with prominent superficial veins (Fig. 2, D and E). No acanthosis nigricans was present. She had graying and thinning of scalp hair. There was also marked diminution of hair over her eyebrows and upper and lower extremities and complete absence of hair over axillary areas (Fig. 2C). She had thin, spindle-shaped fingers (Fig. 2D) with mild flexion contractures of distal and proximal interphalangeal and elbow joints. Calluses were noted on the heels. Liver was palpable 10 cm below the right costal margin, and spleen was palpable 1 cm below the left costal margin. She had generalized loss of sc fat over the face, neck, upper chest area, hips, and extremities. Breast development was at Tanner stage 2 with sparse pubic hair and no evidence of clitoromegaly. Lateral quadriceps appeared prominent bilaterally. Neurological examination was normal.

View larger version (38K): [in this window] [in a new window]   FIG. 2. Anterior and right lateral views of patient 2 (A and B, respectively). Note marked lipodystrophy and the graying and thinning of hair, beaked nose, and thin lips with deep furrows. C, Close-up of her axillary region shows mottled skin pigmentation. D and E, Atrophic appearance of the skin and the prominence of the veins over the hand and foot, respectively.

Anthropometric measurements. Height and body weight were measured by standard procedures. Skinfold thickness was measured with a Lange caliper (Cambridge Scientific Industries, Cambridge, MD) at five truncal (chest, midaxillary, abdomen, subscapular, and suprailiac) and six peripheral (biceps, triceps, forearm, hip, thigh, and calf) sites on the right side of the body and the chin. The mean of three repeat measurements at each site was calculated. Body volume was measured under water with a Whitmore volumeter (Whitmore Enterprise, San Antonio, TX). Pulmonary residual volume was measured using the helium dilution method (16). Proportion of body fat was estimated by Siri’s equation (17).

Magnetic resonance imaging (MRI). MRI studies were performed using a 1.5 Tesla imaging device (Philips Medical Systems, Best, The Netherlands) and 5.2–2 software. The patients were evaluated using 10-mm-thick T1 imaging technique with repetition time of 580 msec and a echo time of 8 msec and a 384 x 512 matrix combined with a 45-cm field of view. Adipose tissue distribution and thickness was assessed by visual inspection of the films.

Dual-energy x-ray absorptiometry (DEXA). Whole-body and regional fat in the head, trunk, and upper and lower extremities were determined using a DEXA scan with a multiple detector fan-beam Hologic QDR-2000 densitometer (Hologic, Inc., Waltham, MA). The proportion of fat in individual regions as well as whole body was calculated as percentage of body mass.

Metabolic assessments and genetic analysis

Biochemical analyses. Plasma glucose was measured by the glucose oxidase method with a glucose analyzer (Beckman Coulter, Inc., Fullerton, CA). Serum insulin and leptin levels were determined by immunoassays using commercial kits (Linco Research, Inc., St. Charles, MO). Serum cholesterol, triglycerides, high-density lipoprotein cholesterol, and chemistry as well as blood hemoglobin A1C were analyzed as part of a systematic multichannel analysis (Synchron CX9 ALX clinical system; Beckman, Fullerton, CA).

Oral glucose tolerance test. After an overnight fast, an oral glucose tolerance test was performed on patient 1. Seventy-five grams of dextrose was given orally, and venous blood was collected for determination of serum glucose and insulin concentrations at 30 min, 15 min, and immediately before glucose administration and at 30-min intervals thereafter for 180 min. Patient 2 was known to have diabetes and thus did not undergo this test.

Mutational and haplotype analyses. The LMNA gene was sequenced according to Chen et al. (8). We ascertained the haplotypes in the two subjects for the known exonic single-nucleotide polymorphisms (SNPs) in the LMNA gene.

Immunofluorescence microscopy. Primary fibroblasts from skin biopsy samples were grown on coverslips and fixed for 20 min in methanol at –20 C. The cells were made permeable by incubating in 0.1% Triton X-100 for 15 min at room temperature and blocked for nonspecific binding by incubating them with 5% normal serum containing 0.3% BSA. The cells were incubated with antibody for lamin A, which recognizes both the forms, lamin A and C (antibody H-110 at 1:100 dilution in blocking buffer; Santa Cruz Biotechnology, Santa Cruz, CA.) for 60 min at 37 C. Primary antibody was removed, and the coverslip was washed with PBS and incubated with the secondary antibody conjugated with green fluorescent dye (Alexa flour 488, diluted 1:100) and DNA staining dye TO-PRO-3 iodide (diluted 1:1000; Molecular Probes, Eugene, OR) for 60 min at 37 C. After washing, the coverslips were mounted using commercial mounting medium for fluorescent microscopy (Aqua Poly/Mount; Polysciences, Inc., Warrington, PA.) and were examined using the Axiovert 100M microscope (Carl Zeiss USA, Thornwood, NY).

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
The metabolic characteristics of the patients are summarized in Table 1. Patient 1 had normal fasting plasma glucose and triglyceride levels, but her 120-min postprandial plasma glucose level was elevated at 9.66 mmol/liter, consistent with impaired glucose tolerance. The fasting insulin level was 432 pmol/liter, with an exaggerated postprandial response ranging from 7,789 to 17,901 pmol/liter. Serum leptin level was 12.63 ng/ml (50th percentile for women) (18). In contrast, patient 2 showed marked insulin resistance diabetes mellitus and hypertriglyceridemia. Because she was already on high-dose insulin therapy, we did not measure her baseline insulin levels. Her serum leptin level was 0.77 ng/ml (<5th percentile for women) (18).

Overall, patient 1 showed near-normal body fat content. By underwater weighing, her body fat was estimated to be 25.5% of the body mass, which was slightly higher than the mean value of 24.4% reported for 18- to 55-yr-old women by Jackson et al. (19). By DEXA, her body fat was estimated to be 27%. The fat content in the trunk and arms was 30.2 and 32.2%, respectively, which was higher, compared with average values (29.0 and 30.2%, respectively) obtained for normal female subjects using DEXA scan (20). Her skinfold thicknesses in chest and axillae were near the 90th percentile of normal values, whereas the triceps skinfold thicknesses was near the 10th percentile of normal (17). MRI findings also revealed relative paucity of sc fat in the distal extremities with well-preserved sc fat over the abdomen and chest (Figs. 3–5). Interestingly, she had thick dorsocervical fat accumulation of 4.2 cm in comparison with sc dorsocervical fat thickness of less then 1.0 cm in two healthy control women. There was no excess fat noted over her chin or anterior neck area (Fig. 5A). She had mild hepatomegaly, with a liver size of about 18 cm in the cephalocaudal axis on MRI; her spleen measured 7.7 cm longitudinally and 3.2 cm at its greatest width. Head MRI showed normal amount of orbital, infratemporal, and buccal fat (Fig. 5).

View larger version (60K): [in this window] [in a new window]   FIG. 3. T1-weighted transaxial MRI of the arm and distal forearm and sagittal MRI of the hand from patient 1 (A, D, and G, respectively), patient 2 (B, E, and H, respectively), and a healthy 25-yr-old woman (C, F, and I, respectively). Sections through the distal forearm in patient 1 show more prominent loss of sc adipose tissue, compared with the arm. Note the reduction of sc fat over the palmar and dorsal aspects of the hands in both the patients (G and H, respectively).

View larger version (84K): [in this window] [in a new window]   FIG. 4. T1-weighted transaxial MRI at the level of the thigh and distal leg and sagittal MRI of the foot from patient 1 (A, D, and G, respectively), patient 2 (B, E, and H, respectively), and a healthy 25-yr-old woman (C, F, and I, respectively). Sections through the thigh reveal decreased intermuscular fat in patients 1 and 2, compared with the normal control. Note that although patient 1 has preserved sc thigh fat, there is asymmetric reduction in the posterolateral region (A). Patient 2 had marked loss of sc thigh fat (B). There is also a substantial decrease in the sc fat in the calves (D and E), dorsum, and plantar aspects of the feet in both of the patients (G and H). The bone marrow fat is preserved.

View larger version (105K): [in this window] [in a new window]   FIG. 5. Midline sagittal T1-weighted MRI at the level of head and chest region and transaxial MRI at the level of abdomen in patient 1 (A and D, respectively), patient 2 (B and E, respectively), and a healthy 25-yr-old woman (C and F, respectively). Note the increase in the sc adipose tissue in the dorsocervical region of patient 1 (A) when compared with near total loss of sc truncal and neck fat in patient 2 (B). The abdominal MRIs show preserved intraabdominal fat with normal sc fat in patient 1 (D) but decreased sc fat in patient 2 (E), compared with the normal subject (F).

LMNA exonic SNPs

We determined haplotypes associated with the 398G>T LMNA mutation using known intragenic synonymous exonic SNPs [51C>T (Ser17Ser), 612G>A (Leu204Leu), 861T>C (Ala287Ala), 1338T>C (Asp446Asp), and 1698C>T (His566His)] extending 24.2 kb of genomic DNA. The nucleotide numbering starts with the adenine of the first ATG codon for lamin A/C. Patient 1 was heterozygous for the T51-G612-C861-C1338-C1698 and T51-G612-T861-C1338-C1698 haplotypes. Patient 2 was homozygous for the T51-G612-T861-T1338-C1698 haplotype. Clearly their unique haplotypes suggest that the mutations arose independently.

Immunofluorescence microscopy

Skin fibroblasts from these patients were from early (3, 4) passages. Indirect immunofluorescent studies revealed normal localization of the lamin A/C protein in the nuclear envelope in both the affected subjects. From the fibroblasts of patient 2, we captured images of 32 nuclei of which 25 (78%) showed abnormal nuclear morphology. There were several deformed nuclei, showing multilobulations, nuclear membrane invagination, and nuclear hypertrophy (Fig. 6B). Remarkably the DNA staining was normal (data not shown). In contrast to patient 2, only nine of 69 nuclei (13%) from patient 1 showed abnormalities (P < 0.0001) (Fig. 6A). In our experience, only 2–3% of the normal fibroblasts show mild nuclear abnormalities.

View larger version (32K): [in this window] [in a new window]   FIG. 6. A, Indirect immunofluorescence microscopy using lamin A/C antibody (H-110) in skin fibroblasts obtained from a control subject (i–iii), patient 1 (iv–vi), and patient 2 (vii–ix). Panels i, iv, and vii show immunostaining for lamin A/C; panels ii, v, and viii show nuclear DNA staining; and panels iii, vi, and ix show the merged images from the lamin A/C and DNA staining. Occasional nuclear blebs were observed in fibroblasts from patient 1. The multilobulated nuclei were observed more frequently in patient 2. B, Shown also are several individual nuclei from patient 2 stained for lamin A/C protein with various deformities (i–v).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

Interestingly, all three patients with R133L heterozygous LMNA mutation had unique body fat distribution, which differed from the patterns seen in patients with typical and atypical familial partial lipodystrophy of Dunnigan type and those with mandibuloacral dysplasia (13, 21, 22). The loss of sc fat in Dunnigan variety of familial partial lipodystrophy tends to involve the whole upper and lower extremities rather than just the distal parts of the extremity as seen in patient 1. Moreover, patients with familial partial lipodystrophy of Dunnigan type have preserved sc fat in the palms and soles, whereas our patients showed marked loss of fat in these regions. However, dorsocervical fat accumulation as seen in patient 1 has also been reported in a few patients with familial partial lipodystrophy of Dunnigan type and mandibuloacral dysplasia (13, 21, 22). Thus, our study reveals that lipodystrophy in patients with various LMNA mutations can present with either partial or generalized loss of body fat. Partial lipodystrophy can further be divided into two distinct patterns, one that involves the entire extremities as seen in familial partial lipodystrophy, Dunnigan type, and mandibuloacral dysplasia and another form that is seen in patient 1 in which only the distal regions of the extremities are involved.

There were a number of similarities in clinical presentation of our patients, compared with the French patient. All three had early graying of scalp hair beginning in the second decade of life, with thinning of eyebrows and atrophied skin over the dorsum of the hands and feet, giving them a progeroid appearance. They also had a peculiar skin lesion consisting of multiple whitish papules on upper limbs and to a lesser extent on the lower limbs.

Although all three patients had insulin resistance of varying severity, they all lacked acanthosis nigricans. Patient 2 had the most severe form of insulin resistance diabetes requiring more than 200 U of sc insulin per day. She also had clinical evidence of nonalcoholic steatohepatitis. In contrast, patient 1 had only impaired glucose tolerance. Despite generalized lipodystrophy, the French patient had mild insulin resistance, compared with patient 2. We previously reported marked gender difference in the prevalence of metabolic complications of insulin resistance in patients with familial partial lipodystrophy of the Dunnigan variety, with women having higher prevalence of diabetes and dyslipidemia than men (23, 24). Similar gender differences may be present among patients with generalized lipodystrophies due to LMNA mutation.

The precise reasons that patient 1 has a unique lipodystrophy phenotype, compared with patient 2 and the French patient, remain unclear. Various factors such as genetic background, including interactions with other genes that might affect phenotype, differential methylation, and imprinting, and intrauterine and postnatal environmental factors can affect the variability in phenotypic expression. Phenotypic variation has also been observed in other laminopathies associated with myopathies. For example, in affected members of a family with heterozygous T959del LMNA mutation, Brodsky et al. (25) found phenotype ranging from normal, mild Emery-Dreifuss muscular dystrophy, or limb-girdle muscular dystrophy. Muchir et al. (26) also reported phenotypic variance in nuclear families with single LMNA mutation and found some subjects harboring the mutant alleles to have essentially normal muscular strength, whereas others had limb-girdle muscular dystrophy. Unlike these subjects who belonged to nuclear families (25, 26), our patients do have environmental and racial differences that could modify the phenotypic expression of the gene. Patient 1 is of African-American descent, whereas both patient 2 and the French patient are of European origin. Recent genetic studies have shown higher degree of genetic polymorphism, including presence of rare alleles among individuals of African origin when compared with non-African subjects (27, 28). Thus, it is possible that patient 1 might carry rare alleles or polymorphisms in other genes involved in nuclear lamina structure that could result in a milder phenotype. There are candidate genes such as the zinc metalloproteinase (ZMPSTE24), which cleaves prelamin A, that could modify the processing of prelamin A into mature lamin A (29, 30, 31). However, for now, no single modifier gene has been shown to account for any of the phenotypic variations seen in laminopathies due to identical LMNA mutation.

Immunofluorescence microscopy study showed normal lamin A/C localization within the nuclear envelope boundary in the skin fibroblasts. However, there are substantial differences in the nuclear morphology between the two patients. Patient 1 has far less misshaped nuclei than patient 2, which certainly correlates with the severity of fat loss in these two patients. Despite this abnormality, the DNA remains localized in the nucleus. How the same mutation affects the morphology of the nucleus differently in two individuals remains unclear.

In summary, patients with atypical Werner’s syndrome due to heterozygous R133L LMNA mutation present with different patterns of lipodystrophy, distal partial lipodystrophy or generalized lipodystrophy. Our findings demonstrate the clinical heterogeneity in loss of body fat observed in patients harboring R133L LMNA mutation.

	Acknowledgments

 
We acknowledge the cooperation of the patients’ families. We thank Dr. Peter Snell for helping with the anthropometric measurements; Jennifer Sprayberry and Meredith Millay for technical help; Nancy B. Hanson, R.N., for helping us contact one of the subjects; and the staff of the General Clinical Research Center for general patient care support.

	Footnotes

 
This work was supported in part by National Institute of Health Grants R01-DK54387 and M01-RR00633 and the Southwestern Medical Foundation.

First Published Online September 20, 2005

Abbreviations: DEXA, Dual-energy x-ray absorptiometry; HGPS, Hutchinson-Gilford progeria syndrome; LMNA, lamin A/C gene; MRI, magnetic resonance imaging; SNP, single-nucleotide polymorphism.

Received April 29, 2005.

Accepted September 8, 2005.

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