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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 5 2360-2364
Copyright © 2004 by The Endocrine Society

Gene and Phenotype Analysis of Congenital Generalized Lipodystrophy in Japanese: A Novel Homozygous Nonsense Mutation in Seipin Gene

Ken Ebihara, Toru Kusakabe, Hiroaki Masuzaki, Nozomi Kobayashi, Tomohiro Tanaka, Hideki Chusho, Fumiko Miyanaga, Takashi Miyazawa, Tatsuya Hayashi, Kiminori Hosoda, Yoshihiro Ogawa and Kazuwa Nakao

Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan

Address all correspondence and requests for reprints to: Dr. Ken Ebihara, Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: kebihara{at}kuhp.kyoto-u.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Congenital generalized lipodystrophy (CGL), Berardinelli-Seip syndrome, is a rare metabolic disorder characterized by a near total lack of adipose tissue from birth or early infancy. Recently, seipin, encoding a 398-amino acid protein of unknown function, and AGPAT2, encoding 1-acyl-sn-glycerol-3-phosphate acyltransferase 2, were identified as causative genes for CGL. Seipin mutations were found in patients from families originating from Europe and the Middle East. AGPAT2 mutations were found predominantly in African ancestry. However, no information is available on these genes in the pathogenesis of CGL in Asian ancestry. We examined the sequences of the entire coding region of seipin and AGPAT2 in four Japanese CGL patients from independent families. Their average body fat content was 4.7 ± 0.5%, and the plasma leptin level was 1.15 ± 0.14 ng/ml. We identified a novel nonsense mutation of seipin at codon 275 (R275X). Of four CGL patients, three were homozygous for R275X. No seipin mutation was found in any exon in one patient. We did not find any AGPAT2 mutations in our Japanese patients, suggesting that AGPAT2 is a minor causative gene, if any, for CGL in Japanese. This is the first report on gene and phenotype analysis of CGL in Japanese.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
CONGENITAL GENERALIZED LIPODYSTROPHY (CGL), Berardinelli-Seip syndrome, is characterized by a near total lack of adipose tissue from birth (1, 2, 3). Patients with CGL show severe insulin resistance, hypertriglyceridemia, and fatty liver. These metabolic abnormalities develop as a consequence of mass reduction of adipose tissue (4, 5). Leptin is an adipocyte-derived hormone that plays an important role in the regulation of glucose and lipid metabolism (6, 7, 8). Plasma leptin concentrations are markedly reduced in patients with lipodystrophy (9, 10). In this context, we and others (11, 12) demonstrated that transgenic overexpression of leptin or exogenous leptin administration reverses the metabolic abnormalities in different mouse models of lipoatrophic diabetes, indicating that the metabolic abnormalities in patients with lipodystrophy are caused mainly by a lack of leptin. However, the genetic defect that causes a failure of adipogenesis or adipocyte differentiation in CGL had long been unknown.

CGL has been suggested to be an autosomal recessive disorder. Recently, two causative genes for CGL were identified. One is a gene encoding a protein named seipin, whose function is unknown (13). The other is the AGPAT2 gene encoding 1-acyl-sn-glycerol-3-phosphate acyltransferase 2 that belongs to the family of acyltransferases and catalyzes the biosynthesis of glycerophospholipids and triglyceride (14). The seipin gene is located in chromosome 11q13, and the AGPAT2 gene is located in chromosome 9q34. Although there is no difference in the prevalence of metabolic disorders such as insulin resistance, hypertriglyceridemia, and fatty liver between patients with the seipin or AGPAT2 mutation, CGL due to seipin mutation appears to be a more severe disease than that due to AGPAT2 mutation, with a higher incidence of premature death and a lower prevalence of partial and/or delayed onset of lipodystrophy (15). Furthermore, patients with the seipin mutation have a higher prevalence of intellectual impairment than those with the AGPAT2 mutation (15).

Seipin mutations were found in patients originating from Europe and the Middle East. AGPAT2 mutations were found predominantly in African ancestry. However, no information is available about these genes in the pathogenesis of CGL in Asian subjects. The present study is the first report on gene and phenotype analysis of CGL in Japanese.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study subjects

Sequence analyses of seipin and AGPAT2 were performed in four Japanese CGL patients (two men and two women). The clinical features and laboratory data of these patients are presented in Tables 1Go and 2Go. All of these patients had a near total lack of body fat from birth. The study was approved by the ethical committee of Kyoto University Graduate School of Medicine. All subjects gave written informed consent for participating in the study.


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  		TABLE 1. Clinical features of patients with CGL

 

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  		TABLE 2. Metabolic characters of patients with CGL

 
Materials and methods

Genomic DNA was isolated from blood using InstaGene Whole Blood kit (Bio-Rad, Hercules, CA) according to the manufacturer’s protocol. The coding regions of seipin and AGPAT2 were amplified by PCR using gene-specific primers (13, 14) in seven and six fragments, respectively. PCR products were separated by electrophoresis in 2% agarose gel, purified, and sequenced directly by the dideoxy chain termination method with both forward and reverse primers on an ABI PRISM 310 Genetic Analyzer (PerkinElmer, PE Applied Biosystems, Foster City, CA). Genotyping of the patients with highly polymorphic microsatellite markers in chromosome 11q13 for the seipin locus and chromosome 9q34 for the AGPAT2 locus was conducted with an ABI PRISM 310 Genetic Analyzer equipped with GeneScan analysis software (version 2.1, PerkinElmer).

The body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Body fat was determined by dual energy x-ray absorptiometry. Body fat distribution was assessed using the whole body magnetic resonance imaging (MRI). MRI was performed using a 1.5-Tesla imaging device (Phillips Medical Systems, Best, The Netherlands). The entire body was surveyed using contiguous axial 10-mm slices and a relatively T1-weighted spin echo sequence. Blood samples were obtained after an overnight fast. Plasma leptin levels were determined by immunoassay using a commercial kit (Linco Research, Inc., St. Charles, MO). Blood glucose and triglyceride levels were determined according to standard methods with the use of automated equipment. Hemoglobin A1c values were measured by ion exchange HPLC. Serum insulin levels were determined by immunoassays using reagents provided by Shibayagi Co. Ltd. (Gunma, Japan). The presence of hypertrophic cardiomyopathy was assessed using echocardiography, electrocardiography, and plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels. Plasma ANP and BNP levels were determined by immunoradiometric assay (Shionogi, Osaka, Japan) (16, 17). Fatty liver was diagnosed by both ultrasound and computed tomographic imaging. Intelligence quotient (IQ) was assessed using the Wechsler Adult Intelligence Scale-revised (18).

Statistical analysis

The average BMI in patient 1’s family members with or without R275X heterozygous mutation were expressed as the mean ± SE. Comparison among groups was assessed by ANOVA and was completed by Fisher’s probable least significant difference test.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
We studied four Japanese CGL patients from independent families. Clinical features of the patients are provided in Tables 1Go and 2Go. These four patients showed generalized reduction or a near total lack of adipose tissue from birth. They presented with low body fat content and plasma leptin levels. Whole body MRI scans were available for patients 1, 3, and 4 (Fig. 1Go). All of these patients showed nearly total absence of sc fat throughout the body, including palm, sole, and head. They also showed near absence of ip fat. Retroorbital and bone marrow fat were preserved only in patient 4, not in patients 1 and 3. Patients 1, 3, and 4 had overt diabetes and markedly elevated hemoglobin A1cvalues. Patient 1 was receiving insulin therapy. Patient 2 was not diabetic, although she presented with hyperinsulinemia. Patients 1 and 3 had both hypertriglyceridemia and fatty liver. In patient 2, hypertriglyceridemia and fatty liver had been observed in childhood. However, her fatty liver was improved on a strict low fat diet. Neither hypertriglyceridemia nor fatty liver was seen in patient 4. The prevalence of hypertrophic cardiomyopathy in CGL was reported as approximately 20% regardless of genotype (15). We assessed the presence of hypertrophic cardiomyopathy using echocardiography, electrocardiography, and plasma ANP and BNP levels. These results are presented in Table 3Go. Echocardiography indicated no apparent sign of hypertrophy in interventricular septal wall and left ventricular posterior wall. Electrocardiography indicated no sign of left ventricular hypertrophy. Plasma levels of ANP and, especially, BNP were elevated in patients with hypertrophic cardiomyopathy (19). Although the plasma BNP level in patient 3 was slightly elevated, all patients’ levels of both ANP and BNP were almost within normal range. None of the four CGL patients had obvious hypertrophic cardiomyopathy. IQ was assessed in patients 1 and 4. Their IQs were 76 and 80, respectively, which were relatively low, but in the normal range. A formal assessment was not available for patients 2 and 3, but they also showed no distinct intellectual impairment that interfered with daily or school life. All four patients had mild to moderate acanthosis nigricans. Patient 2, who was 12 yr of age, had still not experienced menophania. Patient 3 experienced menophania at the age of 12 yr, but presented with oligomenorrhea and polycystic ovary in our study.



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  		FIG. 1. T1-weighted magnetic resonance images at the levels of orbits (A–D), umbilicus (E–H), palm (I–L), and thigh (M–P) in the control (A, E, I, and M) and in patients 1 (B, F, J, and N), 3 (C, G, K, and O), and 4 (D, H, L, and P).

 

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  		TABLE 3. Clinical parameters related to hypertrophic cardiomyopathy in patients with CGL

 
Sequence analysis of the entire coding regions of seipin and AGPAT2 disclosed a novel homozygous C to T mutation at nucleotide 823 in exon 8 of seipin in patients 1, 2, and 3 (Fig. 2Go). This mutation predicts the substitution of arginine at codon 275 by the stop codon (R275X). Patient 4 had no mutation in the coding regions of the seipin gene. We did not find any AGPAT2 gene mutation in all four Japanese patients. The pedigrees of the patients are illustrated in Fig. 3Go. Consanguinity was recognized in the pedigrees of the patients with the seipin mutation, but not in the pedigree of patient 4. Although a DNA sample from the father of patient 3 was not available, the remaining five parents of the three patients with the seipin gene mutation were all heterozygous for the mutation. Parents showed no CGL phenotypes. Their BMI ranged from 23.5–26.3, and they were not diabetic. We also examined 10 family members of patient 1 for the R275X mutation and found six of them to be heterozygous (Fig. 2AGo). We found no significant difference in the average BMI between the family members with or without the R275X heterozygous mutation (25.5 ± 3.6 and 27.8 ± 3.3 kg/m2, respectively; P = 0.33). We also found no difference in the prevalence of diabetes mellitus between these two groups. Of 10 family members, one for each genotype had diabetes mellitus. These observations indicate that CGL caused by the seipin R275X mutation is inherited as an autosomal recessive fashion.



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  		FIG. 2. Sequence analyses of the seipin gene. A, B, and C, Homozygous and heterozygous C to T mutations and normal sequence at nucleotide 823 in patient 1, his father, and his aunt.

 


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  		FIG. 3. Pedigrees of patients 1 (A), 2 (B), 3 (C), and 4 (D). Squares and circles indicate males and females, respectively. The probands are shown as filled symbols, and other family members are shown as unfilled symbols. The R275X homozygous mutation is shown as XX, the heterozygous mutation is shown as RX, and the wild type is shown as RR.

 
We investigated the genotype using microsatellite markers on seipin and AGPAT2 loci and single nucleotide polymorphisms (SNPs) within the seipin gene (13, 20) (Table 4Go). Patients 1–3 were homozygous for the microsatellite markers flanking the seipin gene and the SNPs within the gene. In addition, they were disclosed to have the same genotype of microsatellite markers in this region and the SNPs. On the other hand, patient 4 was heterozygous for both seipin and AGPAT2 loci.


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  		TABLE 4. Status of microsatellites and SNPs at the seipin and AGPAT2 loci in patients

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Seipin is homologous to cDNA of the mouse Gng3lg with unknown function, which is localized in the region of mouse chromosome 19 that is orthologous to human 11q (13, 21, 22, 23). Comparison between mouse and human sequences showed that the human cDNA contained an open reading frame of 1196 nucleotides, starting at position 345. Seipin is a predicted protein with 398 amino acids and more than two hydrophobic amino acid stretches, suggesting that it could be a trans-membrane protein. However, seipin has no similarity with other known proteins or consensus motif that could predict its function. Fourteen different seipin mutations, including R275X, have been identified to date (13, 15). Of these mutations, R275X is the most C-terminally located mutation. R275X results in a deletion of 124 amino acids of its C-terminal region. The patients with the homozygous R275X mutation show typical CGL phenotypes, suggesting that the C-terminal region of 124 amino acids could be important for the protein function, especially in adipogenesis or adipocyte differentiation. The metabolic phenotypes including insulin resistance and dyslipidemia in our subjects were similar to those observed in CGL subjects with the seipin mutation from other ethnic groups (13, 15). This suggests that the seipin gene mutation alone is sufficient for the onset of these metabolic abnormalities.

Of four patients we investigated, three had a homozygous mutation in the seipin gene, and their mutation was the same R275X mutation in all of them. Although they were from independent families living in different remote regions in Japan, they had the same genotype of the microsatellite markers flanking the seipin gene and the SNPs within the gene. This demonstrates that they have a common ancestor in whom the R275X mutation was originated.

We did not find any mutations in the coding regions of seipin and AGPAT2 in patient 4. Genotype analysis using microsatellite markers and SNPs revealed that he is heterozygous for seipin and AGPAT2 loci. His phenotype, without hypertriglyceridemia and fatty liver, is atypical for CGL with seipin or AGPAT2 mutation. Further, retroorbital and bone marrow fats are preserved only in patient 4 in the present study. Taken together, it is unlikely that seipin and AGPAT2 genes link to his disease, although we cannot completely exclude the possibility that he has compound heterozygous mutation in noncoding regions of the genes. In addition, the generalized deficiency of body fat and the typically lipoatrophic face were noticed at birth, and autoimmune or causative disease has not been demonstrated in patient 4. These findings indicate the possible existence of another locus for CGL.

We did not find any AGPAT2 mutations in these four patients. Although the number of subjects we examined was small, these observations indicate that AGPAT2 is a minor causative gene for CGL in the Japanese people. We also elucidated that one of four patients is without seipin or AGPAT2 mutations. He did not present a lipid metabolic disturbance until now, although dyslipidemia is one of the major phenotypes of CGL caused by seipin or AGPAT2 mutations. This observation is consistent with the presence of another CGL-associated gene (20). This is the first report of gene and phenotype analysis of CGL in the Japanese population.


   Acknowledgments
 
Drs. Koji Kitamura, Katsuhiko Tachibana, Masanori Adachi, and Yoichiro Oda originally referred the patients for assessment. We thank Jocelyne Magre, Ph.D., for helpful comments about gene analysis.


   Footnotes
 
This work was supported by grants from the Japanese Ministry of Health, Welfare, and Labor; Kato Memorial Bioscience Foundation; a grant-in-aid from the Japan Medical Association; the Japan Research Foundation for Clinical Pharmacology; and a study grant from the Japan Insulin Study Group.

K.E. and T.K. contributed equally to this work.

Present address for Y.O.: Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan.

Abbreviations: ANP, Atrial natriuretic peptide; BMI, body mass index; BNP, brain natriuretic peptide; CGL, congenital generalized lipodystrophy; IQ, intelligence quotient; MRI, magnetic resonance imaging; SNP, single nucleotide polymorphism.

Received July 11, 2003.

Accepted February 12, 2004.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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