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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 10 3438-3444
Copyright © 1997 by The Endocrine Society

Original Studies

Genetic Exclusion of 14 Candidate Genes in Lipoatropic Diabetes Using Linkage Analysis in 10 Consanguineous Families1

Corinne Vigouroux, Eliane Khallouf, Charlotte Bourut, Jean-Jacques Robert, Marc de Kerdanet, Nadia Tubiana-Rufi, Sabine Fauré, Jean Weissenbach, Jacqueline Capeau and Jocelyne Magré

INSERM U-402, Faculté de Médecine Saint-Antoine (C.V., C.B., J.C., J.M.); Service d’Endocrinologie Pédiatrique, Hôpital Necker-Enfants Malades (J.-J.R.); and Service d’Endocrinologie et de Diabétologie, Hôpital Robert Debré (N.T.-R.), Paris, France; Service de Pédiatrie, Hôpital Hôtel-Dieu de France (E.K.), Beirut, Lebanon; Service d’Endocrinologie Pédiatrique, Hôpital Sud (M.d.K.), Rennes, France; and CNRS URA 1922, Généthon (S.F., J.W.), Evry, France

Address all correspondence and requests for reprints to: Dr. J. Magré, INSERM U-402, Faculté de Médecine Saint-Antoine, 27 rue Chaligny, 75571 Paris Cedex 12, France. E-mail: magre{at}st-antoine.inserm.fr


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Lipoatropic diabetes (LD) is a rare recessive autosomal disorder, mainly characterized by lipoatrophy with alterations in lipid metabolism and extreme insulin resistance. To identify molecular defects responsible for this disease, we tested the implication of 14 candidate genes coding for proteins involved either in insulin action, i.e. insulin receptor, insulin receptor substrate 1, insulin-like growth factor I receptor, diabetes-associated ras-like protein (Rad), and glycogen synthase, or in lipid metabolism, i.e. lipoprotein lipase; apolipoproteins CII, AII, and CIII; hepatic lipase; hormone-sensitive lipase; the ß3-adrenergic receptor; leptin; and fatty acid-binding protein 2. To this end, haplotype and linkage analyses using genotyping with microsatellites in 10 consanguineous families provided us with powerful genetic tools. Our results show that in most families, lod scores at a null recombination fraction were less than -2. Haplotype analysis also argues against the involvement of these genes in LD. This implies that mutations in these genes are unlikely to make a major genetic contribution to LD.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
LIPOATROPIC diabetes (LD) is a rare genetic disease that belongs to the syndromes of severe insulin resistance, also including leprechaunism, Rabson Mendenhall syndrome, and type A insulin resistance. In addition to major insulin resistance, these diseases share clinical features, such as acanthosis nigricans, hyperandrogenism, and growth and puberty abnormalities (1). Moreover, in LD, patients present with generalized lipoatrophy affecting both sc and visceral fat, liver steatosis leading to cirrhosis, muscular hypertrophy, and a high level of triglycerides that can cause acute pancreatitis (2). Generalized lipoatrophy can present as the congenital Berardinelli-Seip syndrome occurring at birth or in early infancy (3, 4) or the acquired Lawrence syndrome with the appearance of lipoatrophy delayed in late childhood or adulthood (5). In both forms, a high incidence of parental consanguinity has been documented, suggesting an autosomal recessive transmission.

Although the pathophysiology of LD is not clearly understood at the moment, insulin resistance and lipoatrophy appear to be the main features. Therefore, to identify the gene(s) responsible for LD, we performed a linkage study in affected families using a functional approach. We studied candidate genes involved in insulin action and lipid metabolism, most of which have been shown to be related to insulin resistance in noninsulin-dependent diabetes mellitus (NIDDM) or obese patients.

Defective insulin action may be due to alterations in any protein involved in signal transduction between the receptor and the final insulin-regulated proteins. We previously excluded the implication of the insulin receptor gene (INSR) in two families with LD (6), in accordance with other reports (7, 8, 9), and we now extend this study to eight more families. We also examined the insulin-like growth factor I receptor (IGFIR), which shares with the insulin receptor several steps of intracellular signaling (10). We previously described a reduction in IGF-I-stimulated receptor autophosphorylation in cultured fibroblasts from LD patients (11). We studied insulin receptor substrate 1 (IRS1), an important step in the insulin and IGF-I signaling pathways (12). Diabetes-associated ras-like protein (rad) is overexpressed in muscle of NIDDM patients and could be implicated in insulin action (13). Muscle glycogen synthase (GSY1), the rate-limiting enzyme in the glycogen synthesis pathway, has been shown not to be activated by insulin in a LD patient (14).

Genes affecting lipid metabolism are also candidate genes for contributing to the development of LD. Lipoprotein lipase (LPL), its cofactor apolipoprotein CII (APOC2), and hepatic lipase (LIPC) catalyze the hydrolysis of triglycerides at the endothelial surfaces of extrahepatic and hepatic tissue, respectively, thus providing free fatty acids for adipose, muscular, and hepatic cells. Hormone-sensitive lipase (LIPE) plays a prominent role in the mobilization of free fatty acids from adipose tissue by controlling the rate of lipolysis of the stored triglycerides. Increased activation of this enzyme could produce triglyceride depletion of adipocytes. We also studied apolipoproteins AII (APOA2) and CIII (APOC3), which play an important role in the regulation of plasma lipids. It has been suggested that the APOA2 locus is linked to a gene controlling free fatty acid levels (15). A gene linked to the fatty acid-binding protein 2 locus (FABP2) on chromosome 4q may contribute to insulin resistance in Pima Indians (16). The ß3-adrenergic receptor (ADRB3), located mainly in adipose tissue, is involved in the regulation of lipolysis and thermogenesis. Finally, as leptin is secreted by adipose tissue and is involved in regulation of body fat, it is of interest to examine its gene, ob, for linkage in LD families.

According to the homozygosity mapping theory (17), consanguineous families provide a powerful tool to test the role of a candidate gene in a rare autosomal recessive disorder. Linkage analysis was, therefore, carried out in 10 inbred families using simple tandem repeat DNA polymorphisms at these 14 candidate genes loci.


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

We studied 10 consanguineous families with 1–3 affected children, originating from Senegal, Tunisia, Algeria, Portugal, and Lebanon. Pedigrees of these families are shown in Fig. 1Go. Patients were born of first cousin unions in 6 families (He, Jr, Ma, Ou, Sa, and Ta), second cousin marriages in 2 families (Di and Fa), and a more complex consanguinity is in families Ha and Wa. These latter families, Ha and Wa, cluster in a very small geographic area of Northern Lebanon. The main clinical and biological features of each patient are shown in Table 1Go. All 15 patients exhibited typical features of LD; in addition to lipoatrophy, most of them presented with acanthosis nigricans, hepatomegaly, and muscular hypertrophy. Other clinical characteristics were observed in about half of the patients: acromegaloid dysmorphy (7 of 15), external genitalia enlargement (8 of 15), and mild mental retardation (8 of 15). Polycystic ovary disease was diagnosed in all postpubertal females (Di-1, Ta-1, and Ou-1) with marked hirsutism. Insulin resistance was always present, most frequently worsening with aging; hyperinsulinemia existed in fasting and/or in postabsorptive states, leading to glucose intolerance or diabetes. Di-3, who was 9 months old at the time of the examination, had only mild postabsorptive hyperinsulinemia and mild fasting hypertriglyceridemia. Diagnosis was based essentially on the lipoatropic aspect and the familial antecedents. It is noteworthy that her brother, Di-2, from the age of 7 yr progressively developed frank hyperinsulinemia and clinical features of LD in addition to neonatal lipoatrophy. When insulin therapy was used, very high doses were necessary to lower plasma glucose; patients Di-1, Ou-1, and Jr-1 received 5 U/kg or more daily insulin, without sufficient glycemic control. Two patients exhibited the delayed onset form of the lipoatrophy (Ou-1 and Ta-1), although all other patients were lipoatropic at birth or within the very first months of life.



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  		Figure 1. Pedigrees of the 10 consanguineous families. The geographic origin of each family and the years of birth of the subjects are mentioned. Subjects that have been genotyped for each marker are shown by an asterisk. Solid circle and square, LD; left-striped circle and square, NIDDM; right-striped circle and square, insulin-dependent diabetes; slashed circle and square, deceased; boxes linked on top, dizygotic twins; boxes linked on top and at the side, monozygotic twins.

 

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  		Table 1. Main clinical and biological features of studied patients

 
In vivo and in vitro investigations were previously performed in some of these patients. Precise characterization of insulin resistance using an euglycemic hyperinsulinemic clamp was performed in Di-1, Ta-1, and Ou-1 (18, 19). Binding of insulin to its receptor was normal in erythrocytes and cultured fibroblasts, but receptor tyrosine kinase activity was altered in cultured fibroblasts in Di-1 and Ta-1. In accordance, postbinding defects in glucose metabolic pathways were identified in these patients (11, 20). The sequence of INSR was normal in patients Di-1, Di-2, Ma-1, Ou-1, and Ta-1. Furthermore, segregation analysis of intragenic polymorphisms in the INSR gene excluded a linkage between the IR locus and the LD phenotype in families Di and Ma (6).

The patients and their relatives gave their informed consent to participate in the study. This work was approved by an institutional review board.

Genetic studies

DNA was prepared from peripheral white blood cells using standard procedures (21). Subjects were genotyped at the candidate genes loci, using simple tandem repeat DNA polymorphisms. Published intragenic polymorphisms were used to test INSR, IRS1, IGFIR, FABP2, GSY1, LPL, APOC2, LIPC, APOA2, APOC3, and LIPE. ADRB3, rad, and ob were analyzed using anonymous microsatellites (22) located at, respectively, 0–2.3 centimorgans (cM) (23), 0–2.6 cM (22, 24), and 0 cM (25) from the corresponding gene. Markers were amplified by PCR, using the primer sequences and conditions shown in Table 2Go, following a multiplexing procedure (26).


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  		Table 2. Main features of candidate genes markers

 
Two-point lod scores were calculated using the MLINK program (version 5.2) of the LINKAGE package (27), assuming that LD had an autosomal recessive mode of inheritance with a complete penetrance and a zero phenocopy rate, and that the disease gene had a population frequency of 1/3000. Consanguineous loops were incorporated in the pedigree files and processed by MAKEPED.

When two microsatellites were tested to study a single locus (studies of ADRB3, ob, LIPE, andrad), haplotype analyses were interpreted using the Lander and Botstein theory (17): in rare recessive genetic diseases, affected children from consanguineous families are expected to be homozygous for the defective allele inherited from a common ancestor.


   Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 3Go shows the lod scores calculated for each family at a recombination fraction ({theta}) of 0.00 and, when the microsatellites were not intragenic, also at {theta} corresponding to the maximal possible distance from the genes. Maximal lod scores at {theta} = 0.00 have been calculated by simulating perfect segregation between a rare allele of a fully informative putative marker and the disease.


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  		Table 3. Pedigrees lod scores at {theta} = 0.00 and at {theta} corresponding to the maximal possible distance between the marker and the gene

 
APOA2, APOC2, APOC3,FABP2, GSY1, IGFIR, INSR,IRS1, LIPC, and LPL loci were studied using one polymorphic marker. For all of these loci, most of the families had a lod score below -2, thus excluding the involvement of the corresponding gene as the cause of LD in many cases. In other families, lod scores could not reach significant values. In family Di, the lod score was 1.35 and 1.24 for APOA2 and LIPC loci, respectively, but informativity was not sufficient, the father being homozygous for these two markers. Moreover, these values remained far less than the theoretical maximal lod score of this family (3.38). In only two cases did microsatellite segregation suggest linkage between the marker and the disease: in family Ha at the APOC2 locus (lod score, 1.82) and in family Ta at the APOA2 locus (lod score, 1.17). However, as another significant linkage was not shown in any other family at these loci, the implication of the corresponding gene seems very unlikely. There is another argument against the involvement of APOC2 in family Ha because of its geographic clustering with family Wa. Indeed, as LD is very rare, it could be postulated that an ancient mutation in a single gene is responsible for the disease in the two families (founder effect). The lod score of family Wa at the APOC2 locus was infinitely negative, so we could rule out the involvement of this gene in LD in this family and, thus, most likely in family Ha.

ADRB3 and rad loci were studied using two microsatellites located, respectively, 0–2.3 and 0–2.6 cM from the gene. Lod scores calculated at {theta} corresponding to the maximal genetic distance were, as expected, less significant than those at {theta} = 0.00. However, in addition to lod score calculations, haplotype analysis was performed in each family. With regard to the Lander and Botstein theory (17), affected subjects born from consanguineous unions are expected to be homozygous for the morbid allele inherited from each of their parents. Therefore, assuming a complete penetrance of the disease in the context of full informativity of the markers, we could exclude linkage at a locus because 1) the two parents do not share a common allele; 2) patients are heterozygous; 3) an affected child has the same haplotype as a normal sibling; or 4) affected siblings have different haplotypes. Haplotype analysis formally excluded the involvement of ADRB3 and rad loci in most families. Similar results were obtained for LIPE and ob.

These two analyses of lod scores and haplotype transmission allowed us to exclude most of the loci in each family. Definite exclusion could not be affirmed in only four cases: for the ADRB3 locus in families Ha and He, for the LIPE locus in family He, and for the rad locus in family Sa. In these cases, sufficient informativity of markers was not achieved, as one of the parents or both were homozygous for one or several microsatellite at these loci. Furthermore, as the ADRB3 locus was excluded in family Wa, it is very unlikely that it is involved in family Ha.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
LD is a rare recessive autosomal genetic disease, the molecular alterations of which are still unknown. Although its pathophysiology is not clearly understood, the major alterations associate severe insulin resistance with defective fat storage in adipose tissue. Insulin resistance has been characterized in vivo using euglycemic hyperinsulinemic clamp techniques (14, 18, 19, 28); it concerns hepatic glucose production and lipid oxidation as well as muscle glucose disposal and glycogen synthesis. In vitro studies performed on cultured fibroblasts from patients have shown heterogeneous defects in insulin-stimulated tyrosine kinase activity and glucose metabolism (11, 20, 29). Major alterations in lipid metabolism with lipoatrophy are also typical features of LD. Deficient storage of triglycerides in fat tissue could result, at the adipocyte level, from either a basic defect in lipogenesis (30, 31) or increased lipolysis (32).

Several hypotheses have been proposed to explain both insulin resistance and failure of fat storage in adipocytes. On the one hand, a defect in the insulin transduction pathway could lead to severe insulin resistance with increased lipolysis (28). On the other hand, a primary abnormality in adipose tissue metabolism could explain lipoatrophy and the presence of high levels of nonesterified fatty acids that would trigger secondary insulin resistance. As the primary defect is unknown, genes involved in the mechanism of action of insulin or in lipid metabolism could be considered candidate genes for this disease.

Linkage analysis in inbred families provides a powerful strategy to investigate the roles of these genes in rare recessive disorders. Indeed, in these diseases, affected subjects are expected to inherit 2 copies of the morbid allele transmitted from a common ancestor. The affected individuals are, therefore, said to be homozygous by descent (rather than by state) for the disease allele (17). The 10 consanguineous families described here provided us with substantial family resource to study the implication of candidate genes in LD. Many lod scores were infinitely negative, allowing definite exclusion of corresponding loci in a large proportion of families. In addition, when two microsatellites were typed at a locus, haplotype analysis could be used in a way complementary to lod score calculations to study allele transmission. These 2 approaches led us to exclude the involvement, in most families, of 14 candidate genes coding for proteins involved either in insulin action, i.e. INSR, IRS1, IGFIR, rad, and GSY1, or in lipid metabolism, i.e. LPL, APOCII, APOAII, APOCIII, LIPC, LIPE, ADRB3, leptin, and FABP2. Although a few genes could not be ruled out in a minority of families, these nonexcluded genes differed among those families. This implies that mutations in these genes are unlikely to make a major genetic contribution to LD regardless of whether the form of the disease is congenital or retarded.

Other candidate genes should be studied, such as genes that influence insulin receptor tyrosine kinase activity (i.e. tyrosine phosphatases) or the insulin antilipolytic effect, or those involved in fatty acid transport and adipocyte differentiation. Henceforth, this functional approach will be combined with whole genome scanning, presently performed, in which anonymous markers are tested for homozygosity in these patients. Only candidate genes mapped in a genetic interval where most individuals are homozygous will be retained for further analyses.

The identification of the genetic abnormality in LD will help to understand the pathophysiology of this disease. It will also provide new data concerning insulin resistance and lipid alterations that are common features in more frequent diseases, such as NIDDM.


   Acknowledgments
 
We thank Dr. Tric, Dr. Morel, Dr. Steinschneider, Dr. El Khoury, Dr. Saada, and Prof. Timsit for providing clinical and biological data for their patients; Prof. Kaplan, Dr. Recan, and their colleagues for immortalization of lymphocytes; N. Baudic and S. Pavek for expert technical assistance; Dr. C. Brahimi-Horn for critical reading of the manuscript; and the Infobiogen Group (INSERM SC11).


   Footnotes
 
1 This work was supported by grants from INSERM, Direction de la Recherche Clinique-Assistance Publique-Hôpitaux de Paris at the Clinical Investigation Center of Saint-Antoine University Hospital, Association Française contre les Myopathies, Aide aux Jeunes Diabétiques, and Fondation de France. Back

Received March 7, 1997.

Revised May 23, 1997.

Accepted June 18, 1997.


   References
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 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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