The worldwide mutational landscape of Berardinelli-Seip congenital lipodystrophy

Sarmento, Aquiles Sales Craveiro; Ferreira, Lucas Batista; Lima, Josivan Gomes de; Medeiros, Lázaro Batista de Azevedo; Cunha, Patrícia Tainá Barbosa; Agnez-Lima, Lucymara Fassarella; Ururahy, Marcela Abbott Galvão; Campos, Julliane Tamara Araújo de Melo

doi:10.1016/j.mrrev.2019.03.005

Cited by 23 publications

(16 citation statements)

References 103 publications

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“…Described individuals with mutations in the AGPAT2 gene mainly originated from America or Northern Europe and occasionally from sub-Saharan Africa or Middle Eastern Countries (50). As for Caucasian Italian population the two herein described subjects add up to one other single case previously reported (33).…”

Section: Discussionmentioning

confidence: 73%

“…Testing in vitro the effects of the described mutation may give us further clues, but the assessment of the pathogenic potential of AGPAT2 variants has been proven challenging and has been rarely performed (23,27). Berardinelli Seip syndrome is frequently unveiled by consanguineous marriages or in small and relatively isolated communities (50). This was indeed the case for both patients.…”

Section: Discussionmentioning

confidence: 95%

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Congenital Generalized Lipoatrophy (Berardinelli-Seip Syndrome) Type 1: Description of Novel AGPAT2 Homozygous Variants Showing the Highly Heterogeneous Presentation of the Disease

et al. 2020

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Berardinelli-Seip congenital lipoatrophy (BSCL) is characterized by near total fat atrophy, associated with the progressive development of metabolic complications. BSCL type 1 (BSCL1) is caused by mutations in AGPAT2, encoding 1-acylglycerol-3phosphate-O-acyltransferase β (recently renamed lysophosphatidic acid acyltransferase beta), which catalyzes the transformation of lysophosphatidic acid in phosphatidic acid, the precursor of glycerophospholipids and triglycerides. BSCL1 is an autosomal recessive disease due to AGPAT2 pathogenic variants leading to a depletion of triglycerides inside the adipose organ, and to a defective signaling of key elements involved in proper adipogenesis. We herein investigated the characteristics of two AGPAT2 variants in Caucasian Italian patients with Berardinelli-Seip congenital lipoatrophy. The first patient exhibited a novel homozygous nonsense c.430 C > T AGPAT2 mutation (p.Gln144 *) predicting the synthesis of a truncated enzyme of approximately half of the proper size. The second patient harbored a homozygous AGPAT2 missense variant (p.Arg159Cys), never described previously in BSCL1 patients: the segregation of the disease with the mutation in the pedigree of the family and the in silico analysis are compatible with a causative role of the p.Arg159Cys variant. We remark that BSCL1 can be clinically very heterogeneous at presentation and that the associated complications, occurring in the natural history of the disease, reduce life-expectancy. We point to the necessity for medical treatments capable of reducing the risk of cardiovascular death. In BSCL1 patients, the assessment of cardiovascular disease with conventional diagnostic means maybe particularly challenging.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 95%

Congenital Generalized Lipoatrophy (Berardinelli-Seip Syndrome) Type 1: Description of Novel AGPAT2 Homozygous Variants Showing the Highly Heterogeneous Presentation of the Disease

et al. 2020

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“…Four subtypes are currently distinguished according to the causative gene involved—BSCL1 due to mutations in the gene encoding the enzyme 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) [ 11 ], BSCL2 due to mutations in the gene encoding seipin [ 12 ], BSCL3 and BSCL4 due to mutations in caveolae-associated proteins, respectively caveolin-1 (CAV1) [ 13 ] and PTRF (Polymerase 1 and Transcription Release Factor), also named CAVIN1 [ 14 ]. The first two subtypes linked to AGPAT2 or Seipin are, by far, the most frequent, representing about 95% of the patients [ 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Seipin Deficiency as a Model of Severe Adipocyte Dysfunction: Lessons from Rodent Models and Teaching for Human Disease

Magré

Prieur

2022

IJMS

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Obesity prevalence is increasing worldwide, leading to cardiometabolic morbidities. Adipocyte dysfunction, impairing white adipose tissue (WAT) expandability and metabolic flexibility, is central in the development of obesity-related metabolic complications. Rare syndromes of lipodystrophy characterized by an extreme paucity of functional adipose tissue should be considered as primary adipocyte dysfunction diseases. Berardinelli-Seip congenital lipodystrophy (BSCL) is the most severe form with a near absence of WAT associated with cardiometabolic complications such as insulin resistance, liver steatosis, dyslipidemia, and cardiomyopathy. Twenty years ago, mutations in the BSCL2 gene have been identified as the cause of BSCL in human. BSCL2 encodes seipin, an endoplasmic reticulum (ER) anchored protein whose function was unknown back then. Studies of seipin knockout mice or rats demonstrated how seipin deficiency leads to severe lipodystrophy and to cardiometabolic complications. At the cellular levels, seipin is organized in multimers that are particularly enriched at ER/lipid droplet and ER/mitochondria contact sites. Seipin deficiency impairs both adipocyte differentiation and mature adipocyte maintenance. Experiments using adipose tissue transplantation in seipin knockout mice and tissue-specific deletion of seipin have provided a large body of evidence that liver steatosis, cardiomyopathy, and renal injury, classical diabetic complications, are all consequences of lipodystrophy. Rare adipocyte dysfunctions such as in BSCL are the key paradigm to unravel the pathways that control adipocyte homeostasis. The knowledge gathered through the study of these pathologies may bring new strategies to maintain and improve adipose tissue expandability.

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“…Five years later, Seip described three cases with the same clinical characteristics in Norway. In 1968, autosomal recessive transmission was suggested [2], and compound heterozygosity was found in many of those [3]. However, in rare cases, an autosomal dominant pattern was featured [4].…”

Section: Introductionmentioning

confidence: 99%

Bone Mineral Density in Congenital Generalized Lipodystrophy: The Role of Bone Marrow Tissue, Adipokines, and Insulin Resistance

Freire

d’Alva

Madeira

et al. 2021

IJERPH

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Congenital Generalized Lipodystrophy (CGL) is a rare syndrome characterized by the almost total absence of subcutaneous adipose tissue due to the inability of storing lipid in adipocytes. Patients present generalized lack of subcutaneous fat and normal to low weight. They evolve with severe metabolic disorders, non-alcoholic fatty liver disease, early cardiac abnormalities, and infectious complications. Although low body weight is a known risk factor for osteoporosis, it has been reported that type 1 and 2 CGL have a tendency of high bone mineral density (BMD). In this review, we discuss the role of bone marrow tissue, adipokines, and insulin resistance in the setting of the normal to high BMD of CGL patients. Data bases from Pubmed and LILACS were searched, and 113 articles published until 10 April 2021 were obtained. Of these, 76 were excluded for not covering the review topic. A manual search for additional literature was performed using the bibliographies of the studies located. The elucidation of the mechanisms responsible for the increase in BMD in this unique model of insulin resistance may contribute to the understanding of the interrelationships between bone, muscle, and adipose tissue in a pathophysiological and therapeutic perspective.

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The worldwide mutational landscape of Berardinelli-Seip congenital lipodystrophy

Cited by 23 publications

References 103 publications

Congenital Generalized Lipoatrophy (Berardinelli-Seip Syndrome) Type 1: Description of Novel AGPAT2 Homozygous Variants Showing the Highly Heterogeneous Presentation of the Disease

Congenital Generalized Lipoatrophy (Berardinelli-Seip Syndrome) Type 1: Description of Novel AGPAT2 Homozygous Variants Showing the Highly Heterogeneous Presentation of the Disease

Seipin Deficiency as a Model of Severe Adipocyte Dysfunction: Lessons from Rodent Models and Teaching for Human Disease

Bone Mineral Density in Congenital Generalized Lipodystrophy: The Role of Bone Marrow Tissue, Adipokines, and Insulin Resistance

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