Multisystem dystrophy syndrome due to novel missense mutations in the amino-terminal head and alpha-helical rod domains of the lamin A/C gene

doi:10.1016/S0002-9343(02)01070-7

The American Journal of Medicine

Volume 112, Issue 7, May 2002, Pages 549-555

https://doi.org/10.1016/S0002-9343(02)01070-7 Get rights and content

Abstract

Purpose

Mutations in different domains of the LMNA (lamin A/C) gene encoding nuclear envelope proteins lamin A and lamin C cause familial partial lipodystrophy (Dunnigan variety), dilated cardiomyopathy, and autosomal dominant forms of Emery-Dreifuss and limb-girdle muscular dystrophies. The objective of this study was to evaluate LMNA variants in two families with familial partial lipodystrophy (Dunnigan variety) who also had cardiac conduction system defects and other manifestations related to cardiomyopathy.

Methods

We performed mutational analysis of the lamin A/C gene in affected and unaffected subjects by deoxyribonucleic acid sequencing of the exons.

Results

Two novel missense mutations were identified in exon 1 of the lamin A/C gene. One mutation, R28W (CGG→TGG), affected the amino-terminal head domain, and the other, R62G (CGC→GGC), affected the α-helical rod domain. Affected subjects from both families had an increased prevalence of cardiac manifestations, such as atrioventricular conduction defects, atrial fibrillation, and heart failure due to ventricular dilatation, as well as pacemaker implantation. The proband from one of the families also had proximal muscle weakness.

Conclusion

Novel genetic defects in the LMNA gene in two families with the Dunnigan variety of familial partial lipodystrophy, cardiac conduction system defects, and other manifestations related to cardiomyopathy suggest the occurrence of a multisystem dystrophy syndrome due to LMNA mutations.

Section snippets

Methods

The protocol was approved by the appropriate Institutional Review Board, and all subjects gave informed consent. For diagnosis of familial partial lipodystrophy (Dunnigan variety) phenotype, lack of subcutaneous fat, and extreme muscularity in all the extremities commencing at puberty were considered the essential criteria. Other supportive criteria included excess fat accumulation in the face and neck resulting in cushingoid appearance; presence of acanthosis nigricans, hirsutism, diabetes

Pedigrees

Both pedigrees from the United States are of European origin (Figure 1). The probands were referred to us with a diagnosis of familial partial lipodystrophy (Dunnigan variety). We have previously reported linkage of both pedigrees to chromosome 1q21-22 (19). Clinical features of adult subjects with familial partial lipodystrophy (Dunnigan variety) from each pedigree are described in Table 1.

Discussion

A genetic alteration (genotype) is usually associated with a particular feature or trait (phenotype), and vice versa. However, mutations of a single gene can cause distinct phenotypes, and a phenotype can sometimes be a result of mutations in several genes. The two families that we studied had unique mutations of the lamin A/C gene, which resulted in more than one distinct phenotype. The genetic alterations caused not only familial partial lipodystrophy (Dunnigan variety), but also cardiac

Acknowledgements

We are indebted to the members of the families who participated in the study; Mark D. Shepherd, MD, and Robert A. Kreisberg, MD, for referring the families; Mark Drazner, MD, for manuscript review and helpful discussions; and Angela Osborn, Travis Petricek, and the staff of the General Clinical Research Center for technical support.

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Five adults with PL enrolled in a 16-week placebo-controlled, randomized, double blind study of volanesorsen, 300 mg weekly, followed by 1-year open label extension.
Within-subject effects of volanesorsen before and after 16 weeks of active drug are reported due to small sample size. From week 0 to 16, apoC-III decreased from median (25^th, 75^th %ile) 380 (246, 600) to 75 (26, 232) ng/mL, and triglycerides decreased from 503 (330, 1040) to 116 (86, 355) mg/dL while activation of LPL by subjects’ serum increased from 21 (20, 25) to 36 (29, 42) nEq/mL*min. Although, A1c did not change, peripheral and hepatic insulin sensitivity (glucose disposal and suppression of glucose production during hyperinsulinemic clamp) increased and palmitate turnover decreased. After 32-52 weeks of volanesorsen, liver fat decreased. Common adverse events included injection site reactions and decreased platelets.
In PL, volanesorsen decreased apoC-III and triglycerides, in part through an LPL dependent mechanism, and may improve insulin resistance and hepatic steatosis.
Cardiovascular complications of lipodystrophic syndromes – focus on laminopathies
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Citation Excerpt :
In addition to premature atherosclerosis, cardiomyopathic features have been reported in few patients with typical FPLD2 carrying heterozygous substitutions at the codon 482 of the LMNA gene [8]. Furthermore, lipodystrophic complex laminopathy phenotypes, mostly due to non-codon 482-associated LMNA pathogenic variants have been described, associating lipodystrophy and skeletal and/or cardiac dystrophic features [15–20]. Frequent dilated or, to a lower extent, hypertrophic cardiomyopathies are observed in such patients [8].
Autophagy in adipose tissue
2021, Autophagy in Health and Disease
Adipose tissue is at the center of metabolic homeostasis, as it is the site for energy storage and the source of many adipokines that have regulatory functions such as modulating food intake and insulin sensitivity. Therefore, perturbations, such as adipose excess, insufficiency, or dysfunction, can profoundly affect whole-body energy homeostasis. One mechanism central to proper adipose tissue functioning is autophagy. In addition to the recycling of macronutrients and clearance of damaged proteins and organelles, autophagy has recently been shown to modulate various adipose tissue functions including adipogenesis, lipolysis, and thermogenesis. It has also become evident that dysregulation of autophagy contributes to obesity, insulin resistance, and type 2 diabetes in both humans and animal models. In this chapter, we will summarize recent work defining the role of autophagy in key adipose tissue functions. Additionally, we will examine the current thinking regarding the involvement of autophagy in the pathologies of obesity, type 2 diabetes, and lipodystrophy.
Genetic Lipodystrophies
2020, Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics: Metabolic Disorders
Inherited lipodystrophies are rare disorders characterized by selective loss of body fat and predisposition to diabetes, hypertriglyceridemia, hepatic steatosis and atherosclerotic vascular disease. The autosomal-recessive congenital generalized lipodystrophy is due to mutations in AGPAT2, BSCL2, CAV1, or CAVIN1 and autosomal-dominant familial partial lipodystrophy is due to mutations in LMNA, PPARG, ADRA2A, AKT2, or PLIN1. Other extremely rare types are due to mutations in CIDEC, LIPE, LMNA, ZMPSTE24, PIK3R1, POLR3A, FBN1, CAV1, PSMB8, POLD1, or unknown genes. The clinical management is challenging and includes cosmetic surgery and treatment of metabolic complications with diet, exercise, hypoglycemic and lipid-lowering agents, and metreleptin.
A complex case of diabetes due to LMNA mutation
2017, Revue de Medecine Interne
Les laminopathies (maladies liées aux mutations des lamines A/C) sont des maladies génétiques rares, au spectre phénotypique étendu, incluant les syndromes lipodystrophiques (se caractérisant par une perte sélective de tissu adipeux), dont la forme familiale partielle de type Dunnigan est la plus fréquente.
Il s’agit d’une patiente âgée de 55 ans, atteinte d’un diabète, rapportant de longue date des myalgies invalidantes. Son morphotype cushingoïde associé à une lipo-atrophie cutanée et à une hypertrophie musculaire, avec notion d’atteinte familiale, nous a conduit au diagnostic de lipodystrophie familiale partielle complexe avec mutation hétérozygote c.82C>T, p.Arg28Trp dans le gène LMNA.
Les syndromes lipodystrophiques partiels d’origine familiale peuvent revêtir des phénotypes variés, à dominance cardio-métabolique, pouvant mimer un diabète de type 2 particulièrement sévère. La prise en charge doit comporter la recherche attentive de troubles du rythme et/ou de la conduction paroxystique pourvoyeur de mort subite, ainsi qu’un conseil génétique. La leptine recombinante peut parfois être proposée.
Laminopathies (diseases related to A/C mutations of lamines) are rare genetic diseases with an extensive phenotypic spectrum, including lipodystrophic syndromes—characterized by a selective loss of adipose tissue—of which the partial Dunnigan family type is the most frequent.
We report on a 55-year-old woman with diabetes and long-term disabling myalgia. Her cushingoid morphotype, associated with cutaneous lipo-atrophy and muscle hypertrophy in addition to a genetic heritage, led us to the diagnosis of complex partial familial lipodystrophy heterozygous LMNA_c.82C>T, p.Arg28Trp mutation.
Familial partial lipodystrophic syndromes may have varied phenotypes, mainly cardio-metabolic, which could mimic a particularly severe type 2 diabetes. The diagnostic work-up of this disease has to include a careful investigation of gait troubles and paroxysmal conduction that could lead to sudden death, as well as a genetic examination. In some cases, recombinant leptin can be proposed.
Complex phenotype linked to a mutation in exon 11 of the lamin A/C gene: Hypertrophic cardiomyopathy, atrioventricular block, severe dyslipidemia and diabetes
2017, Revista Portuguesa de Cardiologia
The lamin A/C (LMNA) gene encodes lamins A and C, which have an important role in nuclear cohesion and chromatin organization. Mutations in this gene usually lead to the so-called laminopathies, the primary cardiac manifestations of which are dilated cardiomyopathy and intracardiac conduction defects. Some mutations, associated with lipodystrophy but not cardiomyopathy, have been linked to metabolic abnormalities such as diabetes and severe dyslipidemia. Herein we describe a new phenotype associated with a mutation in exon 11 of the LMNA gene: hypertrophic cardiomyopathy, atrioventricular block, severe dyslipidemia and diabetes.
A 64-year-old woman with hypertrophic cardiomyopathy and a point mutation in exon 11 of the LMNA gene (c.1718C>T, Ser573Leu) presented with severe symptomatic ventricular hypertrophy and left ventricular outflow tract obstruction. She underwent septal alcohol ablation, followed by Morrow myectomy. The patient was also diagnosed with severe dyslipidemia, diabetes and obesity, and fulfilled diagnostic criteria for metabolic syndrome. No other characteristics of LMNA mutation-related phenotypes were identified. The development of type III atrioventricular block with no apparent cause, and mildly depressed systolic function, prompted referral for cardiac resynchronization therapy.
In conclusion, the association between LMNA mutations and different phenotypes is complex and not fully understood, and can present with a broad spectrum of severity.
O gene LMNA codifica a lâmina A/C, com importante papel na manutenção da coesão nuclear e organização da cromatina. Mutações neste gene estão geralmente associadas a doenças denominadas laminopatias. As manifestações cardíacas primárias destas mutações são miocardiopatia dilatada e defeitos da condução intracardíaca. Algumas mutações, associadas a lipodistrofia, mas não cardiomiopatia, estão também associadas a alterações metabólicas, como diabetes ou dislipidemia grave. Assim, descrevemos um novo fenótipo associado a uma mutação no exão 11 do gene LMNA: miocardiopatia hipertrófica, bloqueio auriculoventricular, dislipidemia grave e diabetes.
Apresentamos a situação clínica de uma doente de 64 anos de idade, com miocardiopatia hipertrófica e mutação patogénica identificada no exão 11 do gene LMNA (c.1718C>T, Ser573Leu). A doente apresentou-se com hipertrofia ventricular grave sintomática, obstrutiva, refratária à terapêutica médica. Foi submetida a ablação septal por álcool e, posteriormente, a miectomia cirúrgica. Foi também diagnosticada dislipidemia grave, diabetes e obesidade, cumprindo os critérios para síndrome metabólica. Não foi identificada nenhuma outra característica fenotípica associada a mutações no gene LMNA. A doente foi ainda submetida a terapêutica de ressincronização cardíaca após o desenvolvimento de bloqueio auriculoventricular completo, sem causa aparente, na presença de ligeiro compromisso da função sistólica ventricular.
A correlação de mutações no gene LMNA com diferentes fenótipos é complexa e ainda não completamente compreendida, englobando um largo espectro de gravidade clínica.

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^☆: Supported in part by the National Institutes of Health grants R01-DK54387 and M01-RR00633, as well as grants from the Moss Heart Foundation and the Southwest Medical Foundation.

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Clinical studyMultisystem dystrophy syndrome due to novel missense mutations in the amino-terminal head and alpha-helical rod domains of the lamin A/C gene☆

Abstract

Purpose

Methods

Results

Conclusion

Section snippets

Methods

Pedigrees

Discussion

Acknowledgements

Am J Hum Genet

Metabolism

J Biol Chem

Trends Cell Biol

Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy

Hum Mol Genet

LMNA, encoding lamin A/C, is mutated in partial lipodystrophy

Nat Genet

Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease

N Engl J Med

Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement

Circulation

Mutations in the gene encoding lamin A/C cause autosomal dominant Emery-Dreifuss muscular dystrophy

Nat Genet

Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy

Am J Hum Genet

Identification of mutations in the gene encoding lamins A/C in autosomal dominant limb girdle muscular dystrophy with atrioventricular conduction disturbances (LGMD1B)

Hum Mol Genet

Autosomal dominant Emery-Dreifuss dystrophy due to mutations in rod domain of the lamin A/C gene

Neurology

A newly recognized autosomal dominant limb girdle muscular dystrophy with cardiac involvement

Ann Neurol

Emery-Dreifuss syndrome in three generations of females, including identical twins

Clin Genet

Familial lipoatrophic diabetes with dominant transmission. A new syndrome

QJM

Clinical study
Multisystem dystrophy syndrome due to novel missense mutations in the amino-terminal head and alpha-helical rod domains of the lamin A/C gene☆