A case of Dunnigan-type familial partial lipodystrophy (FPLD) due to lamin A/C (LMNA) mutations complicated by end-stage renal disease

Imachi, Hitomi; Murao, Koji; Ohtsuka, Shouji; Fujiwara, Mako; Muraoka, Tomie; Hosokawa, Hitoshi; Ishida, Toshihiko

doi:10.1007/s12020-008-9127-1

Cited by 18 publications

(17 citation statements)

References 25 publications

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“…In contrast, a second patient with a LMNA missense mutation at R644C developed FSGS [3]. A third patient with a R482Q mutation and FPLD of the Dunnigan type developed renal failure but was not biopsied [4]. It is notable that all four mutations (including our pedigree) are missense changes and cluster in the C-terminal half of the protein (fig.…”

Section: Discussionmentioning

confidence: 99%

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Cosegregation of Focal Segmental Glomerulosclerosis in a Family with Familial Partial Lipodystrophy due to a Mutation in LMNA

Thong

Cook

et al. 2013

Nephron Clin Pract

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Background and Aim: Focal segmental glomerulosclerosis (FSGS) is a common cause of idiopathic nephrotic syndrome in adults (35%). A number of genetic and familial forms of FSGS have been recognized. Here, we report a large pedigree with a pathogenic mutation in LMNA (R349W) in which four members were found to have biopsy-proven FSGS. The LMNA gene codes for lamins A and C, major components of the nuclear lamina which function in nuclear architecture, integrity and the regulation of gene expression. Methods: Pedigree screening and mutation analysis of LMNA gene in all family members. Renal biopsies were performed in proteinuric patients. A molecular 3D model of the familial LMNA mutation was constructed. Results: There were a total of 16 affected members from four generations, 12 of whom were found to carry the germline LMNA mutation. All affected adults had clinical features of familial partial lipodystrophy (FPLD) of the non-Dunnigan variety. Four patients within the same generation presented with a variable degree of renal impairment and proteinuria. Renal biopsies from all four revealed FSGS. The familial mutation is a missense change (R349W) in exon 6 of LMNA (c.1045C>T). Conclusions: We report a genetic link between LMNA and biopsy-proven FSGS in a large pedigree with FPLD. This unexpected association extends the disease spectrum of LMNA to the kidney and suggests that the physiological role of LMNA could be relevant to the maintenance of glomerular structure and function.

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Section: Discussionmentioning

confidence: 99%

“…Although LMNA mutations result in diverse phenotypic presentations, there have only been three reports of renal involvement in affected patients [2,3,4]. Conversely, the association between renal disease and various forms of congenital or acquired generalized lipodystrophy is well recognized [5,6,7], but not for FPLD.…”

Section: Introductionmentioning

confidence: 99%

Cosegregation of Focal Segmental Glomerulosclerosis in a Family with Familial Partial Lipodystrophy due to a Mutation in LMNA

Thong

Cook

et al. 2013

Nephron Clin Pract

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“…The patient gave birth to two healthy children. Her BMI at diagnosis was 20.7 kg/m 2 , much lower than in previously described LMNA Arg482Gln mutation carriers [14][15][16][17][18]. She was 150 cm in height, the shortest among all 5 siblings as the height of her 2 brothers and 2 sisters varied between 162 and 180 cm.…”

Section: Resultsmentioning

confidence: 66%

“…1). The LMNA Arg482Gln mutation was previously reported [14][15][16][17][18]. Of interest, she was also heterozygous for a polymorphism in intron 6 of the LMNA gene (NCBI refSNP ID: rs 534807) and for the silent D446D (GAT ?…”

Section: Resultsmentioning

confidence: 95%

LMNA gene mutation search in Polish patients: new features of the heterozygous Arg482Gln mutation phenotype

Klupa

Szopa

Skupień

et al. 2009

Endocr

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Mutations of the LMNA gene have been shown to cause an autosomal dominant form of insulin resistance with familial partial lipodystrophy (PLD), frequently accompanied by diabetes. LMNA mutations are considered to be a rare cause of monogenic diabetes; however, they are probably sometimes misdiagnosed as type 2 diabetes (T2DM). We examined whether skin fold thickness measurements may be an effective screening procedure to select individuals with T2DM for molecular testing of the LMNA gene. We also aimed to search for mutations in diabetic patients with evident clinical features of lipodystrophy. Skin fold measurements were performed in 249 not pre-selected T2DM patients. The sum of two trunk skin fold measurements divided by the sum of two peripheral was obtained. Men with a skin fold ratio above 2.5 and women above 1.5 were selected for further molecular analysis of the LMNA gene by direct sequencing. We also examined eight patients presenting typical clinical features of lipodystrophy. We selected 16 patients with T2DM on the basis of skin fold measurements. LMNA gene sequencing in this group revealed no mutation that could be attributable to diabetic phenotype. However, in the group of subjects with apparent lipodystrophic phenotype, we identified one Arg482Gln mutation. This female, diagnosed with diabetes at the age of 51 years, was characterized by insulin resistance but, unlike previously reported LMNA Arg48Gln mutation carriers, she was not overweight. The patient also presented with chronic kidney disease and pulmonary fibrosis that could potentially be a part of the phenotype related to the identified LMNA mutation. We did not find the evidence that screening based on skin fold measurements alone could be an efficient approach to select T2DM patients for molecular testing of the LMNA gene; the presence of features typical for laminopathy seems to be required for such testing. A clinical picture related to the LMNA Arg482Gln mutation may be more diversified than it was previously considered and include low BMI and pulmonary fibrosis.

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“…On the other hand, none of the patients was overweight, while most of the patients carrying the W482R mutation described to date have had BMI above the normal range [22,23]. Although the molecular basis and precise pathophysiology of FPLD is still not fully known, early diagnosis of Dunnigan-type familial partial lipodystrophy caused by mutation in LMNA gene should be performed when characteristic FPLD phenotype with concomitant one or more metabolic abnormalities are observed.…”

Section: Discussionmentioning

confidence: 99%

Dunnigan-type familial partial lipodystrophy associated with the heterozygous R482W mutation in LMNA gene — case study of three women from one family

Nabrdalik

Strózik²,

Minkina-Pedras³

et al. 2013

Endokrynologia Polska

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Lipodystrophies are a heterogeneous group of diseases affecting adipose tissue distribution. Familial partial lipodystrophy of the Dunnigan type (FPLD) is a rare autosomal, dominant disorder caused by missense mutations in lamin A/C (LMNA) gene where selective loss of subcutaneous adipose tissue from the limbs and trunk, and accumulation of fat in the neck and face, is usually associated with a variety of metabolic disorders including insulin resistance, diabetes mellitus, dyslipidemia, hepatic steatosis and high blood pressure. In this report we present clinical and molecular features of three Polish women with FLPD phenotype coming from one family (a mother and her two daughters). FPLD was recognised under the circumstances of diabetes treatment, where sequencing of LMNA gene revealed heterozygous R482W mutation. In order to be able to recognise monogenic diabetes associated with lipodystrophy, it is important to be very precise in physical examination while diagnosing diabetes and to be aware of the necessity of performing genetic testing. Diabetesappropriate differential diagnosis is essential for the treatment strategy, anticipation of the disease progression, and determination of the prognosis. It is necessary for an individual mutation carrier to look carefully at the patient's family. StreszczenieLipodystrofie są heterogenną grupą chorób dotyczących rozmieszczenia tkanki tłuszczowej w organizmie. Rodzinna częściowa lipodystrofia typu Dunnigana (FPLD, familial partial lipodystrophy of the Dunnigan type) jest rzadkim autosomalnie dominującym schorzeniem, którego przyczyną jest mutacja braku sensu w genie laminy A/C (gen LMNA). W chorobie tej dochodzi do selektywnej utraty podskórnej tkanki tłuszczowej kończyn i tułowia oraz jej kumulacji w okolicy karku i twarzy, co zwykle jest związane z występowaniem różnych schorzeń metabolicznych, w tym insulinooporności, cukrzycy, dyslipidemii, stłuszczenia wątroby i nadciśnienia tętniczego. W przedstawionym raporcie opisujemy kliniczne i molekularne cechy trzech polskich kobiet pochodzących z jednej rodziny charakteryzujących się fenotypem FLPD (matka i jej dwie córki). Obecność FLPD rozpoznano w trakcie leczenia cukrzycy na podstawie sekwencjonowania genu LMNA i ujawnienia heterozygotycznej mutacji R482W. W celu rozpoznania cukrzycy monogenowej związanej z lipodystrofią ważne jest przeprowadzenie szczegółowego badania fizykalnego w toku diagnostyki cukrzycy oraz świadomość konieczności diagnostyki genetycznej wątpliwych przypadków. Prawidłowa diagnostyka różnicowa cukrzycy jest niezbędna w celu ustalenia strategii leczenia, przewidywania progresji choroby, określenia rokowania, a także jest potrzebna w celu wzmożenia czujności diagnostycznej w odniesieniu do rodziny osoby będącej nosicielem mutacji. (Endokrynol Pol 2013; 64 (4): 306-310)

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A case of Dunnigan-type familial partial lipodystrophy (FPLD) due to lamin A/C (LMNA) mutations complicated by end-stage renal disease

Cited by 18 publications

References 25 publications

Cosegregation of Focal Segmental Glomerulosclerosis in a Family with Familial Partial Lipodystrophy due to a Mutation in <b><i>LMNA</i></b>

Cosegregation of Focal Segmental Glomerulosclerosis in a Family with Familial Partial Lipodystrophy due to a Mutation in <b><i>LMNA</i></b>

LMNA gene mutation search in Polish patients: new features of the heterozygous Arg482Gln mutation phenotype

Dunnigan-type familial partial lipodystrophy associated with the heterozygous R482W mutation in LMNA gene — case study of three women from one family

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