Mandibuloacral Dysplasia Is Caused by a Mutation in LMNA-Encoding Lamin A/C

Novelli, Giuseppe; Muchir, Antoine; Sangiuolo, Federica; Helbling-Leclerc, Anne; D’Apice, Maria Rosaria; Massart, Catherine; Capon, Francesca; Sbraccia, Paolo; Federici, Massimo; Lauro, Renato; Tudisco, Cosimo; Pallotta, R; Scarano, Gioacchino; Dallapiccola, Bruno; Merlini, Luciano; Bonne, Gisèle

doi:10.1086/341908

Cited by 492 publications

(396 citation statements)

References 27 publications

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“…HEK293 were cultured in D‐MEM plus 10% fetal bovine serum. Skin fibroblasts expressing P4R LMNA from atypical progeria syndrome (APS) (Garg et al, 2009), R527H LMNA from mandibuloacral dysplasia (MADA) (Novelli et al, 2002), G608G LMNA from HGPS (De Sandre Giovannoli et al, 2003; Eriksson et al, 2003; Pellegrini et al, 2015), and cells from Emery‐Dreifuss muscular dystrophy (EDMD2) expressing Y259D mutated LMNA (Mattioli et al, 2011) or control fibroblasts were included in this study (Table 1). …”

Section: Methodsmentioning

confidence: 99%

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Mattioli¹,

Andrenacci²,

Garofalo

et al. 2018

Aging Cell

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Defects in stress response are main determinants of cellular senescence and organism aging. In fibroblasts from patients affected by Hutchinson–Gilford progeria, a severe LMNA‐linked syndrome associated with bone resorption, cardiovascular disorders, and premature aging, we found altered modulation of CDKN1A, encoding p21, upon oxidative stress induction, and accumulation of senescence markers during stress recovery. In this context, we unraveled a dynamic interaction of lamin A/C with HDAC2, an histone deacetylase that regulates CDKN1A expression. In control skin fibroblasts, lamin A/C is part of a protein complex including HDAC2 and its histone substrates; protein interaction is reduced at the onset of DNA damage response and recovered after completion of DNA repair. This interplay parallels modulation of p21 expression and global histone acetylation, and it is disrupted by LMNAmutations leading to progeroid phenotypes. In fact, HGPS cells show impaired lamin A/C‐HDAC2 interplay and accumulation of p21 upon stress recovery. Collectively, these results link altered physical interaction between lamin A/C and HDAC2 to cellular and organism aging. The lamin A/C‐HDAC2 complex may be a novel therapeutic target to slow down progression of progeria symptoms.

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Section: Methodsmentioning

confidence: 99%

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

Mattioli¹,

Andrenacci²,

Garofalo

et al. 2018

Aging Cell

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“…17 At least seven diseases result from mutant LMNA, 18 including some that have lipodystrophy as a clinical feature, such as MAD (MIM 248370) and progeria (MIM 176670). 19 Some LMNA mutations give rise to 'overlap syndromes' characterized by dystrophy in adipose tissue, cardiac myocytes and/or skeletal myocytes. 20 The mechanism(s) by which specific LMNA mutations cause specific tissue involvement and clinical manifestations is unclear.…”

Section: Introductionmentioning

confidence: 99%

Lessons from human mutations in PPARγ

Hegele

2005

Int J Obes

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Familial partial lipodystrophy (FPLD) is characterized by adipose tissue repartitioning with multiple metabolic disturbances, including insulin resistance and dyslipidemia. Classical FPLD results from mutations in LMNA encoding nuclear lamin A/C (FPLD2), but recently some families with partial lipodystrophy and normal LMNA sequence were found to have germline mutations in PPARg (FPLD3). For instance, all four affected subjects in a three-generation Canadian FPLD3 kindred ascertained based upon a clinical diagnosis of partial lipodystrophy were heterozygous for the PPARg F388L mutation, which altered a highly conserved residue within helix 8 of the predicted ligand-binding pocket of PPARg. The mutation was absent from normal subjects, and functional studies showed that the mutant receptor had significantly decreased basal transcriptional activity and impaired stimulation by rosiglitazone, with no evidence of a dominant-negative mechanism. Other reported FPLD3 patients with mutant PPARg were ascertained either directly based on a clinical diagnosis of lipodystrophy (R425C mutation), or based on insulin resistance with subsequent demonstration of lipodystrophy (V290M and P467L mutations). Compared to subjects with mutant LMNA, lipodystrophic subjects with mutant PPARg had less severe adipose involvement, together with more severe clinical and biochemical manifestations of insulin resistance, and more variable response to treatment with thiazolidinediones. Thus, rare natural mutations affecting PPARg ligand binding and/or transactivation functions cause partial lipodystrophy, with associated components that resemble the metabolic syndrome.

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“…The notion that a mutation without a clinically discernable phenotype might, in combination with a second mutation, produce a pathological phenotype is supported by the observations made in kindreds with an arginine-527-histidine (R527H) mutation. R527H heterozygotes were said to be phenotypically "normal", whilst R527H homozygotes develop mandibulo-acral dysplasia [8], a complex phenotype including partial lipodystrophy and insulin resistance. Compound heterozygosity has been reported in one other subject with FPL [5].…”

mentioning

confidence: 99%