Novel<i>LMNA</i>mutations cause an aggressive atypical neonatal progeria without progerin accumulation

Soria‐Valles, Clara; Carrero, Dido; Gabau, Elisabeth; Velasco, Gloria; Quesada, Vı́ctor; Bárcena, Clea; Moens, M.; Fieggen, Karen; Möhrcken, Silvia; Owens, Martina; Puente, Diana; Asensio, Òscar; Loeys, Bart; Perez, Ana Beatriz Alvarez; Benoît, Valérie; Wuyts, Wim; Lévy, Nicolas; Hennekam, Raoul C. M.; Sandre-Giovannoli, Annachiara De

doi:10.1136/jmedgenet-2015-103695

Cited by 18 publications

(16 citation statements)

References 38 publications

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“…Mandibulo-acral dysplasia, due to mutations in LMNA or ZMPSTE24 , was identified as the first laminopathy associating premature ageing and lipodystrophic features [ 63 , 64 ]. This phenotypic combination was further observed with other LMNA mutations in typical Hutchinson-Gilford progeria [ 66 , 67 ] or in atypical progeroid syndromes [ 65 , 68 , 69 ].…”

Section: Defects In Adipocyte Differentiation In Lmna supporting

confidence: 56%

Lipodystrophic syndromes due toLMNAmutations: recent developments on biomolecular aspects, pathophysiological hypotheses and therapeutic perspectives

Vigouroux

Guénantin

Vatier

et al. 2018

Nucleus

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Mutations in LMNA, encoding A-type lamins, are responsible for laminopathies including muscular dystrophies, lipodystrophies, and premature ageing syndromes. LMNA mutations have been shown to alter nuclear structure and stiffness, binding to partners at the nuclear envelope or within the nucleoplasm, gene expression and/or prelamin A maturation. LMNA-associated lipodystrophic features, combining generalized or partial fat atrophy and metabolic alterations associated with insulin resistance, could result from altered adipocyte differentiation or from altered fat structure.Recent studies shed some light on how pathogenic A-type lamin variants could trigger lipodystrophy, metabolic complications, and precocious cardiovascular events. Alterations in adipose tissue extracellular matrix and TGF-beta signaling could initiate metabolic inflexibility. Premature senescence of vascular cells could contribute to cardiovascular complications. In affected families, metabolic alterations occur at an earlier age across generations, which could result from epigenetic deregulation induced by LMNA mutations. Novel cellular models recapitulating adipogenic developmental pathways provide scalable tools for disease modeling and therapeutic screening.

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Section: Defects In Adipocyte Differentiation In Lmna supporting

confidence: 56%

Lipodystrophic syndromes due toLMNAmutations: recent developments on biomolecular aspects, pathophysiological hypotheses and therapeutic perspectives

Vigouroux

Guénantin

Vatier

et al. 2018

Nucleus

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“…Segmental progeroid syndromes, defined as syndromes with signs of premature aging affecting more than one tissue or organ (Martin 1978), are highly heterogenous genetic disorders. Studies utilizing next-generation sequencing (NGS) approaches have revealed several novel progeroid genes in recent years (Ehmke et al 2017;Jay et al 2016;Lessel et al 2014bLessel et al , 2017bLessel et al , 2018Marbach et al 2019;Paolacci et al 2018;Puente et al 2011;Schrauwen et al 2015;Wambach et al 2018), and broadened the spectrum of phenotypes of many known progeroid conditions and the number of associated genetic causes (Lessel et al 2014a(Lessel et al , 2015Rodriguez-Garcia et al 2018;Soria-Valles et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Two novel cases further expand the phenotype of TOR1AIP1-associated nuclear envelopathies

et al. 2020

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Biallelic variants in TOR1AIP1, encoding the integral nuclear membrane protein LAP1 (lamina-associated polypeptide 1) with two functional isoforms LAP1B and LAP1C, have initially been linked to muscular dystrophies with variable cardiac and neurological impairment. Furthermore, a recurrent homozygous nonsense alteration, resulting in loss of both LAP1 isoforms, was identified in seven likely related individuals affected by multisystem anomalies with progeroid-like appearance and lethality within the 1st decade of life. Here, we have identified compound heterozygosity in TOR1AIP1 affecting both LAP1 isoforms in two unrelated individuals affected by congenital bilateral hearing loss, ventricular septal defect, bilateral cataracts, mild to moderate developmental delay, microcephaly, mandibular hypoplasia, short stature, progressive muscular atrophy, joint contractures and severe chronic heart failure, with much longer survival. Cellular characterization of primary fibroblasts of one affected individual revealed absence of both LAP1B and LAP1C, constitutively low lamin A/C levels, aberrant nuclear morphology including nuclear cytoplasmic channels, and premature senescence, comparable to findings in other progeroid forms of nuclear envelopathies. We additionally observed an abnormal activation of the extracellular signal-regulated kinase 1/2 (ERK 1/2). Ectopic expression of wild-type TOR1AIP1 mitigated these cellular phenotypes, providing further evidence for the causal role of identified genetic variants. Altogether, we thus further expand the TOR1AIP1associated phenotype by identifying individuals with biallelic loss-of-function variants who survived beyond the 1st decade of life and reveal novel molecular consequences underlying the TOR1AIP1-associated disorders.

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“…Recently, an atypical aggressive neonatal form of HGPS without progerin accumulation has been reported. The molecular exploration found an association of two de novo heterozygous point mutations in LMNA : c.163G > A, p.E55K and c.164A > G, p.E55G [ 58 ].…”

Section: Diseases Caused By Mutations Affecting Proteins Of the Nuclementioning

confidence: 99%

Nuclear envelopathies: a complex LINC between nuclear envelope and pathology

Janin

Bauer

Ratti

et al. 2017

Orphanet J Rare Dis

103

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Since the identification of the first disease causing mutation in the gene coding for emerin, a transmembrane protein of the inner nuclear membrane, hundreds of mutations and variants have been found in genes encoding for nuclear envelope components. These proteins can be part of the inner nuclear membrane (INM), such as emerin or SUN proteins, outer nuclear membrane (ONM), such as Nesprins, or the nuclear lamina, such as lamins A and C. However, they physically interact with each other to insure the nuclear envelope integrity and mediate the interactions of the nuclear envelope with both the genome, on the inner side, and the cytoskeleton, on the outer side. The core of this complex, called LINC (LInker of Nucleoskeleton to Cytoskeleton) is composed of KASH and SUN homology domain proteins. SUN proteins are INM proteins which interact with lamins by their N-terminal domain and with the KASH domain of nesprins located in the ONM by their C-terminal domain.Although most of these proteins are ubiquitously expressed, their mutations have been associated with a large number of clinically unrelated pathologies affecting specific tissues. Moreover, variants in SUN proteins have been found to modulate the severity of diseases induced by mutations in other LINC components or interactors. For these reasons, the diagnosis and the identification of the molecular explanation of “nuclear envelopathies” is currently challenging.The aim of this review is to summarize the human diseases caused by mutations in genes coding for INM proteins, nuclear lamina, and ONM proteins, and to discuss their potential physiopathological mechanisms that could explain the large spectrum of observed symptoms.

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NovelLMNAmutations cause an aggressive atypical neonatal progeria without progerin accumulation

Cited by 18 publications

References 38 publications

Lipodystrophic syndromes due toLMNAmutations: recent developments on biomolecular aspects, pathophysiological hypotheses and therapeutic perspectives

Lipodystrophic syndromes due toLMNAmutations: recent developments on biomolecular aspects, pathophysiological hypotheses and therapeutic perspectives

Two novel cases further expand the phenotype of TOR1AIP1-associated nuclear envelopathies

Nuclear envelopathies: a complex LINC between nuclear envelope and pathology

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