Genotype‐phenotype analysis of<i>LMNA</i>‐related diseases predicts phenotype‐selective alterations in lamin phosphorylation

Lin, Eric; Brady, Graham F.; Kwan, Raymond; Nesvizhskii, Alexey I.; Omary, M. Bishr

doi:10.1096/fj.202000500r

Cited by 20 publications

(21 citation statements)

References 76 publications

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“…In addition to Src, EGFR and the insulin receptor are predicted to be able to phosphorylate lamin A Tyr45 by the NetPhos 3.1 Server. In addition, the Tyr45 and Tyr481 of lamin A were predicated to be phosphorylation (UniProt), both of which are associated with laminopathies ( Lin et al, 2020 ). Tsai et al (2015) described a large-scale determination of absolute phosphorylation stoichiometries by motif-targeting quantitative proteomics.…”

Section: Discussionmentioning

confidence: 99%

“…The epidermal growth factor receptor (EGFR) was reported to phosphorylate lamin A at several tyrosine residues in vitro, including Y45, Y81, Y211, Y359, Y376, Y481, and Y646 ( Tsai et al, 2015 ). Among which, Y45 and Y481 are known to be associated with laminopathies and predicated to be phosphorylation ( Lin et al, 2020 ). Nevertheless, tyrosine phosphorylation has been reported in other intermediate filaments.…”

Section: Introductionmentioning

confidence: 99%

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Tyrosine phosphorylation of lamin A by Src promotes disassembly of nuclear lamina in interphase

et al. 2021

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Lamins form the nuclear lamina, which is important for nuclear structure and activity. Although posttranslational modifications, in particular serine phosphorylation, have been shown to be important for structural properties and functions of lamins, little is known about the role of tyrosine phosphorylation in this regard. In this study, we found that the constitutively active Src Y527F mutant caused the disassembly of lamin A/C. We demonstrate that Src directly phosphorylates lamin A mainly at Tyr45 both in vitro and in intact cells. The phosphomimetic Y45D mutant was diffusively distributed in the nucleoplasm and failed to assemble into the nuclear lamina. Depletion of lamin A/C in HeLa cells induced nuclear dysmorphia and genomic instability as well as increased nuclear plasticity for cell migration, all of which were partially restored by re-expression of lamin A, but further promoted by the Y45D mutant. Together, our results reveal a novel mechanism for regulating the assembly of nuclear lamina through Src and suggest that aberrant phosphorylation of lamin A by Src may contribute to nuclear dysmorphia, genomic instability, and nuclear plasticity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tyrosine phosphorylation of lamin A by Src promotes disassembly of nuclear lamina in interphase

et al. 2021

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“…Second, pathogenic mutations may alter kinase-recognition motifs surrounding phosphorylation sites. While this scenario has not been explored in detail, Lin et al predicted that pathogenic LMNA mutations decrease Lamin A/C phosphorylation overall in an in silico analysis [ 150 ]. Third, pathogenic mutations may alter the accessibility of kinases or phosphatases to target residues through protein conformation changes.…”

Section: Laminopathy Mutations That Affect Lamin Phosphorylationmentioning

confidence: 99%

“…Cenni et al reported strong reduction of overall Lamin A/C phosphorylation in myoblasts and myotubes derived from various muscular dystrophy patients with LMNA gene mutations [ 89 ]. Lin et al reported that R60G substitution, which causes dilated cardiomyopathy, renders this mutant protein more resistant to phosphorylation by p38 MAPK at undefined sites [ 150 ]. These studies highlight multiple ways in which pathogenic LMNA mutations could affect Lamin A/C phosphorylation.…”

Section: Laminopathy Mutations That Affect Lamin Phosphorylationmentioning

confidence: 99%

Nuclear lamin phosphorylation: an emerging role in gene regulation and pathogenesis of laminopathies

Liu

Ikegami

2020

Nucleus

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Decades of studies have established that nuclear lamin polymers form the nuclear lamina, a protein meshwork that supports the nuclear envelope structure and tethers heterochromatin to the nuclear periphery. Much less is known about unpolymerized nuclear lamins in the nuclear interior, some of which are now known to undergo specific phosphorylation. A recent finding that phosphorylated lamins bind gene enhancer regions offers a new hypothesis that lamin phosphorylation may influence transcriptional regulation in the nuclear interior. In this review, we discuss the regulation, localization, and functions of phosphorylated lamins. We summarize kinases that phosphorylate lamins in a variety of biological contexts. Our discussion extends to laminopathies, a spectrum of degenerative disorders caused by lamin gene mutations, such as cardiomyopathies and progeria. We compare the prevailing hypothesis for laminopathy pathogenesis based on lamins’ function at the nuclear lamina with an emerging hypothesis based on phosphorylated lamins’ function in the nuclear interior.

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“…Hierarchical cluster association studies have shown that phenotypes characterized by primary cardiac and neurological involvement are more frequently associated with LMNA mutations located in the helical rod domain, upstream of the nuclear localization signal sequence (NLS), placed at codons 416–423, while diseases affecting primarily the adipose tissue or leading to premature ageing are likely caused by mutations located in the tail or immunoglobulin (IgG)-like domain, downstream of the NLS [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Partial Lipodystrophy and LMNA p.R545H Variant

Magno

Ceccarini

Barison

et al. 2021

JCM

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Laminopathies are disorders caused by LMNA gene mutations, which selectively affect different tissues and organ systems, and present with heterogeneous clinical and pathological traits. The molecular mechanisms behind these clinical differences and tissue specificity have not been fully clarified. We herein examine the case of a patient carrying a heterozygous LMNA c.1634G>A (p.R545H) variant with a mild, transient myopathy, who was referred to our center for the suspicion of lipodystrophy. At physical examination, an abnormal distribution of subcutaneous fat was noticed, with fat accumulation in the anterior regions of the neck, resembling the fat distribution pattern of familial partial lipodystrophy type 2 (FPLD2). The R545H missense variant has been found at very low allelic frequency in public databases, and in silico analysis showed that this amino acid substitution is predicted to have a damaging role. Other patients carrying the heterozygous LMNA p.R545H allele have shown a marked clinical heterogeneity in terms of phenotypic body fat distribution and severity of organ system involvement. These findings indicate that the LMNA p.R545H heterozygous variant exhibits incomplete penetrance and highly variable expressivity. We hypothesized that additional genetic factors, epigenetic mechanisms, or environmental triggers might explain the variable expressivity of phenotypes among various patients.

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Genotype‐phenotype analysis ofLMNA‐related diseases predicts phenotype‐selective alterations in lamin phosphorylation

Cited by 20 publications

References 76 publications

Tyrosine phosphorylation of lamin A by Src promotes disassembly of nuclear lamina in interphase

Tyrosine phosphorylation of lamin A by Src promotes disassembly of nuclear lamina in interphase

Nuclear lamin phosphorylation: an emerging role in gene regulation and pathogenesis of laminopathies

Partial Lipodystrophy and LMNA p.R545H Variant

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