Increased progerin expression associated with unusual<i>LMNA</i>mutations causes severe progeroid syndromes

Moulson, Casey L.; Fong, Loren G.; Gardner, Jennifer M.; Farber, Emily; Go, Gloriosa; Passariello, Annalisa; Grange, Dorothy K.; Young, Stephen G.; Miner, Jeffrey H.

doi:10.1002/humu.20536

Cited by 102 publications

(101 citation statements)

References 35 publications

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“…However, in contrast to HGPS, the patient described here had a much more severe clinical phenotype, resulting in early death at an age of 84 days. The severe phenotype of patient N is similar to that observed in patient I in Moulson et al, 12 who had the same pathogenic mutation in LMNA and died after 26 days. Unlike patient I, our patient did not show intrauterine growth retardation or a cleft palate.…”

Section: Discussionsupporting

confidence: 82%

“…Common to both patients was a higher expression of progerin, exceeding the amount of mature lamin A and a higher ratio of progerin to lamin A. 12 The manuscript describes a patient with severe neonatal progeria and death at 3 months of age caused by the c.1821G4A mutation in LMNA. In contrast to classical HGPS, expression of normal lamin A generated from the unaffected allele was severely reduced, giving new insights into the pathogenesis of premature ageing.…”

Section: Introductionmentioning

confidence: 97%

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Neonatal progeria: increased ratio of progerin to lamin A leads to progeria of the newborn

et al. 2012

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Hutchinson-Gilford progeria syndrome (HGPS) is an important model disease for premature ageing. Affected children appear healthy at birth, but develop the first symptoms during their first year of life. They die at an average age of 13 years, mostly because of myocardial infarction or stroke. Classical progeria is caused by the heterozygous point mutation c.1824C4T in the LMNA gene, which activates a cryptic splice site. The affected protein cannot be processed correctly to mature lamin A, but is modified into a farnesylated protein truncated by 50 amino acids (progerin). Three more variations in LMNA result in the same mutant protein, but different grades of disease severity. We describe a patient with the heterozygous LMNA mutation c.1821G4A, leading to neonatal progeria with death in the first year of life. Intracellular lamin A was downregulated in the patient's fibroblasts and the ratio of progerin to lamin A was increased when compared with HGPS. It is suggestive that the ratio of farnesylated protein to mature lamin A determines the disease severity in progeria.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 97%

Neonatal progeria: increased ratio of progerin to lamin A leads to progeria of the newborn

et al. 2012

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“…Until now, this transcript had only been reported in association with a restrictive dermopathy-like phenotype in a patient carrying the c.1968+1G4A heterozygous LMNA mutation, 15 failing to be identified in another patient affected with a neonatal progeroid syndrome carrying the same mutation. 14 We thus both confirm (for the c.1968+1GA heterozygous LMNA mutation) and report for the first time (for the heterozygous LMNA mutations c.1968G4A and c.1968+5GG4A), the identification of the prelamin AΔ90 transcript ('dermopathin') in patients presenting with variably severe HGPS-like syndromes.…”

Section: Discussionsupporting

confidence: 75%

“…11,[14][15][16]21,22 Using specific macros on ImageJ, we then analyzed the ratio of abnormal nuclei, based on DAPI staining in at least 100 cells, for patients 1 and 2, an HGPS patient and a healthy control. No differences were observed between patients' cells regarding the circularity (0.83 for HGPS, 0.78 for P1 and 0.80 for P2) but all patients presented a significantly higher level of circular nuclei in contrast to control cells (0.69% for control).…”

Section: Deleted Prelamin a Isoform Identificationmentioning

confidence: 99%

“…[8][9][10] Other LMNA-dominant mutations have been associated with the production of progerin or other deleted prelamin A isoforms (prelamin AΔ35 and prelamin AΔ90). [11][12][13][14][15][16] We enrolled eight patients, including two sibs and a parent of a family in which the disease segregated on an autosomal dominant basis, carrying four different LMNA mutations affecting prelamin A splicing. The aim of our study was to explore in detail the transcriptional prelamin A-/lamin C-expression patterns associated to the different mutations, in either lymphoblastoid or fibroblast cell lines of the patients.…”

Section: Introductionmentioning

confidence: 99%

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Truncated prelamin A expression in HGPS-like patients: a transcriptional study

et al. 2015

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Premature aging syndromes are rare genetic disorders mimicking clinical and molecular features of aging. A recently identified group of premature aging syndromes is linked to mutation of the LMNA gene encoding lamins A and C, and is associated with nuclear deformation and dysfunction. Hutchinson-Gilford progeria syndrome (HGPS) was the first premature aging syndrome linked to LMNA mutation and its molecular bases have been deeply investigated. It is due to a recurrent de novo mutation leading to aberrant splicing and the production of a truncated and toxic nuclear lamin A precursor (prelamin AΔ50), also called progerin. In this work and based on the literature data, we propose to distinguish two main groups of premature aging laminopathies: (1) HGPS and HGP-like syndromes, which share clinical features due to hampered processing and intranuclear toxic accumulation of prelamin A isoforms; and (2) APS (atypical progeria syndromes), due to dominant or recessive missense mutations affecting lamins A and C. Among HGPS-like patients, several deleted prelamin A transcripts (prelamin AΔ50, AΔ35 and AΔ90) have been described. The purpose of this work was to characterize those transcripts in eight patients affected with HGP-like rare syndromes. When fibroblasts were available, the relationships between the presence and ratios of these transcripts and other parameters were studied, aiming to increase our understanding of genotype-phenotype relationships in HGPS-like patients. Altogether our results evidence that progerin accumulation is the major pathogenetic mechanism responsible for HGP-like syndromes due to mutations near the donor splice site of exon 11.

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Genetics of Human Laminopathies

Novelli

D’Apice

2017

Encyclopedia of Life Sciences

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Lamins A/C, encoded by LMNA gene, are constituents of the nuclear lamina, a meshwork of proteins underneath the nuclear envelope. Human disorders linked to LMNA mutations are known as laminopathies and include cardiac and muscular dystrophies, lipodystrophies, progeroid syndromes and overlapping phenotypes. Associated with this wide clinical variability, there is also a large allelic heterogeneity that is still expanding. New links between LMNA mutations and human diseases with already known or unknown molecular cause have been established. In other cases, no evidence that a human disease is another laminopathy has been found. Moreover, the recent availability of high‐throughput sequencing technologies has made feasible to uncover the disease‐causing mutations in patients who were originally diagnosed with laminopathies but whose mutational analysis of candidate gene did not reveal any change in LMNA . Key Concepts Mutations in the LMNA gene, encoding A‐type lamin proteins, lead to a wide range of diseases known as laminopathies. The clinical and allelic heterogeneity of laminopathies is still expanding. Studies of the molecular mechanisms underlying laminopathies have led to advances in the understanding of lamin A functions and developing novel therapeutic strategies. A group of progeroid phenotypes is phenocopy of progeroid laminopathies. High‐throughput sequencing technologies have made it possible to uncover the disease‐causing mutations in genes that encode proteins involved in nuclear envelope architecture or in control of genomic stability. Nuclear alterations are linked to human ageing.

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Increased progerin expression associated with unusualLMNAmutations causes severe progeroid syndromes

Cited by 102 publications

References 35 publications

Neonatal progeria: increased ratio of progerin to lamin A leads to progeria of the newborn

Neonatal progeria: increased ratio of progerin to lamin A leads to progeria of the newborn

Truncated prelamin A expression in HGPS-like patients: a transcriptional study

Genetics of Human Laminopathies

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