Compound heterozygous ZMPSTE24 mutations reduce prelamin A processing and result in a severe progeroid phenotype

@article{Shackleton2005CompoundHZ,
  title={Compound heterozygous ZMPSTE24 mutations reduce prelamin A processing and result in a severe progeroid phenotype},
  author={Sue Shackleton and Dawn T. Smallwood and Peter T. Clayton and Louise C Wilson and Anil Kumar Agarwal and Anshu Garg and Richard C. Trembath},
  journal={Journal of Medical Genetics},
  year={2005},
  volume={42},
  pages={e36 - e36}
}
Hutchinson–Gilford progeria syndrome (HGPS; OMIM 176670) is an extremely rare but devastating disorder that mimics premature aging.1–3 Affected children appear normal at birth but typically develop failure to thrive in the first two years. Other features include alopecia, micrognathia, loss of subcutaneous fat with prominent veins, abnormal dentition, sclerodermatous skin changes, and osteolysis of the clavicles and distal phalanges. The mean age of death is at age 13 years, most commonly due… 

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Increased progerin expression associated with unusual LMNA mutations causes severe progeroid syndromes
TLDR
Two patients with extraordinarily severe forms of progeria caused by unusual mutations in LMNA are presented, and farnesyltransferase inhibitors may prove to be useful even when progerin expression levels are higher than those in typical HGPS patients.
Compound heterozygosity for mutations in LMNA causes a progeria syndrome without prelamin A accumulation.
TLDR
A critical role for the C-terminal globular lamin A/C region in nuclear structure is suggested and support a major contribution of abnormal assembly to the progeroid phenotype is supported.
HUTCHINSON-GILFORD PROGERIA SYNDROME: A PREMATURELY AGING DISORDER
TLDR
The clinical characteristics of this disease, the underlying mutation in the lamin A (LMNA) gene that results in this phenotype and the recent advances in treatment strategies are summarized.
A homozygous ZMPSTE24 null mutation in combination with a heterozygous mutation in the LMNA gene causes Hutchinson‐Gilford progeria syndrome (HGPS): insights into the pathophysiology of HGPS
TLDR
The mutations of this patient indicate that farnesylated prelamin A is the deleterious agent leading to the HGPS phenotype, which gives further insights into the pathophysiology of the disorder.
Type B mandibuloacral dysplasia with congenital myopathy due to homozygous ZMPSTE24 missense mutation
TLDR
A 30-year longitudinal clinical survey of a patient harboring a novel severe and complex phenotype, combining an early-onset progeroid syndrome and a congenital myopathy with fiber-type disproportion is reported, extending the clinical spectrum of ZMPSTE24 gene mutations and suggesting that defective prelamin A processing affects muscle regeneration and development.
Severe mandibuloacral dysplasia caused by novel compound heterozygous ZMPSTE24 mutations in two Japanese siblings
TLDR
It is concluded that ZMPSTE24 deficiency results in accumulation of farnesylated prelamin A, which may be responsible for cellular toxicity and the MAD phenotype.
New ZMPSTE24 (FACE1) mutations in patients affected with restrictive dermopathy or related progeroid syndromes and mutation update
TLDR
A comprehensive analysis of the molecular pathology supported the general rule: complete loss-of-function of ZMPSTE24 leads to RD, whereas other less severe phenotypes are associated with at least one haploinsufficient allele.
Hutchinson-Gilford Progeria Syndrome
TLDR
Surprisingly, progerin has also been found in normal unaffected individuals and its level increases with age, suggesting a similar genetic mecha‐ nism in progeria as in normal physiological ageing.
Antisense-Based Progerin Downregulation in HGPS-Like Patients’ Cells
TLDR
It is shown that morpholino antisense oligonucleotides (AON) prevent pathogenic LMNA splicing, markedly reducing the accumulation of Progerin and/or other truncated Prelamin A isoforms in HGPS-like patients’ cells.
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    Proceedings of the National Academy of Sciences of the United States of America
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TLDR
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