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

  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},
  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
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.
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.
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
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
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
It is concluded that ZMPSTE24 deficiency results in accumulation of farnesylated prelamin A, which may be responsible for cellular toxicity and the MAD phenotype.
Hutchinson-Gilford Progeria Syndrome
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
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.
Focal Segmental Glomerulosclerosis in Patients with Mandibuloacral Dysplasia Owing to ZMPSTE24 Deficiency
Observations suggest focal segmental glomerulosclerosis as a phenotypic manifestation in patients with ZMPSTE24 deficiency.


Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome
Evidence of mutations in lamin A (LMNA) as the cause of Hutchinson–Gilford progeria syndrome is presented, and the discovery of the molecular basis of this disease may shed light on the general phenomenon of human ageing.
Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia.
It is concluded that mutations in ZMPSTE24 may cause MAD by affecting prelamin A processing by affecting the mating defect of the haploid MATa yeast lacking STE24 and Ras-converting enzyme 1 (RCE1; another prenylprotein-specific endoprotease) genes.
Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C.
Pat skin fibroblasts showed nuclei that presented abnormal lamin A/C distribution and a dysmorphic envelope, thus demonstrating the pathogenic effect of the R527H LMNA mutation, which was shared by all affected patients.
LMNA, encoding lamin A/C, is mutated in partial lipodystrophy
As LMNA is ubiquitously expressed, the finding of site-specific amino acid substitutions in PLD, EDMD–AD and CMD1A reveals distinct functional domains of the lamin A/C protein required for the maintenance and integrity of different cell types.
Heterozygosity for Lmna deficiency eliminates the progeria-like phenotypes in Zmpste24-deficient mice
  • L. FongJ. K. Ng S. Young
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2004
The data suggest that prelamin A is toxic and that reducing its levels by as little as 50% provides striking protection from disease.
Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson–Gilford progeria syndrome
It is shown by light and electron microscopy that HGPS is associated with significant changes in nuclear shape, including lobulation of the nuclear envelope, thickening of thenuclear lamina, loss of peripheral heterochromatin, and clustering of nuclear pores.
Defective prelamin A processing and muscular and adipocyte alterations in Zmpste24 metalloproteinase–deficient mice
Results indicate that prelamin A is a specific substrate for Zmpste24 and demonstrate the usefulness of genetic approaches for identifying the in vivo substrates of proteolytic enzymes.
The laminopathies: nuclear structure meets disease.