Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome

  title={Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome},
  author={Maria Eriksson and William Ted Brown and Leslie B Gordon and Michael W. Glynn and Joel Singer and Laura J. Scott and Michael R. Erdos and Christiane M. Robbins and Tracy Y. Moses and Peter Berglund and Amalia S Dutra and Evgenia Pak and Sandra Durkin and Antonei B Csoka and Michael Boehnke and Thomas W. Glover and Francis S. Collins},
Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by features reminiscent of marked premature ageing. [] Key Result Sequencing of LMNA, located in this interval and previously implicated in several other heritable disorders, revealed that 18 out of 20 classical cases of HGPS harboured an identical de novo (that is, newly arisen and not inherited) single-base substitution, G608G(GGC > GGT), within exon 11.
Homozygous missense mutation in the lamin A/C gene causes autosomal recessive Hutchinson-Gilford progeria syndrome
It is reported that heterozygous, recurrent de novo point mutations in the lamin A/C gene, a component of the filamentous meshwork of the nuclear lamina, caused Hutchinson-Gilford progeria syndrome.
Paternal origin of LMNA mutations in Hutchinson–Gilford progeria
It is shown that G608G mutation responsible for the majority of cases of HGPS arises in the paternal germline, and an advanced paternal age in the fathers of affected individuals is confirmed.
Hutchinson–Gilford progeria syndrome
The discovery of the HGPS mutations brings the total number of diseases caused by mutant Lmna to nine, underscoring the astonishing spectrum of laminopathies.
Compound heterozygous ZMPSTE24 mutations reduce prelamin A processing and result in a severe progeroid phenotype
A genetic cause has now been implicated following the identification of de novo heterozygous mutations in the LMNA gene in the majority of HGPS patients, which is an extremely rare but devastating disorder that mimics premature aging.
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.
An inherited LMNA gene mutation in atypical Progeria syndrome
The observation of a non‐consanguineous Moroccan patient presenting with atypical progeria is discussed and the molecular studies showed the heterozygous mutation c.412G>A (p.Gly608Gly) of the LMNA gene, previously reported as a de novo mutation, was inherited from the apparently healthy father who showed a somatic cell mosaicism.
There is presently no effective therapy is available for Hutchinson-Gilford progeria syndrome (HGPS), but, it is essential to monitor carefully cardiovascular and cerebrovascular disease.
Hutchinson-Gilford progeria syndrome
Recent studies have shown that blocking famesylation of progerin via the use of farnesyltransferase inhibitors can reduce nuclear blebbing and thus HGPS pathogenicity and pharmacological targeting to correct cellular phenotypes associated with HGPS could be utilized in the future for therapeutic intervention.
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.


Mutations in the LMNA gene encoding lamin A/C
The reports of lamination mutations including the corresponding phenotype are of great interest in order to gain insights into the function of lamin A/C.
Maternal uniparental disomy of chromosome 1 with reduction to homozygosity of the LAMB3 locus in a patient with Herlitz junctional epidermolysis bullosa.
A unique patient with H-JEB, who was homozygous for a nonsense mutation, Q243X, in the LAMB3 gene on chromosome 1 and who had normal karyotype 46,XY, is described, the first description of uniparental disomy of human chromosome 1.
Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A/C.
The FPLD mutations R482Q and R482W occurred on different haplotypes, indicating that they are likely to have arisen more than once, and mutations responsible for dilated cardiomyopathy and conduction-system disease are observed in the rod domain of the protein.
Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis.
This patient represents the first case of paternal uniparental disomy of chromosome 1 and provides conclusive evidence that paternally derived genes on human chromosome 1 are not imprinted.
Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot-Marie-Tooth disorder type 2) and mouse.
This report constitutes the first evidence of the recessive inheritance of a mutation that causes CMT2; additionally, it is suggested that mutations in LMNA may also be the cause of the genetically overlapping disorder CMT1B1.
Progeria: a human-disease model of accelerated aging.
  • W. Brown
  • Biology, Medicine
    The American journal of clinical nutrition
  • 1992
It is hypothesize that the failure of patients with progeria to thrive may be due to a bioinactive form of GH and a lack of vasculogenesis caused by excess HA, a key gene with a major effect on normal aging.
Del(1)(q23) in a patient with Hutchinson-Gilford progeria.
The cytogenetical analyses of this patient suggest that the B4GALT3 gene could be involved in the pathogenesis of HGP, and this gene has been mapped in the interval 1q21-23.
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.
Evidence for autosomal recessive inheritance of progeria (Hutchinson Gilford).
  • A. Maciel
  • Medicine
    American journal of medical genetics
  • 1988
Progeria can be inherited as an autosomal recessive trait because four other individuals with progeria were born in another consanguineous sibship in the same family.