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Lamin A expression levels are unperturbed at the normal and mutant alleles but display partial splice site selection in Hutchinson-Gilford progeria syndrome
  1. C J Reddel,
  2. A S Weiss
  1. School of Molecular and Microbial Biosciences, University of Sydney, NSW 2006, Australia
  1. Correspondence to:
 Professor Anthony Weiss
 School of Molecular and Microbial Biosciences, University of Sydney, NSW 2006, Australia;

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Hutchinson-Gilford progeria syndrome (HGPS) is a rare fatal genetic disorder which is characterised by the very early appearance of accelerated ageing in children. It was first described by Hutchinson1 and Gilford.2 Children with HGPS appear healthy at birth, with distinctive clinical features appearing within the first few years of life, including severe growth retardation, atherosclerosis, incomplete sexual maturation, loss of subcutaneous fat, craniofacial abnormalities, alopecia (hair loss), stiffness of joints, and other skeletal abnormalities including coxa valga (giving a “horse-riding” stance), delayed and abnormal dentition, and scleroderma-like areas of skin, with normal mental and emotional development.3

A specific causal mutation for HGPS in the LMNA gene was identified4,5 and down-regulation of isoforms of the protein arising from the LMNA gene were found in HGPS patients.6 The LMNA gene encodes the A-type lamins, lamins A and C, in which several other laminopathies have their causal mutation.7,8 The heterozygous de novo point mutation is located in exon 11 of the LMNA gene, which is transcribed to lamin A while the shorter lamin C is unaffected by the mutation. The GGC>GGT G608G single-base substitution reveals a cryptic splice site and is proposed to result in a truncated transcript encoding a protein that is 50 amino acid shorter. This mutant protein will be referred to as progerin. A less common mutation in the same codon (GGC>AGC), predicted to have similar effects on lamin A splicing, was also identified.4 Western blots reveal progerin and the normal lamin A protein in HGPS patient cells.5

This hypothesised mechanism raises questions about allelic expression and splicing efficiency. De Sandre-Giovannoli et al4 postulated that only the mutated allele may be expressed in HGPS cells. We now examine lamin A transcript levels in HGPS cells, identify their allelic sources …

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  • Conflict of interest: none declared.