Hutchinson-Gilford Progeria Syndrome

Clincians

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disorder phenotypically characterised by many features of premature aging. It is clinically characterised by postnatal growth retardation, midface hypoplasia, micrognathia, premature atherosclerosis, absence of subcutaneous fat, alopecia and generalised osteodysplasia.

At birth, the appearance of patients is generally normal, but by one year of age patients show severe growth retardation, balding and sclerodermatous skin changes. Patients live a median of 13.4 years and die of heart attacks or congestive heart failure.

HGPS is caused by the mutation in nuclear lamin A/C (LMNA) gene. It is a very rare condition; it affects one in 4 million newborns worldwide. Hutchinson-Gilford Progeria Syndrome image

Image above: In HGPS patients the cell nucleus has dramatically aberrant morphology (bottom, right) rather than the uniform shape typically found in healthy individuals (top, right). From Public Library of Science.

Molecular cause and consequences

Lamin proteins are distributed throughout the nucleoplasm and are involved in numerous functions, including DNA replication, transcription, chromatin organisation, nuclear positioning and shape, as well as the assembly/disassembly of the nucleus during cell division.

Out of 14 mutations affecting lamin A/C, three have been reported to specifically alter lamin A splicing. The changes in splicing lead to the production of truncated protein products (p.G608G, p.T623S and IVS11+1G>A). Most of the typical Hutchinson-Gilford progeria cases are due to a recurrent, de novo point mutation in LMNA exon 11: c.1824C>T. This mutation occurs in a probable exon splicing enhancer. As a result, a cryptic splice site is activated in transcripts generated from the mutated allele, which is located 5 nucleotides upstream of the mutation. The use of the cryptic splice site leads to the production of a truncated Lamin A protein lacking the last 150 base pairs of exon 11. The truncated protein is called “progerin” and acts in a dominant fashion to generate the HGPS phenotype.