Hutchinson-Gilford, reviewed and re-reviewed

It slays me when there are more reviews than primary papers coming out on a subject — one would think that the ratio of reviews to primary articles should be far less than 1, and that journal editors might reasonably be expected to (say) search PubMed, in order to determine whether the field needs yet another review, before soliciting yet another one.

But on the other hand, there are times when something generally new is happening, and everyone needs to get their heads around it. When that happens, a lot of different perspectives on the same data can be helpful.

Lately I’ve noticed that Hutchinson-Gilford progeria is getting a healthy share of reviews. The lamin A/C mutation story is a genuinely new mechanism for progeria, so I appreciate why there is so much interest. Hence I’ll provide some links to three recent review articles, and leave the determination of overkill as an exercise for the reader.

Altered splicing in prelamin A-associated premature aging phenotypes, Sandre-Giovannoli & Lévy:

… The major pathophysiological mechanism involved in progeria is an aberrant splicing of pre-mRNAs issued from the LMNA gene, due to a de novo heterozygous point mutation, leading to the production and accumulation of truncated lamin A precursors. Aberrant splicing of prelamin A pre-mRNAs causing the production of more extensively truncated precursors is involved in the allelic disease restrictive dermopathy. … In functional terms, all these conditions share the same pathophysiological basis: intranuclear accumulation of lamin A precursors, which cannot be fully processed (due to primary or secondary events) and exert toxic, dominant negative effects on nuclear homeostasis. … In any case, the impact of these mutations on pre-mRNA splicing has rarely been assessed. These disorders affect different tissues and organs, mainly including bone, skin, striated muscles, adipose tissue, vessels, and peripheral nerves in isolated or combined fashions, giving rise to syndromes whose severity ranges from mild to perinatally lethal. In this chapter we … envisage possible targeted therapeutic strategies on the basis of recent research results.

Human laminopathies: nuclei gone genetically awry, Capell & Collins:

Few genes have generated as much recent interest as LMNA, LMNB1 and LMNB2, which encode the components of the nuclear lamina. Over 180 mutations in these genes are associated with at least 13 known diseases – the laminopathies. In particular, the study of LMNA, its products and the phenotypes that result from its mutation have provided important insights into subjects ranging from transcriptional regulation, the cell biology of the nuclear lamina and mechanisms of ageing. Recent studies have begun the difficult task of correlating the genotypes of laminopathies with their phenotypes, and potential therapeutic strategies using existing drugs, modified oligonucleotides and RNAi are showing real promise for the treatment of these diseases.

Human progeroid syndromes, aging and cancer: new genetic and epigenetic insights into old questions, Ramírez et al.:

… With the progress that has been made in understanding the etiologies of these conditions in the past decade, potential therapeutic options have begun to move from the realm of improbability to initial stages of testing. Among these syndromes, relevant advances have recently been made in Werner syndrome, one of several progeroid syndromes characterized by defective DNA helicases, and Hutchinson-Gilford progeria syndrome, which is characterized by aberrant processing of the nuclear envelope protein lamin A. Although best known for their causative roles in these illnesses, Werner protein and lamin A have also recently emerged as key players vulnerable to epigenetic changes that contribute to tumorigenesis and aging. These advances further demonstrate that understanding progeroid syndromes and introducing adequate treatments will not only prove beneficial to patients suffering from these dramatic diseases, but will also provide new mechanistic insights into cancer and normal aging processes.

That last line is the money shot, and an important reason why the study of these rare diseases is important (beyond the value to patients and their families, which we also must not forget): To the extent that progerias represent accelerations of bona fide aging, treatments for these diseases might help us design therapeutics that slow or arrest aspects of normal aging.