Genetic instability syndromes with progeroid features

Abstract

We discuss examples of the rare human genetic instability syndromes as they present themselves at the chromosome, telomere, and nuclear envelope level. Destabilization of the nuclear envelope due to mutations in the Lamin A/C gene lead to global impairments of the chromatin structure and gene expression with the fatal consequences observed in the Hutchinson-Gilford juvenile progeria syndrome. Patients with Dyskeratosis congenita have defective telomerase function. These patients exhibit a number of progeroid features, suggesting a causal connection between short telomeres and premature ageing. The most prominent example of the chromosomal instability syndromes is the Werner adult progeria syndrome where impaired helicase and exonuclease functions cause a multitude of (albeit superficial) similarities with the normal ageing process. A less well-know example is Fanconi anemia (FA) a multisystem disorder caused by biallelic mutations in one of at least 13 different genes which include the BRCA2 breast cancer gene. Unlike cells from any other human disorder, FA cells are uniquely sensitive to oxidative stress. In a situation of defective DNA repair, oxidative stress leads to accumulation of (unrepaired) DNA damage. Oxidative stress is the likely culprit of bone marrow failure, risk of neoplasia, and features of premature ageing in FA, rendering this rare disease into the only known human model of the free radical theory of ageing.