Werner's Syndrome: Genetics

Werner’s syndrome (WS) is an autosomal recessive genetic disorder caused by a very specific series of molecular events, resulting in the fairly homogenous symptoms displayed by all WS patients. The disease is caused by a mutation of the WRN gene, cloned in 1996 by Yu et al., which results in the production of a shortened version of the WRN protein. This protein lacks the locator signals which allow normal versions of WRN to move to the nucleus. Without these nuclear localization signals, the protein fails to perform its cellular function.

The WRN gene can be mutated in many ways to cause the syndrome, but virtually all of these mutation fall into one of two larger categories: homozygous or compound mutations. The most common Werner mutations are frameshift, nonsense, or deletion mutations, although up to 40 different separate mutations have been found to cause the disease. Far less commonly, WS can also be caused by a missense mutation on the WRN locus, but this is rarely if ever seen in practice.

Physiologically, the WRN gene codes for a protein that is 1432 amino acids long and one of a family of DNA helicases responsible for aiding the process of genomic repair. These helicases are collectively known as RecQ proteins, and mutations to other members of this important family are known to cause other types of progeria. The WRN protein, however, is different from other members of this family because, in addition to its helicase duties, it doubles as an exonuclease as well. This means that it is capable of catalyzing a process of hydrolysis that results in the removal of a single nucleotide from a nucleic acid (DNA or RNA) chain. Other RecQ proteins do not have this function.

WRN protein has been shown to have many cellular functions. It interacts with Bloom protein (see Bloom’s syndrome) to synergistically repair DNA. It also has been found localized to the telomeres, where it interacts with TRF2 ( a telomeric repeat binding factor) to preserve telomere structure. Telomeres are the ‘cap’ at the ends of chromosomes that help preserve DNA structure, and, it has been suggested, play a crucial role in the natural process of ageing. Lack of functional WRN protein has been demonstrated to result in unstable and non-homogenous telomeres, a state which has been shown to considerably shorten the lifespan of mice. WRN protein also directly interacts with p53. Too much WRN precipitates p53-induced cell apoptosis (apoptosis is the manner by which a cell self-destructs), while too little WRN protein causes inefficient apoptosis.

What do all of these interactions mean on a more holistic cellular level? The WS cell is less able to efficiently repair extant DNA, and is hampered in its ability to accurately replicate new DNA. Deficient DNA repair mechanisms mean a greatly increased chance of random new mutations, a likely cause of the high cancer incidence of Werner’s patients. During cellular division, WS cells are far more likely to experience chromosomal deletion and large-scale translocation. Overall, WS is hallmarked by great genomic instability.