Disease and the telomere connection

Chromosomes (in blue) and their ends (in red).

The shortening of telomeres—the ends of chromosomes—affects a gene involved in a muscle disorder called facioscapulohumeral muscular dystrophy (FSHD). This finding, reported this week in Nature Structural & Molecular Biology, describes the first known case in which increased expression of a gene near a shortening telomere contributes to the human disease.

FSHD is an inherited disease that causes the upper body muscles to waste away gradually. Unlike most other genetic disorders that manifest during early childhood, symptoms of FSHD usually appear only when people are in their teens or early twenties. Telomeres shorten with age and, once they reach a critical length, can induce growth arrest and inhibit tumour growth (Frontline, April 24, May 8, and November 6, 2009). Telomere shortening can also affect the expression of genes near chromosome ends, a phenomenon called telomere position effect (TPE).

Woodring Wright and colleagues compared the effect of telomere length on the expression of the FSHD-associated DUX4 gene in cells derived from FSHD patients and their unaffected family members. The authors found that DUX4 is normally silenced because it is situated close to the telomere but its expression is dramatically increased in FSHD-derived cells with short telomeres. The effect increases (almost 10-fold) with decreasing telomere length and occurs long before growth arrest would be induced, suggesting that TPE could explain the delayed onset and progression of this prevalent muscle disorder. The authors found that decreasing telomere length could affect genes at least 100 kilobases from the telomere, a distance much greater than anticipated.

There also seems to be some evidence for telomeres influencing a gene (FRG2) that is even more distant on the chromosome, 1,000 kb away—an effect that disappears as the telomere shortens. The authors feel that owing to shrinking telomeres, many genes might gradually become more active as we get older and this may have significance for several diseases of old age.