Ten human hereditary laminopathies, including Emery-Dreifuss muscular dystrophy (EDMD), are associated with mutations in the LMNA gene that codes for the nuclear filament proteins, lamins A and C. Dr. Brain Kennedy and colleagues at the University of Washington have used a mouse model of EDMD to elucidate the mechanism by which altered expression of A-type lamins causes progressive muscular degeneration.

Adult skeletal muscle is derived from satellite stem cells, known as myoblasts, which differentiate into mature skeletal muscle cells. While several different types of proteins are known to be involved in myogenesis, the role of A-type lamins in muscle differentiation has remained unclear. Dr. Kennedy and colleagues used Lmna-deficient cells, as well as siRNA-mediated knock-down of Lmna and emerin (a lamin-associated protein) to study the affect of decreased A-type lamin or emerin expression on myoblast differentiation.

The authors found that decreased expression of A-type lamins or emerin changes the expression levels of proteins involved in myogenesis (MyoD, pRB, desmin and M-cadherin), and reduces myoblast differentiation potential. Furthermore, forced expression of MyoD or desmin in Lmna-deficient myoblasts restores this defect. By identifying key myogeneic differentiation factors that are altered in Lmna-deificient cells, Dr. Kennedy and colleagues provide new mechanistic insight into how LMNA mutations contribute to EDMD.

They found that the long term CBC risk was significantly higher in women with hereditary breast cancer compared to the risk of developing a primary breast cancer in the general population. The overall probability for these women was 5.5 percent at 5 years and up to 27.3 percent at 20 years compared to only 1.9 percent at 5 years and 4.9 percent at 20 years for the general population. Further analysis by age group showed clearly that the 15 year probability of developing a CBC was significantly elevated for women under 50 years old compared to women over 50 years old (40 percent and 10 percent, respectively).

Women who took adjuvant hormonal therapy had significantly lowered risk for a CBC compared to those who did not take it. Adjuvant chemotherapy had no apparent effect on risk.

In the first published study to characterize CBC risk in non-BRCA hereditary breast cancers, the authors demonstrate "that women with hereditary/familial non-BRCA1/BRCA2 breast cancer have a very high risk of developing CBC." The impact of these results is most apparent for premenopausal women, in who 1 in 5 will develop CBC after only 10 years. Consequently, conclude the authors, "it is important to consider and provide information about the risk of CBC."

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