Wheeler V C, Persichetti F, McNeil S M, Mysore J S, Mysore S S, MacDonald M E, Myers R H, Gusella J F, Wexler N S
Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
J Med Genet. 2007 Nov;44(11):695-701. doi: 10.1136/jmg.2007.050930. Epub 2007 Jul 27.
The Huntington disease (HD) CAG repeat exhibits dramatic instability when transmitted to subsequent generations. The instability of the HD disease allele in male intergenerational transmissions is reflected in the variability of the CAG repeat in DNA from the sperm of male carriers of the HD gene.
In this study, we used a collection of 112 sperm DNAs from male HD gene-positive members of a large Venezuelan cohort to investigate the factors associated with repeat instability. We confirm previous observations that CAG repeat length is the strongest predictor of repeat-length variability in sperm, but we did not find any correlation between CAG repeat instability and either age at the time of sperm donation or affectedness status. We also investigated transmission instability for 184 father-offspring and 311 mother-offspring pairs in this Venezuelan pedigree. Repeat-length changes were dependent upon the sex of the transmitting parent and parental CAG repeat length but not parental age or birth order. Unexpectedly, in maternal transmissions, repeat-length changes were also dependent upon the sex of the offspring, with a tendency for expansion in male offspring and contraction in female offspring.
Significant sibling-sibling correlation for repeat instability suggests that genetic factors play a role in intergenerational CAG repeat instability.
亨廷顿舞蹈症（HD）的CAG重复序列在传递给后代时表现出显著的不稳定性。HD疾病等位基因在男性代际传递中的不稳定性反映在HD基因男性携带者精子DNA中CAG重复序列的变异性上。
在本研究中，我们使用了来自一个大型委内瑞拉队列中112名HD基因阳性男性成员的精子DNA集合，以研究与重复序列不稳定性相关的因素。我们证实了之前的观察结果，即CAG重复序列长度是精子中重复序列长度变异性的最强预测指标，但我们未发现CAG重复序列不稳定性与捐精时的年龄或患病状态之间存在任何相关性。我们还研究了这个委内瑞拉家系中184对父子和311对母子的传递不稳定性。重复序列长度的变化取决于传递亲本的性别和亲本CAG重复序列长度，而不取决于亲本年龄或出生顺序。出乎意料的是，在母系传递中，重复序列长度的变化还取决于后代的性别，男性后代有扩增趋势，女性后代有收缩趋势。
重复序列不稳定性的显著同胞相关性表明，遗传因素在代际CAG重复序列不稳定性中起作用。
