Factors Associated with HD CAG repeat instability in Huntington's disease

A new study based on Venezuela data examines factors that might be associated with expansion of the CAG repeat from generation to generation.

The US-Venezuela Collaborative Research Group has provided new data about the intergenerational instability in CAG counts.

Normal genes for the huntingtin's protein are stably transmitted. If you inherit a normal copy of gene from a parent who has, say 19 repeats on that allele, the CAG count will stay at 19 on your copy of the gene. However, CAG counts for the HD gene are not necessarily stable. There can be large expansions (increases in CAG count), small expansions, small contractions (decreases in CAG count), or the count could remain the same. For example, if a parent with a CAG count of 43 transmitted the gene with 46 repeats that would be a small expansion. If that same parent transmitted the gene with 41 repeats, that would be a small contraction.

The team looked at intergenerational transmissions of the HD gene from both affected mothers and affected fathers. As shown in the table below, contractions and expansions are equally likely with maternal transmission. However, expansions are more common than contractions with paternal tranmission.

Number of transmissions495311184
Mean CAG of the parent44.444.743.9
Changed alleles364
(74%)
214
(69%)
150
(82%)
Contractions137
(28%)
107
(34.5%)
30
(16%)
Expansions227
(46%)
107
(34.5%)
120
(65%)
Mean repeat length change+1.27-.04+3.5
Range of repeat length changes-7 to +41-5 to +10-7 to +41
CAG Transmission Table by Gender of Parents
 TotalFemaleMale

As expected for parents with a normal gene and an HD gene, both women and men were equally likely to transmit the HD gene and the normal gene was as likely to be transmitted as the HD gene - confirming the 50-50 odds for the children of both sexes.

In both males and females, the larger their own CAG repeat, the larger the average change in the CAG count transmitted to their offspring. The researchers also looked at sperm cells from gene positive fathers and found that the larger the CAG count of the father, the larger the change in the CAG count in the sperm cells.

The researchers analyzed the data on parental transmission by the sex of the offspring to see if that made a difference and got a surprise. As shown by the table below, there is no gender effect in how fathers transmit the HD gene to their sons and daughters. However, when mothers transmit the HD gene, it is more likely to contract for daughters and expand for sons.

 

CAG Transmission by Gender of Parents and Offspring
 MOTHERSFATHERS
 daughterssonsdaughterssons
Number of transmissions1471649688
Mean CAG of the parent44.844.544.343.6
Changed alleles99
(67%)
115
(70%)
79
(82%)
71
(81%)
Contractions62
(42%)
45
(27%)
18
(19%)
12
(14%)
Expansions37
(25%)
70
(43%)
61
(64%)
59
(67%)
Mean repeat length change-.04+.28+3.0+4.0
Range of repeat length changes-5 to +5-5 to +10-6 to +29-7 to +41

They also looked for other factors associated with CAG intergenerational instability.

One hypothesis was that perhaps age was a factor, but that was not supported.

  • Older mothers are no more likelier to transmit changed CAG counts than younger mothers.
  • Older fathers were somewhat more likely than younger fathers, but the difference was not statistically significant.

Another way to look at age as a factor is to see whether the birth order of the children who had inherited HD was associated with intergenerational instability. It was not.

They also examined sperm samples from male donors to see if men who were already affected by the disease were more likely to transmit changed CAG counts than were gene-positive men who were not yet symptomatic. This hypothesis was not supported; there was no difference between affected and unaffected fathers.

These three results, which show that CAG instability is not a consequence of aging or disease progression, suggest that the instability is a property inherit in the expanded CAG repeats themselves.

However, that can't be the only explanation since some men with the same CAG count had more variability in the sperm cells they produced than did other men with the same count. Other factors must be involved. They also looked at sibling data and found that instability tends to run in families which suggests that another unknown genetic factor (or factors) has an influence on instability.

In summary, this study reminds us that the CAG counts of the HD gene aren't stable and can either expand or contract. The higher the CAG count of the affected parent, the more instability seen in the counts of offspring who inherit the gene. The study also shows that there are other, still unknown genetic factors involved, since instability tends to run in families independent of the CAG count.

Marsha L. Miller, Ph.D.
Factors Associated with HD CAG repeat instability in Huntington's disease

Vanessa Wheeler, Francesca Persichetti, Sandra McNeil, Jayalakshmi Mysore , Sony Mysore, Marcy MacDonald, Richard Myers, James Gusella, Nancy Wexler, and the US-Venezuela Collaborative Research Group

Background:

The Huntington's disease (HD) CAG repeat exhibits dramatic instability upon transmission 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 HD gene carriers.

Objective:

To investigate the factors associated with intergenerational HD CAG repeat instability

Methods:

We investigated HD CAG repeat variability in a collection of 112 sperm DNAs from HD gene positive males of a large Venezuelan cohort and transmission instability for 184 father-offspring and 311 mother-offspring pairs from this pedigree.

Results:

We confirm previous observations that CAG repeat length is the strongest predictor of repeat length variability in sperm, but do not find any correlation between CAG repeat instability and either age at the time of sperm donation or affection status. 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 sib-sib correlation for repeat instability suggests that genetic factors play a role in intergenerational CAG repeat instability.

Conclusions:

Although CAG repeat length is the main contributor to intergenerational instability, genetic factors may play a modifying role.

Journal of Medical Genetics 2007 Jul 27; [Epub ahead of print]