Molecular Genetics of Huntington’s Disease

Huntington’s disease is caused by an autosomal dominant mutation in the gene encoding for huntingtin protein (htt).

NB KO htt is inviable- so it is of some importance, but we still do not know what this is.

The genetic defect is an expansion of a CAG repeat pattern found in the first exon of the gene.  The normal gene carries around 30 CAG repeats.  Individuals with HD typically have around 40 (the threshold is usually 36/7, but can range to >100).

The age of onset is typically affected by the number of CAG repeats.  Those with 36/7 will usually develop HD in their old age, whereas those with 100 can develop HD in their twenties.

Note that not all indivuals with 37 CAG repeats will develop HD, and patients with 35 can.  This, combined with age, results in a picture of age-dependent, incomplete penetrance.

Expanded CAG repeats are unstable

In normal alleles, CAG repeat changes occur in less than 1% of offspring (i.e. Mendelian inheritance).  In HD alleles, CAG repeat changes occur in 70% of offspring, 73% of which are expansions.  This causes anticipation, that is for HD to occur at an earlier age in offspring (it is technically possible for one generation to be diagnosed before the parent).  Large expansions (>7 CAG) are more common in paternal transmission.

HD mutations are probably gain of function/dominant-negative

Dominant – negative mutations are those in which the mutated protein interferes with the normal WT protein to cause >50% loss of function.

This is probably the case given that transgenic mice which have two WT alleles and a HD allele (i.e. triploid) display features of HD.  Also, HD/- mice (monoploid) are normal.

Hypoxanthine-guanine phosphoribosyltransferase (HPRT) is a gene in which the number of CAG repeats can be manipulated and has been used as an alternative model for HD.  In mice with polyQ (CAG repeats) HPRT, they show neurological deficit(despite HPRT not known to be involved with any neurological CAG disorders).

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