Transition mutations at CpG dinucleotides are the most frequent in vivo spontaneous single-base substitution mutation in the human HPRT gene
✍ Scribed by J. Patrick O'Neill; Barry A. Finette
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 106 KB
- Volume
- 32
- Category
- Article
- ISSN
- 0893-6692
No coin nor oath required. For personal study only.
✦ Synopsis
of CpG dinucleotides within the HPRT gene and the fre-Studies of human genetic disorders have suggested that quency of mutations at these sites. 5-methylcytosine moieties in DNA may act as endoge-Germ cell mutations in the X-chromosome HPRT gene nous mutagens due to the increased deamination of C clinically result in either Lesch-Nyhan syndrome (severe when it is methylated in CpG dinucleotide sequences. loss of enzyme activity) or gout (partial loss of enzyme This deamination of C to yield T can result in a DNA activity). The human HPRT gene has a 1.4 kilobase replication mediated C/G r T/A transition mutation. Fully mRNA containing a 657 base-coding region. The dinucle-32% of human germline single-base substitution (SBS) otide sequence CpG would be expected to appear 27 times mutations in the LDL receptor gene and 50% of germline by random distribution, but is only found eight times; i.e., SBS mutations in the p53 gene (Li-Fraumeni syndrome) it is reduced by 70%. It has been proposed that this is the are found in CpG dinucleotide sequences [Rideout et al., result of mutational pressure against this highly mutable 1990; Cooper and Krawczak, 1990]. Deamination of C dinucleotide [Kricker et al., 1992]. The eight CpG dinuyields U, while deamination of 5-methylcytosine yields cleotides are shown in Table II, where the A of the AUG T. These C to T (or G to A) transitions have been proposed initiation codon is designated base 1. These eight CpG to be due to the decreased rate of repair of T:G misdinucleotides present 16 possible SBS (transition) mutamatches versus U:G mismatches [Schmutte et al., 1995].
tions: CpG r TpG or CpG r CpA. Four of these result It is this difference in repair which causes 5-methylcytoin no predicted amino acid change, ten in a missense sine to stand out as a ''hot spot.'' mutation, and two in a chain-terminating (TGA) codon. We recently determined the HPRT mutations in two Five of the possible 12 mutations have been found to unrelated families each with a Lesch-Nyhan syndromeoccur in in vivo or in vitro studies and these are shaded affected male and found that both contain a C 151 to T transiin Table II. Table III summarizes the distribution of SBS tion mutation by cDNA sequencing (Table I). In the first (transition) mutations at these five sites, as reported in the family (HPRT Estrie ), we determined that both the mother and Cariello HPRT database [Cariello, 1997]. Two of these the sister of the affected boy showed the elevated thioguamutations (CpG 481 r CpA and CpG 509 r CpA) have been nine-resistant (TG r ) mutant frequency expected for carrier reported only in human cells in in vitro studies, the former females [Skopek et al., 1990; Hunter et al., 1996] and both showed the C 151 GA to TGA mutation in the mutant allele cDNA. In the second family (HPRT Sagamie ), the proband Contract grant sponsor: the National Institute of Child Health and Huand his heterozygous mother showed the same mutation.