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Case Reports
. 2009 Sep;9(5):340-5.
doi: 10.1016/j.mito.2009.05.002. Epub 2009 Jun 6.

De novo mutation in POLG leads to haplotype insufficiency and Alpers syndrome

Sherine S L Chan  1 , Robert K Naviaux, Alice A Basinger, Kari A Casas, William C Copeland
Affiliations
Case Reports

De novo mutation in POLG leads to haplotype insufficiency and Alpers syndrome

Sherine S L Chan et al. Mitochondrion. 2009 Sep.

Abstract

Mutations in POLG are a major contributor to pediatric and adult mitochondrial diseases. However, the consequences of many POLG mutations are not well understood. We investigated the molecular cause of Alpers syndome in a patient harboring the POLG mutations A467T in trans with c.2157+5_+6 gc-->ag in intron 12. Analysis of transcripts arising from the c.2157+5_+6 gc-->ag allele revealed alternative splicing with an insertion of 30 intronic nucleotides leading to a premature termination codon. These transcripts were subsequently removed through nonsense-mediated decay, leading to haplotype insufficiency due to expression of the A467T allele and decreased expression of the c.2157+5_+6 gc-->ag allele, which is likely responsible for the Alpers syndrome phenotype.

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Figures

Figure 1
Figure 1
Pedigree of proband. Black symbol indicates Alpers syndrome. WT = wild-type.
Figure 2
Figure 2
Genomic DNA sequence of exon 12 - exon 14 from the POLG allele containing the c.2157+5_+6 gc>ag mutation. This alters a ‘gc’ to ‘ag’ at the 5th and 6th position 3' of the exon 12 - intron 12 splice junction.
Figure 3
Figure 3
Splice sites as predicted by NetGene2 server, which produces neural network prediction of splice sites in human DNA (http://www.cbs.dtu.dk/services/NetGene2/) (Brunak et al., 1991; Hebsgaard et al., 1996). (A) Wild-type POLG sequence. (B)POLG sequence containing the c2157+5_+6 gc>ag mutation.
Figure 4
Figure 4
Sequence analysis of individual clones from cDNA spanning exons 11 – 14 reveals an inclusion of part of intron 12 in the final fully-spliced transcript. The extra 30 nucleotide insert contains an in-frame PTC at nucleotides 28–30 just before the alternative splice site.
Figure 5
Figure 5
Sequence analysis of genomic DNA and fully-spliced mRNA fragments. (A) Fully-spliced message from fibroblasts (direct sequencing after amplification from cDNA) showed that most transcripts contain the A467T mutation. (B) Sequencing of individual clones revealed both populations, with the A467T allele predominating.
See this image and copyright information in PMC

References

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