title: De novo mutation in POLG leads to haplotype insufficiency and Alpers syndrome.
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.
authors.affiliation: Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Sherine S L
authors.initials: SS
authors.lastname: Chan
authors.forename: Robert K
authors.initials: RK
authors.lastname: Naviaux
authors.forename: Alice A
authors.initials: AA
authors.lastname: Basinger
authors.forename: Kari A
authors.initials: KA
authors.lastname: Casas
authors.forename: William C
authors.initials: WC
authors.lastname: Copeland
mesh_terms: D001483:Base Sequence; D018389:Codon, Nonsense; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000172:deficiency*; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009154:Mutation; D017354:Point Mutation; D012326:RNA Splicing; D020871:RNA Stability
chemical_list: D018389:Codon, Nonsense; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C413027:POLG protein, human