Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/10139
Title: Double-strand DNA break repair with replication slippage on two strands: a novel mechanism of deletion formation.
Authors: MacLean, Helen E;Favaloro, Jenny M;Warne, Garry L;Zajac, Jeffrey D
Affiliation: Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia. hmaclean@unimelb.edu.au
Issue Date: 1-May-2006
Citation: Human Mutation; 27(5): 483-9
Abstract: We have characterized an unusual family with two different androgen receptor (AR) gene deletions, in which we propose a novel mechanism of deletion formation has occurred. Affected individuals have the X-linked disorder androgen insensitivity syndrome, and we previously showed that different family members have deletions of different exons of the AR gene. We have now fully sequenced the deletions from affected individuals, and confirmed the presence of different deletions in different affected family members. Most affected and heterozygote individuals have a 4,430-bp deletion of exon 5 that occurred between repeated GTGGCAT motifs in introns 4 and 5. One affected hemizygous individual has a 4,033-bp deletion of exons 6 and 7 that occurred between repeated CCTC motifs in introns 5 and 7. The intron 5 breakpoint junctions of the two deletions are only 11 bp apart. Surprisingly, the maternal grandmother of the original index case was found to be mosaic for both deletional events, as well as having the normal AR gene. Karyotyping ruled out 47,XXX trisomy, indicating triple mosaicism for the two different deleted AR alleles and a normal AR allele. This triple mosaicism must have occurred early in embryonic development, as both deletions were passed on to different children. Based on these findings, we propose a novel mechanism of deletion formation. We suggest that during AR gene replication, a double strand DNA break occurred in intron 5, and that a variant of replication slippage occurred on both newly synthesized strands between the repeat motifs of microhomology, leading to the formation of the two different AR gene deletions.
Internal ID Number: 16619235
URI: http://ahro.austin.org.au/austinjspui/handle/1/10139
DOI: 10.1002/humu.20327
URL: http://www.ncbi.nlm.nih.gov/pubmed/16619235
Type: Journal Article
Subjects: Androgen-Insensitivity Syndrome.genetics
Chromosomes, Human, X
DNA Mutational Analysis
DNA Repair
DNA Replication.physiology
Exons
Female
Gene Deletion
Genetic Linkage
Heterozygote
Humans
Karyotyping
Male
Molecular Sequence Data
Mosaicism
Pedigree
Receptors, Androgen.genetics
Appears in Collections:Journal articles

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