C1 inhibitor gene sequence facilitates frameshift mutations

John Bissler, Qin Shao Meng, Theresa Emery

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Mutations disrupting the function or production of C1 inhibitor cause the disease hereditary angioneurotic edema. Patient mutations identified an imperfect inverted repeat sequence that was postulated to play a mechanistic role in the mutations. To test this hypothesis, the inverted repeat was cloned into the chloramphenicol acetyltransferase gene in pBR325 and its mutation rate was studied in four bacterial strains. These strains were selected to assay the effects of recombination and superhelical tension on mutation frequency. Mutations that revert bacteria to chloramphenicol resistance (Cm(r)) were scored. Both pairs of isogenic strains had reversion frequencies of approximately 10-8. These rare reversion events in bacteria were most often a frameshift that involved the imperfect inverted repeat with a deletion or a tandem duplication, an event very similar to the human mutations. Increased DNA superhelical tension, which would be expected to enhance cruciform extrusion, did not accentuate mutagenesis. This finding suggests that the imperfect inverted repeat may form a stem-loop structure in the single-stranded DNA created by the duplex DNA melting prior to replication. Models explaining the slippage can be drawn using the lagging strand of the replication fork. In this model, the formation of a stemloop structure is responsible for bringing the end of the deletion or duplication into close proximity.

Original languageEnglish (US)
Pages (from-to)795-806
Number of pages12
JournalMolecular Medicine
Volume4
Issue number12
StatePublished - 1998
Externally publishedYes

Fingerprint

Frameshift Mutation
Mutation
Genes
Mutation Rate
Inverted Repeat Sequences
Chloramphenicol Resistance
Hereditary Angioedemas
Nucleic Acid Denaturation
Bacteria
Superhelical DNA
Chloramphenicol O-Acetyltransferase
Single-Stranded DNA
Mutagenesis
Genetic Recombination

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

C1 inhibitor gene sequence facilitates frameshift mutations. / Bissler, John; Meng, Qin Shao; Emery, Theresa.

In: Molecular Medicine, Vol. 4, No. 12, 1998, p. 795-806.

Research output: Contribution to journalArticle

Bissler, J, Meng, QS & Emery, T 1998, 'C1 inhibitor gene sequence facilitates frameshift mutations', Molecular Medicine, vol. 4, no. 12, pp. 795-806.
Bissler, John ; Meng, Qin Shao ; Emery, Theresa. / C1 inhibitor gene sequence facilitates frameshift mutations. In: Molecular Medicine. 1998 ; Vol. 4, No. 12. pp. 795-806.
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