Molecular characterization of the breakpoints of a 12-kb deletion in the NF1Gene in a family showing germ-line mosaicism

Conxi Lázaro, Antonia Gaona, Michael Lynch, Helena Kruyer, Anna Ravella, Xavier P. Estivill

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Abstract

Neurofibromatosis type 1 (NF1) is caused by deletions, insertions, translocations, and point mutations in the NF1 gene, which spans 350 kb on the long arm of human chromosome 17. Although several point mutations have been described, large molecular abnormalities have rarely been characterized in detail. We describe here the molecular breakpoints of a 12-kb deletion of the NF1 gene, which is responsible for the NF1 phenotype in a kindred with two children affected because of germ-line mosaicism in the unaffected father, who has the mutation in 10% of his spermatozoa. The mutation spans introns 31-39, removing 12,021 nt and inserting 30 bp, of which 19 bp are a direct repetition of a sequence located in intron 31, just 4 bp before the 5′ breakpoint. The 5′ and 3′ breakpoints contain the sequence TATTTTA, which could be involved in the generation of the deletion. The most plausible explanation for the mechanism involved in the generation of this 12kb deletion is homologous/nonhomologous recombination. Since sperm of the father does not contain the corresponding insertion of the 12-kb deleted sequence, this deletion could have occurred within the NF1 chromosome through loop formation. RNA from lymphocytes of one of the NF1 patients showed similar levels of the mutated and normal transcripts, suggesting that the NF1-mRNA from mutations causing frame shifts of the reading frame or stop codons in this gene is not degraded during its processing. The mutation was not detected in fresh lymphocytes from the unaffected father by PCR analysis, supporting the case for true germ-line mosaicism.

Original languageEnglish
Pages (from-to)1044-1049
Number of pages6
JournalAmerican Journal of Human Genetics
Volume57
Issue number5
Publication statusPublished - 1995
Externally publishedYes

Fingerprint

Neurofibromatosis 1
Mosaicism
Germ Cells
Neurofibromatosis 1 Genes
Fathers
Point Mutation
Introns
Mutation
Spermatozoa
Lymphocytes
Reading Frames
Chromosomes, Human, Pair 17
Frameshift Mutation
Terminator Codon
Sequence Deletion
Insertional Mutagenesis
Homologous Recombination
Human Chromosomes
Chromosomes
RNA

ASJC Scopus subject areas

  • Genetics

Cite this

Molecular characterization of the breakpoints of a 12-kb deletion in the NF1Gene in a family showing germ-line mosaicism. / Lázaro, Conxi; Gaona, Antonia; Lynch, Michael; Kruyer, Helena; Ravella, Anna; Estivill, Xavier P.

In: American Journal of Human Genetics, Vol. 57, No. 5, 1995, p. 1044-1049.

Research output: Contribution to journalArticle

Lázaro, Conxi ; Gaona, Antonia ; Lynch, Michael ; Kruyer, Helena ; Ravella, Anna ; Estivill, Xavier P. / Molecular characterization of the breakpoints of a 12-kb deletion in the NF1Gene in a family showing germ-line mosaicism. In: American Journal of Human Genetics. 1995 ; Vol. 57, No. 5. pp. 1044-1049.
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