Novel point mutation within intron 10 of FMR-1 gene causing fragile X syndrome

Hum Mutat. 1997;10(5):393-9. doi: 10.1002/(SICI)1098-1004(1997)10:5<393::AID-HUMU10>3.0.CO;2-V.

Abstract

The majority of cases involving fragile X syndrome are due to expansion of a (CGG)n trinucleotide repeat at the 5' untranslated region of the FMR-1 gene. Deletion and intragenic loss of function mutations of the FMR-1 gene also have been reported. Here, we report a C to T point mutation at the 14th nucleotide in intron 10 of the FMR-1 gene in three unrelated fragile X patients. However, the (CGG)n repeat of FMR-1 in those patients does not expand. To determine the effect of this mutation on the patients' FMR-1 transcripts, total RNA from peripheral blood cells was reverse transcribed and amplified by polymerase chain reaction (RT-PCR). Direct and subcloned sequencing of the RT-PCR products revealed that the transcripts from the allele with C to T mutation skip exon 10 entirely, resulting in a joining of exons 9 and 11. Deletion of exon 10 results in frame-shift and premature termination of translation, which removes the highly conserved region that encoding the KH2 and RGG box domains of FMRP. Interestingly, a male of the three patients has another G to A substitution in exon 15. However, the intron 10 mutation is sufficient for development of fragile X syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Alternative Splicing
  • Base Sequence
  • Child
  • DNA, Complementary
  • Fragile X Mental Retardation Protein
  • Fragile X Syndrome / genetics*
  • Humans
  • Introns*
  • Male
  • Nerve Tissue Proteins / genetics*
  • Point Mutation*
  • Polymerase Chain Reaction
  • Polymorphism, Single-Stranded Conformational
  • RNA-Binding Proteins*
  • Trinucleotide Repeats

Substances

  • DNA, Complementary
  • FMR1 protein, human
  • Nerve Tissue Proteins
  • RNA-Binding Proteins
  • Fragile X Mental Retardation Protein