Homozygosity at variant MLH1 can lead to secondary mutation in NF1, neurofibromatosis type I and early onset leukemia

Mutat Res. 2008 Jan 1;637(1-2):209-14. doi: 10.1016/j.mrfmmm.2007.08.003. Epub 2007 Aug 9.


Heterozygous germ-line variants of DNA mismatch repair (MMR) genes predispose individuals to hereditary non-polyposis colorectal cancer. Several independent reports have shown that individuals constitutionally homozygous for MMR allelic variants develop early onset hematological malignancies often associated to features of neurofibromatosis type 1 (NF1) syndrome. The genetic mechanism of NF1 associated to MMR gene deficiency is not fully known. We report here that a child with this form of NF1 displays a heterozygous NF1 gene mutation (c.3721C>T), in addition to a homozygous MLH1 gene mutation (c.676C>T) leading to a truncated MLH1 protein (p.R226X). The parents did not display NF1 features nor the NF1 mutation. This new NF1 gene mutation is recurrent and predicts a truncated neurofibromin (p.R1241X) lacking its GTPase activating function, as well as all C-terminally located functional domains. Our findings suggest that NF1 disease observed in individuals homozygous for deleterious MMR variants may be due to a concomitant NF1 gene mutation. The presence of both homozygous MLH1 and heterozygous NF1 mutation in the child studied here also provides a mechanistic explanation for early onset malignancies that are observed in affected individuals. It also provides a model for cooperation between genetic alterations in human carcinogenesis.

Publication types

  • Case Reports

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Consanguinity
  • Genes, Neurofibromatosis 1*
  • Homozygote
  • Humans
  • Infant
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Male
  • MutL Protein Homolog 1
  • Neurofibromatosis 1 / genetics*
  • Nuclear Proteins / genetics*
  • Pedigree


  • Adaptor Proteins, Signal Transducing
  • MLH1 protein, human
  • Nuclear Proteins
  • MutL Protein Homolog 1