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

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Alotaibi H., Ricciardone M. D., Ozturk M.

MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS, cilt.637, sa.1-2, ss.209-214, 2008 (SCI-Expanded) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 637 Sayı: 1-2
  • Basım Tarihi: 2008
  • Doi Numarası: 10.1016/j.mrfmmm.2007.08.003
  • Dergi Adı: MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED)
  • Sayfa Sayıları: ss.209-214
  • Anahtar Kelimeler: neurofibromatosis type 1, MLH1, NF1, cooperative effect, downstream mutation, HEMATOLOGICAL MALIGNANCY, GENE, PREDISPOSES, CANCERS, DOMAIN
  • Dokuz Eylül Üniversitesi Adresli: Hayır

Özet

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 NF I 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 NF I 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. (c) 2007 Elsevier B.V. All rights reserved.