Homozygosity at variant MLH1 can lead to secondary mutation in NF1, neurofibromatosis type I and early onset leukemia.
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.
Alotaibi
Hani
H
Bilkent University, Department of Molecular Biology and Genetics, 06800, Ankara, Turkey.
Ricciardone
Marie D
MD
Ozturk
Mehmet
M
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D003241:Consanguinity; D016514:Genes, Neurofibromatosis 1; D006720:Homozygote; D006801:Humans; D007223:Infant; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D008297:Male; D000070957:MutL Protein Homolog 1; D009456:Neurofibromatosis 1 / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree
D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1