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

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dc.citation.epage214en_US
dc.citation.issueNumber1-2en_US
dc.citation.spage209en_US
dc.citation.volumeNumber637en_US
dc.contributor.authorAlotaibi, H.en_US
dc.contributor.authorRicciardone, M. D.en_US
dc.contributor.authorOzturk, M.en_US
dc.date.accessioned2016-02-08T10:10:40Z
dc.date.available2016-02-08T10:10:40Z
dc.date.issued2008en_US
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.description.abstractHeterozygous 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. © 2007 Elsevier B.V. All rights reserved.en_US
dc.description.provenanceMade available in DSpace on 2016-02-08T10:10:40Z (GMT). No. of bitstreams: 1 bilkent-research-paper.pdf: 70227 bytes, checksum: 26e812c6f5156f83f0e77b261a471b5a (MD5) Previous issue date: 2008en
dc.identifier.doi10.1016/j.mrfmmm.2007.08.003en_US
dc.identifier.issn0027-5107
dc.identifier.urihttp://hdl.handle.net/11693/23237
dc.language.isoEnglishen_US
dc.publisherElsevieren_US
dc.relation.isversionofhttp://dx.doi.org/10.1016/j.mrfmmm.2007.08.003en_US
dc.source.titleMutation Research - Fundamental and Molecular Mechanisms of Mutagenesisen_US
dc.subjectCooperative effecten_US
dc.subjectDownstream mutationen_US
dc.subjectMLH1en_US
dc.subjectNeurofibromatosis type 1en_US
dc.subjectNF1en_US
dc.subjectGenomic DNAen_US
dc.titleHomozygosity at variant MLH1 can lead to secondary mutation in NF1, neurofibromatosis type I and early onset leukemiaen_US
dc.typeArticleen_US

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