Mutational Analysis of the NF1 Gene in Two Families with Neurofibromatosis 1 Accompanied by Pheochromocytoma.

Hyon Seung Yi; Sei Hyun Kim; Jihoon Kim; Eun Jin Bae; Suntaek Hong; Ie Byung Park; Yu Jin Kim; Sihoon Lee

doi:10.3803/EnM.2011.26.2.177

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Case Report Mutational Analysis of the NF1 Gene in Two Families with Neurofibromatosis 1 Accompanied by Pheochromocytoma.: Hyon Seung Yi, Sei Hyun Kim, Jihoon Kim, Eun Jin Bae, Suntaek Hong, Ie Byung Park, Yu Jin Kim, Sihoon Lee; Endocrinology and Metabolism 2011;26(2):177-184
DOI: https://doi.org/10.3803/EnM.2011.26.2.177
Published online: June 1, 2011

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¹Department of Internal Medicine and Laboratory of Molecular Endocrinology, Gachon University School of Medicine, Incheon, Korea. shleemd@gachon.ac.kr
²Laboratory of Cancer Cell Biology, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Korea.
³Department of Plastic Surgery, Gachon University School of Medicine, Incheon, Korea.

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Abstract

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant inherited disorders affecting the nervous system. NF1 is associated with mutations in the NF1 gene, which is located on chromosome sub-band 17q11.2 and contains 57 exons spanning approximately 300 kb of genomic DNA. NF1 is caused by a loss of function mutation of the NF1 gene, a tumor suppressor gene, which encodes for neurofibromin, a GTPase-activating protein (GAP) involved in the negative regulation of Ras activity. The GAP-related domain, which is encoded for by exons 20-27a, is one of the most important functional domains in neurofibromin. The cysteine-serine-rich domain has been recognized as an important functional domain in NF1-related pheochromocytomas. As the result of many genetic analyses of NF1-related pheochromocytomas, pheochromocytoma has generally been recognized as a true component of NF1. We recently experienced two families with NF1 accompanied by pheochromocytoma. The proband of family 1 is a 31-year-old female diagnosed with NF1 and pheochromocytoma. Gene analysis of the proband and her sister showed that the mutation of the NF1 gene (c.7907+1G>A) led to the skipping of exon 53 during NF1 mRNA splicing. The proband of family 2 is a 48-year-old male who was diagnosed with the same condition. Gene analysis demonstrated the mutation of the NF1 gene (c.5206-8C>G) with missplicing of exon 37. These novel germline mutations did not fall into the GAP-related nor the cysteine-serine-rich domains, but into the C-terminal area of the NF1 gene. This suggests that the correlation between the genotype and phenotype of NF1-related pheochromocytoma is somewhat difficult to characterize. Further studies will be necessary to confirm the function of the C-terminal area of the NF1 gene and its contribution to the development of NF1 and pheochromocytoma.

Keywords: Neurofibromatosis type 1;NF1 gene;Pheochromocytoma;

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Mutation Spectrum of NF1 and Clinical Characteristics in 78 Korean Patients With Neurofibromatosis Type 1
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