Endocrinol Metab > Volume 26(2); 2011 > Article
Endocrinology and Metabolism 2011;26(2):177-184.
DOI: https://doi.org/10.3803/EnM.2011.26.2.177    Published online June 1, 2011.
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
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.
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.
Key Words: Neurofibromatosis type 1, NF1 gene, Pheochromocytoma


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