Endocrinol Metab.  2011 Jun;26(2):177-184. 10.3803/EnM.2011.26.2.177.

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

  • 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.


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.


Neurofibromatosis type 1; NF1 gene; Pheochromocytoma

MeSH Terms

Genes, Neurofibromatosis 1
Genes, Tumor Suppressor
Germ-Line Mutation
GTPase-Activating Proteins
Middle Aged
Nervous System
Neurofibromatosis 1
Neurofibromin 1
RNA, Messenger
GTPase-Activating Proteins
Neurofibromin 1
RNA, Messenger


  • Fig. 1 Schematic representation of the NF1 gene structure. The cysteine-serine rich domain spanning exons 11-17 and the GAP related domain region spanning exons 20-27 are highlighted. CSR, cysteine-serine rich domain; GRD, GAP related domain.

  • Fig. 2 Pedigree of Family 1 with mutation c.7907+1G>A. Filled symbols, NF1 patients; number, age; arrow, proband.

  • Fig. 3 A. 4.0 cm well-enhancing mass in the left adrenal gland on CT scan (arrow, left adrenal mass). B, C. Pathologic finding of a pheochromocytoma in family 1 (B, × 40; C, × 200, H&E stain, expectively).

  • Fig. 4 A. About 8 × 4 cm and 12 × 4 cm sized oval shaped brown colored masses were located on medial aspect of right upper arm. B, C. Multiple café-au-lait spots, multiple colored papules and nodules on whole body.

  • Fig. 5 A. 6.0 cm well-enhancing mass in the right adrenal gland on CT scan (arrow, right adrenal mass). B, C. Pathologic finding of a pheochromocytoma in family 2 (B, × 200, H&E stain; C, × 200, chromogranin stain, expectively).

  • Fig. 6 A. Direct sequencing of the NF1 gene in family 1 (arrow, mutation sites). B. Mutation affecting truncated protein. Reading frame was altered due to skipping of exon 53. The frame shift mutation resulted in a premature stop of protein translation causing a truncated protein.

  • Fig. 7 A. Direct sequencing of the NF1 gene in family 2 (arrow, mutation sites). B. Mutation affecting out of frame for splicing of exon 37. This mutation creates out of frame insertion of intronic sequence into the NF1 mRNA.


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