Japanese Journal of Clinical Oncology Advance Access originally published online on May 19, 2006
Japanese Journal of Clinical Oncology 2006 36(6):395-397; doi:10.1093/jjco/hyl023
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© 2006 Foundation for Promotion of Cancer Research
Cancer Genetics Report |
Novel 14 Base-Pair Deletion of the MEN1 Gene in a Patient with Recurrent Primary Hyperparathyroidism
1 Department of Aging Medicine and Geriatrics and 2 Department of Preventive Medicine, Shinshu University School of Medicine, Matsumoto, Nagano, 3 Noguchi Thyroid Clinic and Hospital Foundation, Beppu, Oita and 4 Shinonoi General Hospital, Nagano, Japan
For reprints and all correspondence: Akihiro Sakurai, Division of Molecular Genetics, Department of Preventive Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan. E-mail: sakurai{at}sch.md.shinshu-u.ac.jp
Received February 10, 2006; accepted March 23, 2006
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Abstract |
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 TOP Abstract CASE REPORT AND GENETIC...METHODS FOR MUTATION DETECTIONReferences |
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MEN1 is the causative gene for multiple endocrine neoplasia type 1 (MEN1), a hereditary syndrome characterized by hyperplastic and neoplastic disorder of endocrine organs such as parathyroid, anterior pituitary and gastroenteropancreatic endocrine tissues. More than 300 germline mutations have already been reported in patients with MEN1. We here report a novel deletional mutation identified in a Japanese woman with apparently sporadic recurrent hyperparathyroidism. Genetic testing revealed a heterozygous deletion involving 14 bp in exon 6 (starting at amino acid codon 293) of MEN1, which results in early termination of the protein. This deletional mutation has not previously been described elsewhere.
Key Words: multiple endocrine neoplasia type 1 • mutation • parathyroid hyperplasia
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CASE REPORT AND GENETIC ANALYSIS |
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TOPAbstractCASE REPORT AND GENETIC...METHODS FOR MUTATION DETECTIONReferences |
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Multiple endocrine neoplasia type 1 (MEN1) is a hereditary disease characterized by hyperplastic and neoplastic disorder of endocrine organs such as parathyroid, anterior pituitary and gastroenteropancreatic endocrine tissues. Less frequent manifestations include adrenal cortex adenoma, foregut carcinoid tumor and lipoma (1). Facial angiofibroma is also a commonly recognized manifestation, although its prevalence apparently varies among different ethnic groups (2,3). Clinical diagnosis of MEN1 is made when at least two lesions in three principal organs (parathyroid, anterior pituitary and pancreas/duodenum) are confirmed (4). Most subjects with MEN1 harbor a germline MEN1 gene mutation, and somatic mutations of the MEN1 gene have been identified in sporadic endocrine tumors to some extent (1). Germline MEN1 mutation has also been identified in a subset of patients with primary hyperparathyroidism (5,6). The MEN1 gene product, menin, is a 610 amino acid nuclear protein [Alternative splicing at exon 2 of the MEN1 gene produces two isoforms of menin, 610 and 615 amino acids in length, respectively. Numbering of amino acid and nucleotide in this manuscript is based on that for 610 amino acid protein since most literature as well as Human Gene Mutation Database (http://www.hgmd.cf.ac.uk) is doing so.] and its physiological function has been extensively studied. To date, several cellular proteins have been shown to physically and functionally interact with menin, but the exact physiological roles of those interactions remain largely elusive (7).
Standardized indication for MEN1 mutation screening is yet to be established. Genetic testing of MEN1 is considered for patients who meet the clinical criteria of MEN1 to confirm diagnosis and to utilize genetic information for family screening. Genetic testing is also offered to patients who do not meet the clinical criteria but are suspicious of having MEN1. For example, patients with multiple parathyroid tumors and/or recurrent hyperparathyroidism are good candidates for genetic testing (4). Such patients are highly likely to have either MEN1 or familial isolated hyperparathyroidism. In a recent report from an Australian national mutation testing service, detection rate of the MEN1 germline mutation was 84% in kindreds with MEN1 and 22% in kindreds with familial isolated hyperparathyroidism (8). In this article we report a patient with recurrent hyperparathyroidism and the result of mutation analysis of MEN1.
The patient was a 48-year-old woman who was referred to our hospital because of recurrent primary hyperparathyroidism. She had histories of urolithiasis beginning at the age of 18 and right nephrectomy was performed 8 years later. At the age of 33, hypercalcemia was found during health screening but no further evaluation was done. She was diagnosed of having primary hyperparathyroidism 11 years later, when she was 44. The right lower parathyroid gland was surgically removed and serum levels of calcium and parathyroid hormone decreased to within normal range. Other parathyroid glands were grossly normal and preserved. Pathological diagnosis of the resected tissue was parathyroid hyperplasia. Results of biochemical and radiological screening for MEN1 were unremarkable except the suspicious 3 mm low signal area of the anterior pituitary detected by MRI with contrast enhancement. This finding indicated a possible pituitary tumor, but a diagnosis could not be given because of its small size and lack of endocrine function. Four years later, when she was 48, recurrence of hypercalcemia with an increased level of parathyroid hormone was found and radiological examination revealed swelling of the left upper parathyroid gland. Left upper- and lower glands and right upper gland were surgically removed and the part of the left upper gland was transplanted to left forearm. Pathological finding of the resected parathyroid glands was hyperplasia. Screening for MEN1 was essentially negative and no change was seen in radiological finding of the pituitary gland. Pedigree of the patient is shown in Fig. 1. Her father and mother had died of gastric cancer and stroke, respectively. Parents and relatives have had no histories of endocrine disorders. Her younger sister is healthy.
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Although our patient did not fulfill the clinical criteria for diagnosis of MEN1 nor has family history of MEN1, longtime history of hypercalcemia with urolithiasis and pathological findings of parathyroid glands suggested genetic predisposition. Thus we sequenced the entire coding region of the MEN1 of the patient and found a heterozygous 14 base deletion in exon 6 (Fig. 2A). This mutation is expected to result in frame-shift at amino acid codon 293 and premature termination of the protein eight amino acids downstream. To confirm this deletion, size of amplicons was examined by 10% PAGE. As shown in Fig. 2B, 272 and 258 bp fragments, representing wild-type allele and mutant allele, respectively, were detected in the patient, while only 272 bp fragment was detected in normal control. The identification of the MEN1 germline mutation rationalized periodic follow-up of the patient and genetic/biochemical screening for family members.
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Although more than 300 MEN1 germline mutations have already been reported and registered (9), this deletional mutation has not been recorded previously. Genetic features of MEN1 and the patient are summarized in Table 1.
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METHODS FOR MUTATION DETECTION |
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Following primers were used to amplify exons 5 and 6 of the MEN1 gene by PCR. Forward primer, 5'-GTTCCGTGGCTCATAACTCT-3'; reverse primer, 5'-TTCTGCACCCTCCTTAGATG-3'. PCR cycle consisted of initial denaturation for 12 min at 95°C, 45 cycles of denaturation for 45 s at 95°C, annealing for 45 s at 58°C and polymerase reaction for 90 s at 72°C, followed by a final extension for 7 min at 72°C. Amplicons were sequenced in both directions using ABI PRISM 310 Genetic Analyzer (Applied Biosystems, Forster City, CA, USA).
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References |
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1 Gagel RF, Marx SJ. Multiple endocrine neoplasia. In: Larsen PR, Kronenberg HM, Melmed S, Polonsky KS, editors. Textbook of Endocrinology. Philadelphia, PA: WB Saunders 2002;1717–62.
2 Darling TN, Skarulis MC, Steinberg SM, Marx SJ, Spiegel AM, Turner M. Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1. Arch Dermatol 1997;133:853–7.
3 Sakurai A, Matsumoto K, Ikeo Y, Nishio SI, Kakizawa T, Arakura F, et al. Frequency of facial angiofibromas in Japanese patients with multiple endocrine neoplasia type 1. Endocr J 2000;47:569–73.[Medline]
4 Brandi ML, Gagel RF, Angeli A, Bilezikian JP, Beck-Peccoz P, Bordi C, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001;86:5658–71.
5 Uchino S, Noguchi S, Sato M, Yamashita H, Yamashita H, Watanabe S, et al. Screening of the MEN1 gene and discovery of germ-line and somatic mutations in apparently sporadic parathyroid tumors. Cancer Res 2000;60:5553–7.
6 Simonds WF, James-Newton LA, Agarwal SK, Yang B, Skarulis MC, Hendy GN, et al. Familial isolated hyperparathyroidism, clinical and genetic characteristics of 36 kindreds. Medicine (Baltimore) 2002;81:1–26.[CrossRef][Medline]
7 Agarwal SK, Burns AL, Sukhodolets KE, Kennedy PA, Obungu VH, Hickman AB, et al. Molecular pathology of the MEN1 gene. Ann NY Acad Sci 2004;1014:189–98.[CrossRef][Web of Science][Medline]
8 Cardinal JW, Bergman L, Hayward N, Sweet A, Warner J, Marks L, et al. A report of a national mutation testing service for the MEN1 gene: clinical presentations and implications for mutation testing. J Med Genet 2005;42:69–74.
9 The Human Gene Mutation Database. http://www.hgmd.cf.ac.uk/
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