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Absence of Germ-Line Mutations of the Multiple Endocrine Neoplasia Type 1 (MEN1) Gene in Familial Pituitary Adenoma in Contrast to MEN1 in Japanese¹

Otsuka Department of Clinical and Molecular Nutrition, The University of Tokushima School of Medicine, 3–18-15, Kuramoto-cho, Tokushima-City, 770; Department of Neurosurgery, Toranomon Hospital (S.Y.), 2–2-2, Toranomon, Minato-ku, Tokyo, 105; and Department of Neurosurgery, Tokyo Medical College (H.N.), 6–7-1, Nishishinjuku, Shinjuku-ku, Tokyo, 160 Japan

Address all correspondence and requests for reprints to: Mitsuo Itakura, M.D., Ph.D., Otsuka Department of Clinical and Molecular Nutrition, The University of Tokushima School of Medicine, 3–18-15, Kuramoto-cho, Tokushima-City, 770, Japan. E-mail: itakura{at}nutr.med.tokushima-u.ac.jp

	Abstract

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Germ-line mutations of the MEN1 gene were analyzed in five cases of familial and four cases of sporadic multiple endocrine neoplasia type 1 (MEN-1), six cases in three independent pedigrees of familial pituitary adenoma without MEN-1, and three cases of familial isolated primary hyperparathyroidism (FIHP) in Japanese. Eight different types of germ-line mutations in all nine cases of MEN-1 were distributed in exons 2, 3, 7, and 10 and intron 7 of the MEN1 gene. Loss of heterozygosity (LOH) on 11q13 was detected in all nine tumors of these cases with microsatellite analysis. No germ-line mutation of the MEN1 gene was detected in three pedigrees of familial pituitary adenoma and three cases of FIHP. LOH on 11q13 was detected in two cases in one pedigree of familial pituitary adenoma, and one of them showed a heterozygous somatic mutation of the MEN1 gene. No LOH on 11q13 was detected in three cases of FIHP. Based on these, we conclude that the loss of function of menin is etiological for familial or sporadic MEN-1, but not for FIHP or most familial pituitary adenoma without MEN-1.

	Introduction

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MULTIPLE endocrine neoplasia type 1 (MEN-1) is a hereditary disorder characterized by multiple endocrine tumors of the parathyroid gland, anterior pituitary gland, and pancreatic endocrine tissue (1). The genetic background of familial pituitary adenoma without MEN-1 and familial isolated primary hyperparathyroidism (FIHP), which are presented as possible subtypes of MEN-1, remains unknown (2, 3, 4, 5, 6, 7). The MEN1 gene on chromosome 11q13 (8, 9) contains 10 exons and encodes a ubiquitously expressed 2.8-kilobase transcript. The predicted 610-amino acid protein product, menin, exhibits no apparent similarities to any previously known proteins. Germ-line mutations of the MEN1 gene were detected at high frequency in both familial and sporadic cases of MEN-1 in Caucasians (9, 10, 11). We had 1 reported (3) and 2 additional pedigrees of familial pituitary adenoma, with 6 cases in total, which comprise a significant number compared to 19 pedigrees with 43 cases in the literature (3). We analyzed germ-line mutations of the MEN1 gene and loss of heterozygosity (LOH) on 11q13 in endocrine tumors in 5 cases of familial MEN-1 in 4 pedigrees, 4 cases of sporadic MEN-1, 6 cases of familial pituitary adenoma without MEN-1 in 3 pedigrees, and 3 cases of FIHP in 1 pedigree in Japanese. In tumors showing LOH on 11q13, somatic mutations of the MEN1 gene were further examined.

	Materials and Methods

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Case presentation of familial pituitary adenoma

Clinical findings and LOH on 11q13 in GH-producing pituitary tumors in one pedigree of familial pituitary adenoma in the absence of MEN-1 with two affected brothers (cases 10 and 11 in this report) were previously reported (3). The 69-yr-old mother (case 12) in the second pedigree presented with acromegaly and diabetes. Endocrine studies showed increased basal serum levels of GH (37 ng/ml; normal range, <5 ng/ml), insulin-like growth factor I (640 ng/ml; female normal range, 24–153 ng/ml), and PRL (29 ng/ml; female normal range, <20 ng/ml). The serum GH level was increased by TRH administration, but not by GnRH administration. Other anterior pituitary hormones were low normal. An acidophilic adenoma was removed by transsphenoidal surgery. The 37-yr-old daughter (case 13) in the second pedigree had transsphenoidal surgery for prolactinoma at the age of 25 yr. Both of the affected brothers (cases 14 and 15) in the third pedigree had GH-producing pituitary adenomas. The 61-yr-old elder brother presented with acromegaly and diabetes. The basal serum GH level was 15.7 ng/ml and was increased by TRH administration. Other anterior pituitary hormone levels were normal. An acidophilic adenoma was removed by the transsphenoidal surgery. The 53-yr-old younger brother also presented with acromegaly. The basal serum GH level was 9.6 ng/ml and was increased by TRH administration. An adenoma was removed by transsphenoidal surgery. Serum hormone levels in all of these cases (cases 10–15) did not indicate the presence of MEN-1. All patients were studied with their informed consents.

Diagnostic criteria

The following diagnostic criteria were used. Familial MEN-1 should have at least two MEN-1 patients in a family. Sporadic MEN-1 should not have MEN-1 patients diagnosed by endocrine or radiographic evaluations in a family. Familial pituitary adenoma should have multiple patients with pituitary adenoma without associating other endocrine tumors in a family. FIHP was diagnosed for three cases (cases 16–18), with hyperparathyroidism in 1 pedigree, as previously reported (12).

Tissue and blood samples, and extraction of DNA from tissues

Tissue samples were obtained at surgical operation or from paraffin-embedded sections. Peripheral blood samples were collected at surgical operation or retrospectively from these patients. Tissue and blood samples were obtained from five cases of familial MEN-1, four cases of sporadic MEN-1, six cases of familial pituitary adenoma, and three cases of FIHP. DNA was isolated as previously described (13). Clinical data on cases 1 (14), 2 and 3 (15), 8 (16), and 16–18 (12) in Tables 2 and 3 were previously reported.

Primers for PCR amplification were listed in Table 1. The coding sequence, including 9 coding exons and 16 splice junctions of the MEN1 gene (9), was first screened with PCR-SSCP (13). Three conditions of 8% polyacrylamide gels, containing 0%, 5%, or 10% glycerol, were routinely used for PCR-SSCP screening for each PCR product.

Assessment of allelic ratios

Allelic ratios in tumor DNA relative to leukocyte DNA were assessed with the previously reported method (13) in regard to five microsatellite markers on 11q13; D11S1883 (17),D11S457 (18), PYGM (19), D11S449 (18), and D11S1889 (17). The allelic ratio of the PYGM locus was examined with two sets of primers. One common 5'-primer was at nucleotides 176–195 (ctagcagagtccacctactg) in GenBank accession no. M77201. Two 3'-primers included nucleotides 277–297 (cacagagagagagagagagag), which amplified PYGM1 including 5'-CA repeats varying from 120–130 bp, and nucleotides 332–351 (gtcagttgctacctgacagc), which amplified PYGM2 including 5'-CA and 3'-GA repeats varying from 156–190 bp (19).

RT-PCR procedure

Total ribonucleic acid (RNA) from tissue was prepared with ISOGEN (Nippon Gene, Tokyo, Japan) and treated with DNase at 37 C for 1 h. Complementary DNA was synthesized from 2 µg total RNA with random hexamers and Moloney murine leukemia virus reverse transcriptase (Promega, Madison, WI) at 37 C for 1 h. The complementary DNA was then amplified by PCR in 35 cycles with the primer pair listed in Table 1 with the initial denaturation at 95 C for 10 min, denaturation at 94 C for 1 min, annealing at 62 C for 1 min, and extension at 72 C for 1 min, followed by electrophoresis on an 8% polyacrylamide gel.

	Results

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Mutations of the MEN1 gene were screened for 12 overlapping PCR products with the corresponding primer sets covering the entire coding region and splice junctions (Table 1). PCR-SSCP analysis of leukocyte or normal tissue DNA from 5 familial and 4 sporadic cases of MEN-1 detected aberrantly shifted bands in 6 cases, including 5 cases of familial (cases 1–5) and 1 case of sporadic (case 9) MEN-1 of 9 cases of MEN-1 (Fig. 1). PCR-SSCP of DNA from tumor tissues and leukocytes of these 6 cases exhibited the identical SSCP patterns, showing that aberrantly shifted bands are common to tumor and leukocyte DNA (data not shown). DNA sequences of the MEN1 gene in 3 cases of sporadic MEN-1 (cases 6–8) in which mutated bands were not separable with PCR-SSCP analysis were determined with sequencing, and mutations were similarly detected in these 3 cases.

View larger version (53K): [in this window] [in a new window]   Figure 1. PCR-SSCP analysis of the MEN1 gene in familial and sporadic MEN-1. Lane numbers are the same as case numbers in Table 2. A, Germ-line mutations detected with PCR-SSCP. a, SSCP patterns of exon 2B in six representative samples. Aberrantly shifted bands were observed in cases 1 and 9. b, SSCP patterns of exon 2C in three representative samples. An aberrantly shifted band was observed in case 4. c, SSCP patterns of exon 7 in four representative samples. An aberrantly shifted band was observed in case 5. d, SSCP patterns of exon 8 in five representative samples. Aberrantly shifted bands were observed in cases 2 and 3. B, SSCP patterns of polymorphic changes at codon 418 of GAC or GAT. The aberrantly shifted bands represent GAC (upper band), GAT (middle band), and GAC and GAT (lower band), respectively. Lane C, Control DNA as a template. Lane N, Template free.

We detected abnormal splicing in RNA extracted from a parathyroid tumor of case 2 with RT-PCR analysis. An 805-bp RT-PCR fragment (Fig. 2, lane 3) amplified with a pair of primers located in exons 7 and 9 (Table 1) was longer than the 344-bp wild-type fragment (Fig. 2, lane 5) in contrast with the 1242-bp PCR product from genomic DNA (Fig. 2, lane 2). Sequencing of the 805-bp fragment proved that intron 7 (461 bp) was not spliced out due to the loss of the splicing acceptor AG sequence, and the inclusion of intron 7 produced a stop codon at the created codon 351.

View larger version (112K): [in this window] [in a new window]   Figure 2. RT-PCR detection of transcripts of the MEN1 gene. Total RNA was reverse transcribed, and PCR products were amplified with primers located in exons 7 and 9 were electrophoresed on a polyacrylamide gel and stained with ethidium bromide. M, øX174 HaeIII-digested DNA fragments used as molecular markers; lane 1, template free; lane 2, genome DNA from case 2 as a template; lane 3, RT treatment of RNA from a parathyroid tumor of case 2 as a template; lane 4, no RT treatment of RNA from a parathyroid tumor of case number 2 as a template; lane 5, RT treatment of RNA from a normal tissue as a template; lane 6, no RT treatment of RNA from a normal tissue as a template.

We detected one synonymous polymorphism at codon 418 of GAC or GAT (Fig. 1B), with the former in 66% (12 of 18), and another polymorphism at codon 541 of GCA or ACA encoding alanine or threonine, respectively, with the former in 39% (7 of 18), in Japanese.

To determine whether the allelic loss is present on 11q13 in tumor tissues, we assessed the allelic ratios for five microsatellite markers using DNA samples of tumor tissues and leukocytes in five cases in four pedigrees of familial MEN-1, four cases of sporadic MEN-1, three cases in two pedigrees of familial pituitary adenoma, and three cases in one pedigree of FIHP with PCR-based microsatellite analysis (Fig. 3). As summarized in Table 4, LOH on 11q13 was detected in all five tumors of familial MEN-1, all four tumors of sporadic MEN-1, and two adenomas from two cases in one pedigree of familial pituitary adenoma, but not in one pituitary adenoma of familial pituitary adenoma or all three parathyroid adenomas of FIHP. Tumor DNA of three cases, including cases 13–15, were not available for microsatellite analysis.

View larger version (21K): [in this window] [in a new window]   Figure 3. Representative examples of microsatellite patterns of D11S1883, D11S457, PYGM, D11S449, and D11S1889 in familial or sporadic MEN-1 patients. Results for cases 1 and 6 are shown in A and B, respectively. DNAs from leukocytes (WBC) and tumor tissue (tumor) were analyzed in each case. Arrowheads denote smaller allele product peaks in tumor DNA compared to leukocyte DNA. R, Retention of both alleles; ni, noninformative.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

We did not find obvious correlation between the type of MEN1 gene mutations and the phenotypes of MEN-1 (Table 2). The incidence of polymorphism at codon 541 of GCA or ACA encoding alanine or threonine, with the former in 39% (7 of 18), in Japanese in our study is higher than the reported incidence of 4% (6 of 142) in Caucasians (10), representing the racial difference.

Germ-line mutations in the RET protooncogene were detected in cases of familial medullary thyroid carcinomas as well as those of MEN-2A (20), suggesting that familial medullary thyroid carcinoma is genotypically similar to MEN-2A. Although familial pituitary adenoma without MEN-1 and FIHP could be variants of MEN-1, Benlian et al. recently reported that their cases with familial acromegaly were not linked to the MEN1 gene locus by segregation analysis (2). Three pedigrees with 6 cases of familial pituitary adenoma in our study, including 1 previously reported pedigree (cases 10 and 11) (3), against the total number of only 19 reported pedigrees afforded us an important opportunity to screen germ-line mutations of the MEN1 gene. Germ-line mutation in the MEN1 gene was not found in 3 pedigrees of familial pituitary adenoma unrelated to MEN-1. LOH on 11q13 was, however, detected in 2 familial pituitary adenomas in 2 cases (cases 10 and 11). We further examined somatic mutations of the MEN1 gene in their 2 pituitary adenomas and detected a somatic mutation in 1 pituitary tumor of case 11. Although methylation-dependent inactivation or mutations in the promoter, introns, or untranslated regions of the MEN1 gene were not excluded in our study, our results suggest that germ-line mutations in the coding regions of the MEN1 gene do not contribute to the pituitary tumorigenesis in familial pituitary adenoma without MEN-1. A somatic mutation of the MEN1 gene with LOH on 11q13 was, however, suggested to contribute to the pituitary tumorigenesis in a subgroup of familial pituitary adenoma without MEN-1. The predominance of GH-producing pituitary tumors in 5 of 6 cases of familial pituitary adenoma vs. that of prolactinoma in 3 of 5 cases of familial or sporadic MEN-1 in our study may suggest that another unidentified tumor-suppressor gene on 11q13 is etiological for familial pituitary adenoma.

Germ-line mutations of the MEN1 gene in its coding sequence were not detected in three cases of usually autosomal dominant FIHP (4, 6, 7). Hyperparathyroidism-jaw tumor syndrome is a related, but genetically distinct, state from MEN-1, and it was mapped to 1q21-q31 by Szabò et al. (5). Either linkage or exclusion of linkage of FIHP to 11q13 was reported (6, 7). We previously reported the absence of LOH on 11q13 in three parathyroid tumors (cases 16–18) in a pedigree of FIHP (12) and did not find MEN1 germ-line mutations in these patients in this study. In addition, no MEN1 germ-line mutations were reported in five probands of familial hyperparathyroidism (10). These suggest that the germ-line mutation of the MEN1 gene is not etiological for FIHP.

The copresence of germ-line mutations of the MEN1 gene and LOH on 11q13 in endocrine tumors in all five familial and four sporadic cases of MEN-1 confirmed that the loss of function of menin is etiological for familial and sporadic MEN-1 (9, 10, 11). The absence of germ-line mutations of the MEN1 gene in its coding sequence or LOH on 11q13 in three cases of FIHP also confirmed that the germ-line mutation of the MEN1 gene is not etiological for this disorder (10). The copresence of LOH on 11q13 and a somatic mutation of the MEN1 gene in one of six cases in three separate pedigrees of familial pituitary adenoma, with another case in the same pedigree associated only with LOH on 11q13, proved that the loss of function of menin plays a role in pituitary tumorigenesis in a subset of familial pituitary adenoma unrelated to MEN-1. In the presence of LOH on 11q13, it is possible that the remaining single MEN1 gene can contribute to somatic mutation even if the familial susceptibility for somatic mutation is transmitted by a different gene on another chromosome. Based on these findings, it is concluded that the germ-line mutation of the coding sequence of the MEN1 gene is not etiological for familial pituitary adenoma without MEN-1.

	Acknowledgments

 
We thank Drs. Akira Yoshida, Yoshihide Fujimoto, Hiroshi Sarui, Hiroko Yasuda, Yuichi Fujinaka, Teruhiko Hattori, and Masaru Tsuyuguchi for providing tumors. We thank Professor Emeritus of Shiro Saito, the president of the University of Tokushima, for his continuous support.

	Footnotes

 
¹ This work was supported in part by a grant from Otsuka Pharmaceutical Factory Inc., for Otsuka Department of Clinical and Molecular Nutrition, The University of Tokushima School of Medicine.

Received September 4, 1997.

Revised November 7, 1997.

Accepted November 14, 1997.

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