Menin Mutations In MEN1 Patients

Bernhard Mayr, Georg Brabant and Alexander von zur Mühlen

Medizinische Hochschule Hannover 30623 Hannover, Germany

Germ-line mutations in the menin gene cause multiple endocrine neoplasia (MEN1) type 1 (1), but in some kindreds no mutations have yet been identified (2). Tanaka et al. (3) reported menin mutations in nine patients with MEN-1 but none in three kindreds with familial pituitary adenoma.

We examined 26 patients from 9 kindreds with MEN1 (Table 1Go) and a kindred of 19 individuals with 3 cases of isolated Familial Pituitary Adenoma (Fig. 1Go)using genomic PCR and direct sequencing as previously described (4).


View this table:
[in this window]
[in a new window]
 
Table 1. Patients from MEN1 families

 


View larger version (12K):
[in this window]
[in a new window]
 
Figure 1. Familial pituitary adenoma kindred (), hormone-inactive pituitary adenoma; , acromegaly).

 
In patients with MEN1, we identified 6 previously described point mutations, deletions and insertions (2, 4), a novel missense mutation [G1378C (W423S)] in exon 9, and a novel G -> T transversion at the very 3' end of the splice acceptor site of intron 3. In a patient with prolactinoma, parathyroid adenoma, and without affected family members, no mutation could be found in the entire coding sequence of the menin gene (Table 1Go). We also tried to identify menin mutations in a patient and her aunt, who both presented with hormone-inactive pituitary adenoma, but no other manifestation of MEN1. The father of the index patient had a negative magnetic resonance imaging study of the pituitary, and her uncle had died of growth hormone-producing pituitary macro-adenoma 5 yr previously and was unavailable for analysis. Throughout the coding region of the menin gene and adjacent intron flanks no mutation could be found in either patient.

Since the cloning of the menin gene, the clinical diagnosis of MEN1 can be confirmed by menin studies. However, there are no identifiable mutations in the menin coding sequence in approximately 5% of clinically proven MEN1 kindreds, and the rates are seemingly higher in sporadic MEN1 cases (2). It is not clear whether these cases are caused by yet unidentified menin alterations or rather represent a different disease entity. The latter seems to be the case for isolated familial pituitary adenoma, as we could confirm the negative menin results of Tanaka et al. and showed, in addition, that the mode of transmission seemed to be different from the autosomal dominant trait with high penetrance (5) of MEN1.

However, in typical MEN1 with negative studies of the menin coding region, it should be considered that, up to now, three intronic menin

mutations have been found (3, 5 and this study). To account for intronic mutations, intronic exon flanks should be included in the analysis. Studies on genomic DNA could be supplemented by messenger RNA analysis, using the common polymorphisms in the menin coding sequence (1, 2, 5) to ensure the expression of two copies of wild-type menin mRNA.

Footnotes

Received April 22, 1998. Address correspondence to: Bernhard Mayr, M.D., Department of Clinical Endocrinology, Medizinische Hochschule Hannover, 30623 Hannover, Germany.

References

  1. Chandrasekharappa SC, Guru SC, Manickam P, et al. 1997 Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 276:404–407.[Abstract/Free Full Text]
  2. Agarwal SK, Kester MB, Debelenko LV, et al. 1997 Germline mutations of the MEN1 gene in familial multiple endocrine neoplasia type 1 and related states. Hum Mol Genet. 6:1169–1175.[Abstract/Free Full Text]
  3. Tanaka C, Yoshimoto K, Yamada S, et al. 1998 Absence of germ-line mutations of the multiple endocrine neoplasia type 1 (MEN1) gene in familial pituitary adenoma in contrast to MEN1 in Japanese. J Clin Endocrinol Metab. 83:960–965.[Abstract/Free Full Text]
  4. Mayr B, Apenberg S, Rothàmel T, von zur Mühlen A, Brabant G. 1997 Menin mutations in patients with multiple endocrine neoplasia type 1. Eur J Endocrinol. 137:684–687.[Medline]
  5. Bassett JH, Forbes SA, Pannett AA, et al. 1998 Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am J Hum Genet. 62:232–244.[CrossRef][Medline]