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 1
)
and a kindred of 19 individuals with 3 cases of isolated Familial
Pituitary Adenoma (Fig. 1
)using genomic PCR and direct sequencing as previously described
(4).
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 1
). 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.
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