Mg. Mutch et al., Germline mutations in the multiple endocrine neoplasia type 1 gene: Evidence for frequent splicing defects, HUM MUTAT, 13(3), 1999, pp. 175-185
Multiple endocrine neoplasia type 1 (MEN 1) is a familial cancer syndrome c
haracterized by parathyroid hyperplasia, pituitary adenomas, and neuroendoc
rine tumors of the pancreas and duodenum. In 1997, the MEN 1 tumor suppress
or gene was identified, and numerous germline mutations have been reported
to be distributed throughout the gene. We used single strand con formationa
l variant (SSCV) analysis to search for germline mutations in the members o
f 33 kindreds with a confirmed diagnosis of MEN 1. SSCV analysis revealed 2
5 conformational Variants representing germline mutations that are predicte
d to result in loss of normal menin function. Twenty different disease-asso
ciated mutations were identified: five resulting in potential abnormal RNA
spicing, two missense mutations, seven nonsense mutations, and six frameshi
ft mutations. The aberrant splice products were identified and confirmed by
RT-PCR and direct sequence analysis for two of the five splice mutations.
Sixteen of the 20 (80%) mutations identified have not been previously repor
ted. Mutations were not identified in eight kindreds with signs and symptom
s consistent with MEN 1, The SSCV analysis revealed mutations in 76% (25 of
33) of the kindreds investigated, thus showing SSCV analysis to be a relia
ble mutation detection strategy. One-fifth of the mutations identified in t
his study involve intron sequences, therefore, highlighting the importance
of including intron sequences in the search for germline mutations in the M
EN 1 gene. The need to investigate the entire gene when characterizing new
MEN 1 families presents challenges in the translation of genetic studies to
efficient clinical diagnostic tests. Hum Mutat 13:175-185, 1999. (C) 1999
Wiley-Liss, Inc.