scholarly journals Modification of multiple endocrine neoplasia 2A phenotype by cell membrane proximity of RET mutations in exon 10

2009 ◽  
Vol 16 (1) ◽  
pp. 171-177 ◽  
Author(s):  
Andreas Machens ◽  
Steffen Hauptmann ◽  
Henning Dralle
Keyword(s):  
Lymph Node ◽  
Lymph Node Metastasis ◽  
Multiple Endocrine Neoplasia ◽  
Germ Line ◽  
Node Metastasis ◽  
Endocrine Neoplasia ◽  
Germ Line Mutations ◽  
Multiple Endocrine Neoplasia 2A ◽  
Exon 11 ◽  
Exon 10

Rearranged during transfection (RET) germ-line mutations in exon 10 are peculiar because they produce both gain-of-function multiple endocrine neoplasia 2A and loss-of-function Hirschsprung's disease phenotypes. Drawing on 38 medullary thyroid cancer patients harboring germ-line mutations in codon 620 (n=8), 618 (n=19), 611 (n=10), and 609 (n=1), this study aimed to test the hypothesis that closer proximity of RET germ-line mutations in exon 10 to the cell membrane may translate into earlier or more advanced disease. The closer mutations in codon 620, 618, and 611 were located to the transmembrane domain (codons 657–636) of the RET receptor, the greater were mean primary tumor diameters (23.5, 18.7, and 7.5 mm, P=0.020), the frequency of lymph node metastasis (75, 68, and 30%, P=0.11) and pheochromocytoma (38, 16, and 0%, P=0.11). Periods of observation were broadly comparable for these groups (mean age 33.4–39.3 years; P=0.71). When mutations in adjoining codons were collapsed (codons 620/618 vs 611/609), the differences in mean primary tumor diameter (20.1 vs 7.4 mm, P=0.005) and lymph node metastasis (70 vs 36%; P=0.07) were accentuated. Compared with 80 carriers of exon 11 mutations (codon 634, n=78; codon 630, n=2), the 38 carriers of exon 10 mutations, which are rarer and confer a weaker transforming activity in vitro than exon 11 mutations, required significantly more time to develop fewer tumors. Although limited in numbers, these data suggested that membrane proximity is an important determinant of tumor development in carriers of RET mutations in exon 10.

scholarly journals Multiple endocrine neoplasia type 1 (MEN1) gene mutations in a subset of patients with sporadic and familial primary hyperparathyroidism target the coding sequence but spare the promoter region

2000 ◽  
Vol 166 (1) ◽  
pp. 1-9 ◽  
Author(s):  
W Karges ◽  
K Jostarndt ◽  
S Maier ◽  
A Flemming ◽  
M Weitz ◽  
...  
Keyword(s):  
Multiple Endocrine Neoplasia ◽  
Multiple Endocrine Neoplasia Type ◽  
Germ Line ◽  
Single Strand Conformational Polymorphism ◽  
Coding Sequence ◽  
Men1 Gene ◽  
Endocrine Neoplasia ◽  
Endocrine Neoplasia Type ◽  
Germ Line Mutations

Germ line mutations of the multiple endocrine neoplasia type 1 (MEN1) tumour suppressor gene cause MEN1, a rare familial tumour syndrome associated with parathyroid hyperplasia, adenoma and hyperparathyroidism (HP). Here we investigated the role of the MEN1 gene in isolated sporadic and familial HP. Using RT-PCR single-strand conformational polymorphism screening, somatic (but not germ line) mutations of the MEN1 coding sequence were identified in 6 of 31 (19.3%) adenomas from patients with sporadic primary HP, but none in patients (n=16) with secondary HP due to chronic renal failure. MEN1 mutations were accompanied by a loss of heterozygosity (LOH) for the MEN1 locus on chromosome 11q13 in the adenomas as detected by microsatellite analysis. No DNA sequence divergence within the 5' region of the MEN1 gene, containing the putative MEN1 promoter, was detectable in HP adenomas. Clinical characteristics were not different in HP patients with or without MEN1 mutation. Heterozygous MEN1 gene polymorphisms were identified in 9.6% and 25% of patients with primary and secondary HP respectively. In a large kindred with familial isolated familial HP, MEN1 germ line mutation 249 del4 and LOH was associated with the HP phenotype and a predisposition to non-endocrine malignancies. We suggest that the bi-allelic somatic loss of MEN1 wild-type gene expression is involved in the pathogenesis of a clinically yet undefined subset of sporadic primary HP adenomas. MEN1 genotyping may further help define the familial hyperparathyroidism-MEN1 disease complex, but it seems dispensable in sporadic primary HP.

Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A

Nature ◽  
1993 ◽  
Vol 363 (6428) ◽  
pp. 458-460 ◽  
Author(s):  
Lois M. Mulligan ◽  
John B. J. Kwok ◽  
Catherine S. Healey ◽  
Mark J. Elsdon ◽  
Charis Eng ◽  
...  
Keyword(s):  
Multiple Endocrine Neoplasia ◽  
Multiple Endocrine Neoplasia Type ◽  
Germ Line ◽  
Endocrine Neoplasia ◽  
Endocrine Neoplasia Type ◽  
Germ Line Mutations

scholarly journals Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans

2006 ◽  
Vol 103 (42) ◽  
pp. 15558-15563 ◽  
Author(s):  
N. S. Pellegata ◽  
L. Quintanilla-Martinez ◽  
H. Siggelkow ◽  
E. Samson ◽  
K. Bink ◽  
...  
Keyword(s):  
Multiple Endocrine Neoplasia ◽  
Germ Line ◽  
Endocrine Neoplasia ◽  
Germ Line Mutations ◽  
Multiple Endocrine Neoplasia Syndrome

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

1998 ◽  
Vol 83 (3) ◽  
pp. 960-965
Author(s):  
Chisato Tanaka ◽  
Katsuhiko Yoshimoto ◽  
Shozo Yamada ◽  
Hiroshi Nishioka ◽  
Setsuko Ii ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Multiple Endocrine Neoplasia ◽  
Multiple Endocrine Neoplasia Type ◽  
Germ Line ◽  
Men1 Gene ◽  
Men 1 ◽  
Endocrine Neoplasia ◽  
Endocrine Neoplasia Type ◽  
Germ Line Mutations

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.

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