Georgitsi Marianthi, Raitila Anniina, Karhu Auli, van der Luijt Rob B, Aalfs Cora M, Sane Timo, Vierimaa Outi, Mäkinen Markus J, Tuppurainen Karoliina, Paschke Ralph, Gimm Oliver, Koch Christian A, Gündogdu Sadi, Lucassen Anneke, Tischkowitz Marc, Izatt Louise, Aylwin Simon, Bano Gul, Hodgson Shirley, De Menis Ernesto, Launonen Virpi, Vahteristo Pia, Aaltonen Lauri A
Department of Medical Genetics, University of Helsinki, Finland.
J Clin Endocrinol Metab. 2007 Aug;92(8):3321-5. doi: 10.1210/jc.2006-2843. Epub 2007 May 22.
Germline mutations in the MEN1 gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome, but in up to 20-25% of clinical MEN1 cases, no MEN1 mutations can be found. Recently, a germline mutation in the CDKN1B gene, encoding p27(Kip1), was reported in one suspected MEN1 family with two acromegalic patients.
Our objective was to evaluate the role of CDKN1B/p27(Kip1) in human tumor predisposition in patients clinically suspected of MEN1 but testing negative for MEN1 germline mutation as well as in familial and sporadic acromegaly/pituitary adenoma patients.
Genomic DNA was analyzed for germline mutations in the CDKN1B/p27(Kip1) gene by PCR amplification and direct sequencing.
The study was conducted at nonprofit academic research and medical centers.
Thirty-six Dutch and one German suspected MEN1 patient, who previously tested negative for germline MEN1 gene mutations, were analyzed. In addition, 19 familial and 50 sporadic acromegaly/pituitary adenoma patients from Europe and the United States were included in the study.
We analyzed germline CDKN1B/p27(Kip1) mutations in individuals with pituitary adenoma and MEN1-like features.
A heterozygous 19-bp duplication (c.59_77dup19) leading to a truncated protein product was identified in one Dutch patient with suspected MEN1 phenotype, pituitary adenoma, carcinoid tumor, and hyperparathyroidism (one of 36, 2.8%). No mutations were detected in either familial or sporadic acromegaly/pituitary adenoma patients.
Our results support the previous finding that germline CDKN1B/p27(Kip1) mutations predispose to a human MEN1-like condition. However, such mutations appear uncommon in suspected MEN1 cases and rare or nonexistent in familial or sporadic acromegaly/pituitary adenoma patients.
MEN1基因的种系突变易患多发性内分泌腺瘤1型（MEN1）综合征，但在高达20%-25%的临床MEN1病例中，未发现MEN1突变。最近，在一个有两名肢端肥大症患者的疑似MEN1家族中，报道了编码p27（Kip1）的CDKN1B基因的种系突变。
我们的目的是评估CDKN1B/p27（Kip）在临床疑似MEN1但MEN1种系突变检测为阴性的患者以及家族性和散发性肢端肥大症/垂体腺瘤患者的人类肿瘤易感性中的作用。
通过PCR扩增和直接测序分析基因组DNA中CDKN1B/p27（Kip1）基因的种系突变。
该研究在非营利性学术研究和医疗中心进行。
分析了36名荷兰人和1名德国疑似MEN1患者，这些患者先前MEN1种系基因突变检测为阴性。此外，来自欧洲和美国的19名家族性和50名散发性肢端肥大症/垂体腺瘤患者也纳入了该研究。
我们分析了患有垂体腺瘤和MEN1样特征个体的种系CDKN1B/p27（Kip1）突变。
在一名患有疑似MEN1表型、垂体腺瘤、类癌肿瘤和甲状旁腺功能亢进的荷兰患者中，鉴定出一个导致截短蛋白产物的杂合19bp重复（c.59_77dup19）（36例中的例，2.8%）。在家族性或散发性肢端肥大症/垂体腺瘤患者中均未检测到突变。
我们的结果支持先前的发现，即种系CDKN1B/p27（Kip1）突变易患人类MEN1样疾病。然而，这种突变在疑似MEN1病例中似乎不常见，在家族性或散发性肢端肥大症/垂体腺瘤患者中罕见或不存在。
