GCM2-Activating Mutations in Familial Isolated Hyperparathyroidism

被引:104
作者
Guan, Bin [1 ]
Welch, James M. [1 ]
Sapp, Julie C. [2 ]
Ling, Hua [3 ]
Li, Yulong [1 ]
Johnston, Jennifer J. [2 ]
Kebebew, Electron [4 ]
Biesecker, Leslie G. [2 ]
Simonds, William F. [1 ]
Marx, Stephen J. [1 ,5 ]
Agarwal, Sunita K. [1 ]
机构
[1] Natl Inst Diabet & Digest & Kidney Dis, Bethesda, MD 20892 USA
[2] NHGRI, Bethesda, MD 20892 USA
[3] Johns Hopkins Univ, Ctr Inherited Dis Res, Baltimore, MD 21224 USA
[4] NCI, Bethesda, MD 20892 USA
[5] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA
关键词
ASYMPTOMATIC PRIMARY HYPERPARATHYROIDISM; AUTOSOMAL-DOMINANT HYPOPARATHYROIDISM; PARATHYROID-GLAND DEVELOPMENT; CELLS-MISSING-HOMOLOG; TRANSCRIPTION FACTOR; GCMB MUTATION; GENE; HORMONE; EXPRESSION; MANAGEMENT;
D O I
10.1016/j.ajhg.2016.08.018
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Primary hyperparathyroidism (PHPT) is a common endocrine disease characterized by parathyroid hormone excess and hypercalcemia and caused by hypersecreting parathyroid glands. Familial PHPT occurs in an isolated nonsyndromal form, termed familial isolated hyperparathyroidism (FIHP), or as part of a syndrome, such as multiple endocrine neoplasia type 1 or hyperparathyroidism-jaw tumor syndrome. The specific genetic or other cause(s) of FIHP are unknown. We performed exome sequencing on germline DNA of eight index-case individuals from eight unrelated kindreds with FIHP. Selected rare variants were assessed for co-segregation in affected family members and screened for in an additional 32 kindreds with FIHP. In eight kindreds with FIHP, we identified three rare missense variants in GCM2, a gene encoding a transcription factor required for parathyroid development. Functional characterization of the GCM2 variants and deletion analyses revealed a small C-terminal conserved inhibitory domain (CCID) in GCM2. Two of the three rare variants were recurrent, located in the GCM2 CCID, and found in seven of the 40 (18%) kindreds with FIHP. These two rare variants acted as gain-of-function mutations that increased the transcriptional activity of GCM2, suggesting that GCM2 is a parathyroid proto-oncogene. Our results demonstrate that germline-activating mutations affecting the CCID of GCM2 can cause FIHP.
引用
收藏
页码:1034 / 1044
页数:11
相关论文
共 42 条
[31]   A Missense Glial Cells Missing Homolog B (GCMB) Mutation, Asn502His, Causes Autosomal Dominant Hypoparathyroidism [J].
Mirczuk, Samantha M. ;
Bowl, Michael R. ;
Nesbit, M. Andrew ;
Cranston, Treena ;
Fratter, Carl ;
Allgrove, Jeremy ;
Brain, Caroline ;
Thakker, Rajesh V. .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2010, 95 (07) :3512-3516
[32]   The Genetic Landscape of the Childhood Cancer Medulloblastoma [J].
Parsons, D. Williams ;
Li, Meng ;
Zhang, Xiaosong ;
Jones, Sian ;
Leary, Rebecca J. ;
Lin, Jimmy Cheng-Ho ;
Boca, Simina M. ;
Carter, Hannah ;
Samayoa, Josue ;
Bettegowda, Chetan ;
Gallia, Gary L. ;
Jallo, George I. ;
Binder, Zev A. ;
Nikolsky, Yuri ;
Hartigan, James ;
Smith, Doug R. ;
Gerhard, Daniela S. ;
Fults, Daniel W. ;
VandenBerg, Scott ;
Berger, Mitchel S. ;
Marie, Suely Kazue Nagahashi ;
Shinjo, Sueli Mieko Oba ;
Clara, Carlos ;
Phillips, Peter C. ;
Minturn, Jane E. ;
Biegel, Jaclyn A. ;
Judkins, Alexander R. ;
Resnick, Adam C. ;
Storm, Phillip B. ;
Curran, Tom ;
He, Yiping ;
Rasheed, B. Ahmed ;
Friedman, Henry S. ;
Keir, Stephen T. ;
McLendon, Roger ;
Northcott, Paul A. ;
Taylor, Michael D. ;
Burger, Peter C. ;
Riggins, Gregory J. ;
Karchin, Rachel ;
Parmigiani, Giovanni ;
Bigner, Darell D. ;
Yan, Hai ;
Papadopoulos, Nick ;
Vogelstein, Bert ;
Kinzler, Kenneth W. ;
Velculescu, Victor E. .
SCIENCE, 2011, 331 (6016) :435-439
[33]   The regulator of early gliogenesis glial cells missing is a transcription factor with a novel type of DNA-binding domain [J].
Schreiber, J ;
Sock, E ;
Wegner, M .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (09) :4739-4744
[34]   The diagnosis and management of asymptomatic primary hyperparathyroidism [J].
Silverberg, Shonni J. ;
Bilezikian, John P. .
NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM, 2006, 2 (09) :494-503
[35]   Familial isolated hyperparathyroidism is rarely caused by germline mutation in HRPT2, the gene for the hyperparathyroidism-jaw tumor syndrome [J].
Simonds, WF ;
Robbins, CM ;
Agarwal, SK ;
Hendy, GN ;
Carpten, JD ;
Marx, SJ .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2004, 89 (01) :96-102
[36]   Familial isolated hyperparathyroidism - Clinical and genetic characteristics of 36 kindreds [J].
Simonds, WF ;
James-Newton, LA ;
Agarwal, SK ;
Yang, B ;
Skarulis, MC ;
Hendy, GN ;
Marx, SJ .
MEDICINE, 2002, 81 (01) :1-26
[37]   Frequent Germ-Line Mutations of the MEN1, CASR, and HRPT2/CDC73 Genes in Young Patients with Clinically Non-familial Primary Hyperparathyroidism [J].
Starker, Lee F. ;
Akerstrom, Tobias ;
Long, William D. ;
Delgado-Verdugo, Alberto ;
Donovan, Patricia ;
Udelsman, Robert ;
Lifton, Richard P. ;
Carling, Tobias .
HORMONES & CANCER, 2012, 3 (1-2) :44-51
[38]   GCMB mutation in familial isolated hypoparathyroidism with residual secretion of parathyroid hormone [J].
Thomée, C ;
Schubert, SW ;
Parma, J ;
Lê, PQ ;
Hashemolhosseini, S ;
Wegner, M ;
Abramowicz, MJ .
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2005, 90 (05) :2487-2492
[39]   Protein stability and domain topology determine the transcriptional activity of the mammalian glial cells missing homolog, GCMb [J].
Tuerk, EE ;
Schreiber, J ;
Wegner, M .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (07) :4774-4782
[40]   Familial isolated hyperparathyroidism is linked to a 1.7 Mb region on chromosome 2p13.3-14 [J].
Warner, J ;
Nyholt, DR ;
Busfield, F ;
Epstein, M ;
Burgess, J ;
Stranks, S ;
Hill, P ;
Perry-Keene, D ;
Learoyd, D ;
Robinson, B ;
Teh, BT ;
Prins, JB ;
Cardinal, JW .
JOURNAL OF MEDICAL GENETICS, 2006, 43 (03)