Central Precocious Puberty Caused by Mutations in the Imprinted Gene MKRN3

被引：348

作者：

Abreu, Ana Paula ^{[1
,2
,6
]}

Dauber, Andrew ^{[3
,5
]}

Macedo, Delanie B. ^{[6
]}

Noel, Sekoni D. ^{[1
,2
]}

Brito, Vinicius N. ^{[6
]}

Gill, John C. ^{[1
,2
]}

Cukier, Priscilla ^{[6
]}

Thompson, Iain R. ^{[1
,2
]}

Navarro, Victor M. ^{[1
,2
]}

Gagliardi, Priscila C. ^{[9
]}

Rodrigues, Tania ^{[8
]}

Kochi, Cristiane ^{[7
]}

Longui, Carlos Alberto ^{[7
]}

Beckers, Dominique ^{[10
]}

de Zegher, Francis ^{[10
]}

Montenegro, Luciana R. ^{[6
]}

Mendonca, Berenice B. ^{[6
]}

Carroll, Rona S. ^{[1
,2
]}

Hirschhorn, Joel N. ^{[3
,4
,5
]}

Latronico, Ana Claudia ^{[6
]}

Kaiser, Ursula B. ^{[1
,2
]}

机构：

[1] Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Boston, MA USA

[3] Boston Childrens Hosp, Div Endocrinol, Boston, MA USA

[4] Boston Childrens Hosp, Div Genet, Boston, MA USA

[5] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[6] Univ Sao Paulo, Fac Med, Hosp Clin,Lab Hormonios & Genet Mol,LIM42, Disciplina Endocrinol,Unidade Endocrinol Desenvol, BR-05403900 Sao Paulo, Brazil

[7] Fac Ciencias Med Santa Casa Sao Paulo, Dept Pediat, Sao Paulo, Brazil

[8] Univ Fed Minas Gerais, Hosp Clin, Div Pediat Endocrinol, Belo Horizonte, MG, Brazil

[9] Nemours Childrens Clin, Div Endocrinol Diabet & Metab, Jacksonville, FL USA

[10] Univ Hosp Gasthuisberg, Dept Pediat, B-3000 Louvain, Belgium

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2013年 / 368卷 / 26期

基金：

巴西圣保罗研究基金会; 美国国家卫生研究院;

关键词：

PRADER-WILLI-SYNDROME; IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM; NEUROBIOLOGICAL MECHANISMS; ARCUATE NUCLEUS; CHINESE GIRLS; NEUROKININ B; ASSOCIATION; EXPRESSION; GROWTH; MOUSE;

D O I：

10.1056/NEJMoa1302160

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND The onset of puberty is first detected as an increase in pulsatile secretion of gonadotropin-releasing hormone (GnRH). Early activation of the hypothalamic-pituitary-gonadal axis results in central precocious puberty. The timing of pubertal development is driven in part by genetic factors, but only a few, rare molecular defects associated with central precocious puberty have been identified. METHODS We performed whole-exome sequencing in 40 members of 15 families with central precocious puberty. Candidate variants were confirmed with Sanger sequencing. We also performed quantitative real-time polymerase-chain-reaction assays to determine levels of messenger RNA (mRNA) in the hypothalami of mice at different ages. RESULTS We identified four novel heterozygous mutations in MKRN3, the gene encoding makorin RING-finger protein 3, in 5 of the 15 families; both sexes were affected. The mutations included three frameshift mutations, predicted to encode truncated proteins, and one missense mutation, predicted to disrupt protein function. MKRN3 is a paternally expressed, imprinted gene located in the Prader-Willi syndrome critical region (chromosome 15q11-q13). All affected persons inherited the mutations from their fathers, a finding that indicates perfect segregation with the mode of inheritance expected for an imprinted gene. Levels of Mkrn3 mRNA were high in the arcuate nucleus of prepubertal mice, decreased immediately before puberty, and remained low after puberty. CONCLUSIONS Deficiency of MKRN3 causes central precocious puberty in humans.

引用

页码：2467 / 2475

页数：9