Pioneering studies on monogenic central precocious puberty

ABSTRACT Pubertal timing in humans is determined by complex interactions including hormonal, metabolic, environmental, ethnic, and genetic factors. Central precocious puberty (CPP) is defined as the premature reactivation of the hypothalamic-pituitary-gonadal axis, starting before the ages of 8 and 9 years in girls and boys, respectively; familial CPP is defined by the occurrence of CPP in two or more family members. Pioneering studies have evidenced the participation of genetic factors in pubertal timing, mainly identifying genetic causes of CPP in sporadic and familial cases. In this context, rare activating mutations were identified in genes of the kisspeptin excitatory pathway (KISS1R and KISS1 mutations). More recently, loss-of-function mutations in two imprinted genes (MKRN3 and DLK1) have been identified as important causes of familial CPP, describing novel players in the modulation of the hypothalamic-pituitary-gonadal axis in physiological and pathological conditions. MKRN3 mutations are the most common cause of familial CPP, and patients with MKRN3 mutations present clinical features indistinguishable from idiopathic CPP. Meanwhile, adult patients with DLK1 mutations present high frequency of metabolic alterations (overweight/obesity, early onset type 2 diabetes and hyperlipidemia), indicating that DLK1 may be a novel link between reproduction and metabolism. Arch Endocrinol Metab. 2019;63(4):438-44

Association of ring-finger protein 3 (MKRN3) gene rs2239669 polymorphism with central precocious puberty susceptibility / 临床儿科杂志

Objectives To explore the association between the single nucleotide polymorphism (SNP) rs2239669 in makorin ring-finger protein 3 (MKRN3) gene and the susceptibility to central precocious puberty (CPP). Methods A case-control study including 246 children with CPP and 269 healthy children was performed.The genotype and MKRN3 expression levels of patients were analyzed by PCR-HRM and RT-PCR,respectively. Results SNP rs2239669 genotype (TT,TC,CC) and allele frequencies (T and C) were different between cases and controls,with higher CC genotype in CPP patients. Under recessive model (CC/TT+TC),CC genotype was higher in CPP group and associated with higher risk of CPP (95%CI:1.062-2.143,P=0.021). MKRN3 expression levels were different among patients with different genotypes,of which TT genotype had the highest level followed by TC and CC (0.376±0.094, 0.330±0.068, 0.250±0.072, P=0.041). Conclusions MKRN3 SNP rs2239669 was associated with increased risk of CPP, and patients with TT genotype had higher MKRN3 levels.

Mutações inativadoras no gene MKRN3 são causa de puberdade precoce central familial / Inactivating mutations in the MKRN3 gene are cause of familial central precocious puberty

A maioria dos casos de puberdade precoce central (PPC) em meninas permanece idiopática. A hipótese de uma causa genética vem se fortalecendo após a descoberta de alguns genes associados a este fenótipo, sobretudo aqueles implicados com o sistema kisspeptina (KISS1 e KISS1R). Entretanto, apenas casos isolados de PPC foram relacionados à mutação na kisspeptina ou em seu receptor. Até recentemente, a maioria dos estudos genéticos em PPC buscava genes candidatos selecionados com base em modelos animais, análise genética de pacientes com hipogonadismo hipogonadotrófico, ou ainda, nos estudos de associação ampla do genoma. Neste trabalho, foi utilizado o sequenciamento exômico global, uma metodologia mais moderna de sequenciamento, para identificar variantes associadas ao fenótipo de PPC. Trinta e seis indivíduos com a forma de PPC familial (19 famílias) e 213 casos aparentemente esporádicos foram inicialmente selecionados. A forma familial foi definida pela presença de mais de um membro afetado na família. DNA genômico foi extraído dos leucócitos do sangue periférico de todos os pacientes. O estudo de sequenciamento exômico global realizado pela técnica ILLUMINA, em 40 membros de 15 famílias com PPC, identificou mutações inativadoras em um único gene, MKRN3, em cinco dessas famílias. Pesquisa de mutação no MKRN3 realizada por sequenciamento direto em duas famílias adicionais (quatro pacientes) identificou duas novas variantes nesse gene. O MKRN3 é um gene de um único éxon, localizado no cromossomo 15 em uma região crítica para a síndrome de Prader Willi. O gene MKRN3 sofre imprinting materno, sendo expresso apenas pelo alelo paterno. A descoberta de mutações em pacientes com PPC familial despertou o interesse para a pesquisa de mutações nesse gene em 213 pacientes com PPC aparentemente esporádica por meio de reação em cadeia de polimerase seguida de purificação enzimática e sequenciamento automático direto (Sanger). Três novas mutações e duas...

Most cases of central precocious puberty (CPP) in girls remain idiopathic. The hypothesis of a genetic cause has been strengthened after the discovery of some genes associated with this phenotype, particularly those involved with the kisspeptin system (KISS1 and KISS1R). However, genetic defects in KISS1 and its receptor are rare and have been identified in only a few patients with CPP.over the past years. To date, most genetic studies in CPP was based mainly on a candidate gene approach, including genes selected in animal studies, human models of patients with hypogonadotropic hypogonadism or in genome wide association studies. In the present study, we used whole exome sequencing, a more advanced method of sequencing, to identify variants associated with CPP. Thirty-six patients with the familial form of CPP (19 families) and 213 apparently sporadic cases were initially selected. The familial form was defined by the presence of more than one member affected in the family. Genomic DNA was extracted from peripheral blood leukocytes in all patients. Whole exome sequencing performed by ILLUMINA technique in 40 members of 15 families with CPP, identified inactivating mutations in a single gene, MKRN3, in five out of these families. Analysis of MKRN3 mutations performed by automatic sequencing in two additional families (four patients) identified two novel mutations. MKRN3 is an introless gene located on chromosome 15, in the Prader Willi syndrome critical region, and it is expressed only by the paternal allele due to the maternal imprinting. Following the initial findings, we searched for MKRN3 mutations in 213 patients with apparently sporadic CPP using polymerase chain reaction followed by direct enzymatic purification and automated sequencing (Sanger). Three new mutations and two previously reported, including four frameshifts and one missense variant was identified in six unrelated girls with CPP. All variants were not described in...

An update on the genetic causes of central precocious puberty

Central precocious puberty (CPP) is caused by the premature reactivation of the hypothalamic-pituitary-gonadal axis. Genetic, nutritional, and environmental factors play a crucial role in determining pubertal timing. Recently mutations in kisspeptin (KISS1), kisspeptin receptor (KISS1R), and makorin RING finger protein 3 (MKRN3) genes have been identified as genetic causes of CPP. In particular, the MKRN3 gene is known to affect pubertal initiation. The MKRN3 gene is located on chromosome 15q11-q13 in the Prader-Willi syndrome (PWS) critical region. MKRN3 deficiency, due to a loss of function mutation, leads to the withdrawal of hypothalamic inhibition and prompts pulsatile gonadotropin-releasing hormone secretion, resulting in precocious puberty. The exact functions of these genes associated with CPP are still not well understood. Larger studies are required to discover the mechanisms involved in pubertal development.

An update on the genetic causes of central precocious puberty

Central precocious puberty (CPP) is caused by the premature reactivation of the hypothalamic-pituitary-gonadal axis. Genetic, nutritional, and environmental factors play a crucial role in determining pubertal timing. Recently mutations in kisspeptin (KISS1), kisspeptin receptor (KISS1R), and makorin RING finger protein 3 (MKRN3) genes have been identified as genetic causes of CPP. In particular, the MKRN3 gene is known to affect pubertal initiation. The MKRN3 gene is located on chromosome 15q11-q13 in the Prader-Willi syndrome (PWS) critical region. MKRN3 deficiency, due to a loss of function mutation, leads to the withdrawal of hypothalamic inhibition and prompts pulsatile gonadotropin-releasing hormone secretion, resulting in precocious puberty. The exact functions of these genes associated with CPP are still not well understood. Larger studies are required to discover the mechanisms involved in pubertal development.

The progress on genes associated with early puberty / 国际儿科学杂志

Puberty onset is triggered by re-emergence of the hypothalamic-pituitary-gonadal axis (HPGA),which is characterized by the significantly increasing amplitude and frequency of gonadotropin-releasing hormone (GnRH) secretion in human being.A series of studies found that many genes control puberty onset,including KISS1 and GPR54 gene,estrogen receptor (ESR) gene,energy balance-related genes,LIN28B gene,MKRN3 gene and so on.Studies have been confirmed that the mutation and single nucleotide polymorphisms (SNP) of the genes above are associated with early puberty.In this paper,the relationship between genetic alterations of these genes and early puberty are summarized as follows.-