Central precocious puberty (central precocious puberty) - Genes MKRN3, KISS1 and KISS1R
Central precocious puberty, as its name suggests, is a condition that leads to early sexual development in children. While puberty usually begins between 8 and 13 in girls and between 9 and 14 years in boys, girls with central precocious puberty begin to show signs before 8 years and children before 9 years. These signs may include the development of underarm hair, rapid growth in height (known as a "growth spurt") and the appearance of acne. Girls also develop breast breasts and start your menstrual periods. Children have growth penis and testicles and change of voice. Because of the "growth spurt", children with central precocious puberty may be higher than other children their age; however, they may stop growing soon. Without proper treatment, some people affected are lower in stature in adulthood compared to other family members. In addition, the fact developed in advance of their peers can be emotionally difficult for affected people and can lead to psychological and behavioral problems.
Often the cause of central precocious puberty is unknown. The most common known genetic cause of central precocious puberty are mutations in MKRN3 (makorin ring finger protein 3) gene. Changes in other genes, such as KISS1 (KiSS-1 metastasis-suppressor) gene and the gene KISS1R (KISS1 receptor), are rare causes of disease. It suspected that changes in certain genes have not yet been identified may also be involved in the central precocious puberty. The timing of puberty is influenced by several factors in addition to genetics, including nutrition, socioeconomic status and exposure to certain chemicals in the environment.
The MKRN3 (makorin ring finger protein 3) gene, located on the long arm of chromosome 15 (15q11.2), encoding the protein makorin ring finger 3 (MKRN3). This protein plays a role in regulating the onset of puberty. Puberty begins when the hypothalamus is stimulated to release gonadotropin - releasing hormone (GnRH). This hormone triggers the release of other hormones that direct sexual development. It is believed that MKRN3 protein inhibits the release of GnRH from the hypothalamus, thereby regulating the onset of puberty. Although the exact function of the MKRN3 protein is unknown, based on their structure, it is believed that the protein plays a role in cellular process that breaks down unwanted proteins, a process known as the ubiquitin-proteasome system, helping to connect molecules ubiquitin unwanted proteins. Ubiquitin acts as a signal to the ubiquitin-proteasome system to decompose the protein. MKRN3 is believed that adds ubiquitin to proteins that would otherwise stimulate the release of GnRH. The breakdown of such proteins ensures that puberty does not start until the right time.
There are more than 20 mutations MKRN3 gene in individuals with central precocious puberty. It is believed that mutations in the gene involved in MKRN3 central precocious puberty lead to the synthesis of a nonfunctional protein MKRN3 a copy of the gene. Because the other copy of the gene is inactive, affected individuals probably do not encode any functional protein MKRN3. Although the mechanism is unclear, it is believed that without the MKRN3 protein to inhibit release of GnRH, the hypothalamus releases bursts hormone, which stimulates the onset of puberty earlier than usual.
The KISS1 (KiSS-1 metastasis-suppressor) gene, located on the long arm of chromosome 1 (1q32.1), is a metastatic suppressor gene suppressing metastasis of melanomas and breast carcinomas without affecting tumorigenicity. The protein encoded by this gene can inhibit chemotaxis and invasion and thus attenuate the metastasis of malignant melanomas. Studies suggest a putative role in the regulation of events after the accession of the cell matrix, perhaps through the reorganization of the cytoskeleton. A protein product of this gene, kisspeptin stimulates gonadotropin secretion induced by GnRH (GnRH) and pubertal regulates activation of GnRH neurons. A polymorphism in the terminal exon of the mRNA results in two protein isoforms. An adenosine present in the polymorphic site represents the third position in a stop codon. When adenosine is absent, a stop codon downstream is used and the encoded protein spans seven other amino acid residues.
The KISS1R (KISS1 receptor) gene, also known as GPR54, is located on the short arm of chromosome 19 (19p13.3). This gene encodes the receptor kisspeptinas and has high homology with the galanin receptor family. Binding of kisspeptinas to its receptor triggers activation of phospholipase C, which leads to greater production of IP3 and facilitates intracellular calcium mobilization. In the central nervous system, the highest expression of kisspeptinas occurs in the arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV), which send signals to the medial preoptic area, where abundant GnRH and therefore KISS1R, and the latter is expressed on the surface of GnRH neurons. In fact, kisspeptinas are considered the most potent stimulator of the secretion of GnRH dependent LH.
The central precocious puberty is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to express the disease. When transmitted from parents to children, this condition is known as central precocious puberty familiar. In familial cases associated with MKRN3 gene, the mutation is inherited from the father. Although in many cases the father is affected, it can not be affected if the altered gene inherited from his mother. A parent may also be affected because some men with a mutation show no signs of disease. A parent can transmit the disease to their children. The condition can also occur in people with no family history. These cases are called sporadic central precocious puberty. Some apparently sporadic cases are due to inherited gene mutations MKRN3 a parent unaffected.
Tests in IVAMI: in IVAMI perform detection of mutations associated with central precocious puberty, by complete PCR amplification of the exons of MKRN3, KISS1 and KISS1R genes, respectively, and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).