Kallmann syndrome ... (Kallmann syndrome) - Genes years1, CHD7, FGF8, FGFR1, PROK2 and PROKR2
Kallmann syndrome is a heterogeneous genetic disorder that is defined by the association of hypogonadotropic hypogonadism (HH) and anosmia or hyposmia. The clinical features associated are the same as those of HH: lack of sexual development, cryptorchidism and micropenis, along with olfactory disorders. Therefore, in most cases the diagnosis is made during puberty. Some additional signs and symptoms may include unilateral renal agenesis, cleft lip with or without cleft palate, abnormal eye movements, hearing loss, and abnormalities in tooth development. In addition, some affected people have bimanual synkinesis, where hand movements are reflected in the other hand.
This process is due to mutations in 20 genes, although most cases may be due to changes in the years1 gene (anosmin 1), CHD7 (chromodomain helicase DNA binding protein 7), FGF8 (Fibroblast growth factor 8), FGFR1 (fibroblast growth factor receptor 1), PROK2 (prokineticin 2) or PROKR2 (prokineticin receptor 2). In some cases, affected individuals have mutations in more than one of these genes. In addition, we have identified mutations in other genes that may contribute to the development and characteristics of Kallmann syndrome, but is unlikely to be responsible for the development of the disease.
The years1 gene (anosmin 1), located on the short arm of the X (Xp22.31) chromosome, encodes the anosmina-1 protein, which is involved in the development before birth. Anosmina-1 is on the cell surface and can act as part of the extracellular matrix. Anosmina-1 is found in many parts of the developing embryo, including the respiratory tract, the kidneys, digestive system, and certain brain regions. Anosmina-1 seems involved in controlling the growth and migration of olfactory neurons and migration of neurons that produce the gonadotropin releasing hormone (GnRH). GnRH controls the production of several other hormones that direct the sexual development before birth and during puberty. These hormones are important for normal function of the gonads.
They have identified at least 140 years1 gene mutations in people with Kallmann syndrome. It is estimated that mutations in the gene years1 represent from 5 to 10 percent of all cases of Kallmann syndrome. In some cases, mutations remove part or all of years1 gene. Other mutations change amino acids in anosmina-1 or alter the size of the protein. While mutations of genes years1 alter the normal function of the protein during embryonic development, it is not clear how these genetic changes result in the characteristic features of Kallmann syndrome. It is believed that altered anosmina-1 protein is unable to direct the migration of olfactory neurons and GnRH - producing neurons to their usual places in the developing brain, disrupting the sense of smell. In addition, misplacement of producing GnRH neurons inhibits the production of certain sex hormones, which interfere with normal sexual development. It is unclear how years1 genetic mutations give rise to other signs and symptoms of Kallmann syndrome, such as unilateral renal agenesis, loss of hearing and bimanual synkinesis.
The CHD7 (chromodomain helicase DNA binding protein 7) gene, located on the long arm of chromosome 8 (8q12.2), encoding Chromodomain helicase with DNA binding protein 7. This is found in many parts of the body before birth , including the eyes, inner ear and brain. The proteins encoded by the CHD genes have capacity to generate changes in chromatin organization to alter the access of transcriptional target genes, thereby regulating gene expression and participating in the regulation of cell cycle machinery and apoptosis . Also they are therefore very relevant proteins in the regulation of embryonic development. There are more than 50 mutations in the CHD7 gene in people with Kallmann syndrome. Mutations in this gene account for 5 to 10 percent of all cases. Many people with Kallmann syndrome due to a mutation of the gene CHD7 have some of the features of CHARGE syndrome, and abnormally shaped ears and hearing loss. However, signs and symptoms tend to be much less severe. Most of the identified mutations alter amino acids in the protein CHD7. Studies suggest that these mutations have a less severe effect on protein function than those responsible for CHARGE syndrome. The altered protein affects the development of the olfactory bulb, which deteriorates the sense of smell. Also it disrupts the development of certain neurons necessary for the production of sex hormones, which interfere with normal sexual development.
The FGF8 gene (fibroblast growth factor 8), located on the long arm of chromosome (10q24.32), encoding the fibroblast growth factor 8. This protein binds to the receptor fibroblast growth factor 1 (FGFR1) in cell surface. The signals activated by FGF8 and FGFR1 play a critical role in the formation, survival and migration of certain neurons. In particular, this signaling appears to be essential for producing neurons gonadotropin releasing hormone (GnRH). The FGF8 protein is also found in other parts of the developing embryo, including other areas of the brain and extremities, heart, ears and eyes, so it is believed to also be involved in the formation and normal development these structures. At least seven mutations in the FGF8 gene have been identified in people with Kallmann syndrome. It is estimated that mutations in the FGF8 gene represent a small percentage of all cases of Kallmann syndrome. Most mutations change the amino acids in FGF8 protein. These mutations reduce or eliminate protein function, including their ability to bind to FGFR1. It is believed that FGF8 functional deficiency disrupts the migration and survival of olfactory neurons and GnRH - producing neurons in the developing brain. If olfactory neurons do not extend to the olfactory bulb, the sense of smell of a person is impaired or absent. Replacement or premature loss of GnRH - producing neurons inhibits the production of sex hormones, which interfere with sexual development. Some people with FGF8 gene mutations have additional features, such as cleft lip and palate with bimanual synkinesis.
FGFR1 (Fibroblast growth factor receptor 1) gene located on the short arm of chromosome 8 (8p11.2) encoding the receptor of the fibroblast growth factor receptor 1. This can be modulated by anosmina-1 and is critical for formation and maintenance of GnRH system. There are more than 140 mutations in the FGFR1 gene in people with Kallmann syndrome. It is estimated that mutations in this gene account for about 10 percent of all cases. These mutations change the amino acids in FGFR1 protein or result encoding an abnormally small version, nonfunctional protein which prevents the protein FGFR1 transmit signals properly. During brain development, the FGFR1 protein non - functional alters the formation and migration of olfactory neurons, which underlies impaired sense of smell. FGFR1 gene mutations also interrupt migration of neurons that produce the gonadotropin releasing hormone (GnRH) in the developing brain. In this sense, an altered protein FGFR1 prevents normal migration of GnRH - producing neurons in the brain, which interferes with sexual development and causes delayed puberty or is absent. It is unclear how the FGFR1 gene mutations give rise to other signs and symptoms of Kallmann syndrome, such as cleft palate and abnormal tooth development.
The PROK2 genes (prokineticin 2), located on the short arm of chromosome 3 (3p13), and PROKR2 (prokineticin receptor 2), located on the short arm of chromosome 20 (20p12.3), encoding the protein prokineticina 2 and its receptor respectively. This receptor interacts with prokineticina 2 from PROK2 encoded gene. On the cell surface, it binds prokineticina 2 receptor triggering a series of chemical signals within the cell that regulate diverse cellular functions. It has been shown to prokineticina 2 and its receptor play a role in the normal development of the olfactory bulb and in the migration of neurons that produce the gonadotropin releasing hormone (GnRH). In addition, it is believed that these proteins help stimulate the movement of food through the intestine and is likely to be involved in angiogenesis.
They have identified at least 30 PROKR2 gene mutations and 16 mutations in the gene PROK2 in people with Kallmann syndrome. It is estimated that mutations in genes PROK2 and PROKR2 together represent approximately 9 percent of all cases of Kallmann syndrome. Most mutations change the amino acids in protein prokineticina 2 and its receptor. It is believed that these genetic changes alter the role of prokineticina 2 and its receptor, but it is unclear how altered proteins give rise to the characteristic features of Kallmann syndrome. Based on experimental animal studies, it is believed that abnormal Prokineticina 2 receptor is unable to direct the migration of olfactory neurons and GnRH - producing neurons to their usual places in the developing brain. If the olfactory nerve cells do not extend to the olfactory bulb, the sense of smell is altered. In addition, inadequate location of GnRH - producing neurons prevents the production of certain sex hormones, which interfere with normal sexual development and causes the absence or delayed puberty.
When Kallmann syndrome is due to mutations in the gene years1, it has a recessive inheritance pattern linked to chromosome X. The years1 gene is on the X chromosome, one of the two sex chromosomes. In males, an altered copy of the gene in each cell is sufficient to express the disease. In women, the mutation must be present in both copies of the gene to express the disease. Males are affected by X - linked recessive disorders much more frequently than women. A feature of the X - linked inheritance is that fathers can not pass X - linked traits to their sons chromosome. Most cases of Kallmann syndrome are described as simple, which means that only one person in a family is affected. Some people inherit a genetic mutation affected years1 their mothers, who carry one mutated copy of the gene in each cell. Other people have the disease as a result of a new mutation in the gene years1.
When Kallmann syndrome is due to mutations in other genes, often it has an autosomal dominant inheritance, which means that a copy of an altered gene in each cell is sufficient to express the disease. In some cases, an affected person inherits the mutation of a mother or father affected. Other cases are due to new mutations in the gene and occur in people with no history of disease in your family. In family, Kallmann syndrome has shown a pattern autosomal recessive inheritance, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
Tests performed in IVAMI: in IVAMI perform the detection of mutations associated with Kallmann syndrome, by complete PCR amplification of the exons of years1 CHD7, FGF8, FGFR1, PROK2 and PROKR2, respectively, and subsequent sequencing genes.
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).