Frasier syndrome ... (Frasier syndrome) - Gen WT1
Frasier syndrome is a disorder that affects the kidneys and genitals. It is characterized by male seudohermafrotidismo, where there are external female genitalia XY genotype, nephropathy and increased risk of developing gonadoblastoma. Affected individuals exhibit resistance to steroid treatment. Affected have a condition called focal segmental glomerulosclerosis, in which scar tissue forms in some glomeruli, which can lead to renal failure. Moreover, while men with the syndrome Frasier have typical male chromosomes (46, XY) pattern, have gonadal dysgenesis or completely female genitalia. Generally, the gonads are not fully developed and often become cancerous. Meanwhile, affected women usually have normal gonads and genitals and show only renal disease characteristics. Because of this, they are generally diagnosed with nephrotic syndrome isolated.
As syndrome Denys-Drash syndrome, Frasier is due to mutations in the WT1 gene, a gene encoding a transcription factor regulating the expression of other genes and plays a critical role in the development of kidney and the genitals. Therefore, differences Frasier syndrome syndrome Denys-Drash - see Denys-Drash syndrome - WT1- gene are usually difficult to distinguish following the pattern of routine diagnosis. Frasier's syndrome, nephropathy appears later and is due to focal segmental glomerulosclerosis and progression is slower. Individuals affected by Frasier syndrome do not develop Wilms tumor, while they do 90% of those affected by the syndrome Denys-Drash. The high risk of gonadoblastoma is proper Frasier syndrome.
The WT1 gene, located on the short arm of chromosome 11 (11p13), encoding a protein necessary for the development of kidney and gonads. Within these tissues, the WT1 protein plays a role in cell growth, cell differentiation and apoptosis. To perform these functions, the WT1 protein regulates the activity of other genes by binding to specific regions of DNA. Based on this action, the WT1 protein is called a transcription factor.
They have been described at least seven mutations in WT1 gene in individuals with Frasier syndrome. Genetic alterations that generate Frasier syndrome alter some amino acids of the connector tightly regulated by its involvement in splicing (cutting and sealing) alternative of three amino acids, lysine, threonine and serine (KTS) leading to the KTS + isoforms and KTS- as the inclusion or exclusion of amino acid triplet. Under normal conditions, there are approximately twice the KTS + isoform that the KTS-. Both isoforms, which differ only in the presence or absence of the triplet KTS have different affinities for DNA and therefore different regulatory functions. Maintaining the proper proportions of each isoform is crucial to the function exercised WT1 protein in controlling the expression of certain genes. In most cases, the Frasier syndrome is caused by specific mutations in intron 9, the most common being: IVS9, +4 C> T (52%) and IVS9, +5 G> A (26%). There are scientific references indicate that sometimes has detected a point mutation in exon 9, mainly R390X and F392L. Genetic alterations result WT1 encoding a protein with an impaired ability to control gene activity and regulate the development of the kidneys and reproductive organs, resulting in signs and symptoms Frasier syndrome.
Frasier syndrome is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to express the disease. However, most cases are due to new mutations in the gene that occur during the formation of reproductive cells or early embryonic development. These cases occur in people with no history of disease in your family.
Tests in IVAMI: in IVAMI perform detection of mutations associated with Frasier syndrome by complete PCR amplification of the exons of the WT1 gene, and subsequent sequencing. It is recommended to begin the study by intron or exon 9 of WT1 gene where most alterations are localized, with possible reduction of time and cost involved in most cases. If not found the mutation in this region, it offers the ability to complete the study of the gene by amplification and sequencing of exons rest.
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).