UNSW Embryology DNA- NCBI Genes and Diseases Signals Back to Index Page Links: Introduction About Notes Ataxia telangiectasia Cockayne Glaucoma Sdy 5-Alpha Reductase Tuberous Sclerosis Waardenburg Syndrome Werner Syndrome Cancer Nervous Muscle Immune Metabolism Signals Transport

INTRODUCTION SIGNAL TRANSDUCTION within and between cells mean that they can communicate important information and act upon it. Hormones released from their site of synthesis carry a message to their target site, as in the case of leptin, which is released from adipose tissue (fat cells) and transported via the blood to the brain. Here, the leptin signals that enough has been eaten. Leptin binds to a receptor on the surface of hypothalamus cells, triggering subsequent intracellular signaling networks.   Intracellular signaling defects account for several diseases, including cancers, ataxia telangiectasia and Cockayne syndrome. Faulty DNA repair mechanisms are also invoked in pathogenesis, since control of cell division, DNA synthesis and DNA repair all are inextricably linked.   The end-result of many cell signals is to alter the expression of genes (transcription) by acting on DNA-binding proteins. Some diseases are the result of a lack of or a mutation in these proteins, which stop them from binding DNA in the normal way.   Since signaling networks impinge on so many aspects of normal function, it is not surprising that so many diseases have at least some basis in a signaling defect. Link to NCBI page

ATAXIA TELANGIECTASIA THE FIRST SIGNS of ataxia telangiectasia (A-T) usually appear in the second year of life as a lack of balance and slurred speech. It is a progressive, degenerative disease characterized by cerebellar degeneration, immunodeficiency, radiosensitivity (sensitivity to radiant energy, such as x-ray) and a predisposition to cancer.   Back in 1988 the gene responsible for A-T was mapped to chromosome 11. The subsequent identification of the gene proved difficult: it was seven more years until the human ATM gene was cloned. The diverse symptoms seen in A-T reflect the main role of ATM, which is to induce several cellular responses to DNA damage. When the ATM gene is mutated, these signaling networks are impaired and so the cell does not respond correctly to minimize the damage. Link to NCBI page

COCKAYNE EDWARD ALFRED COCKAYNE (1880-1956), after whom this disease is named, was a London physician who concentrated particularly on hereditary diseases of children. Cockayne syndrome is a rare inherited disorder in which people are sensitive to sunlight, have short stature and have the appearance of premature aging. In the classical form of Cockayne syndrome (Type I), the symptoms are progressive and typically become apparent after the age of one year. An early onset or congenital form of Cockayne syndrome (Type II) is apparent at birth. Interestingly, unlike other DNA repair diseases, Cockayne syndrome is not linked to cancer.   After exposure to UV radiation (found in sunlight), people with Cockayne syndrome can no longer perform a certain type of DNA repair, known as 'transcription-coupled repair'. This type of DNA repair occurs 'on the fly', right as the DNA that codes for proteins is being replicated. Two genes defective in Cockayne syndrome, CSA and CSB, have been identified so far. The CSA gene is found on chromosme 5. Both genes code for proteins that interacts with components of the transcriptional machinery and with DNA repair proteins.   Escherichia coli, a bacterium, also undergoes transcription-coupled repair, and a yeast counterpart of the CSB gene has also recently been discovered. These similar mechanisms to the one found in humans are invaluable for studying the molecular processes involved in transcription-coupled repair because powerful molecular genetics techniques can be used. A better understanding of the mechanisms involved will help unravel the pathogenesis of disease and may identify potential drug targets. Link to NCBI page

GLAUCOMA 'GLAUCOMA' is a term used for a group of diseases that can lead to damage to the eye's optic nerve and result in blindness. The most common form of the disease is open-angle glaucoma, which affects about three million Americans, half of whom don't know they have it. Glaucoma has no symptoms at first but over the years can steal its victims' sight, with side vision being effected first.   It is estimated that nearly 100,000 individuals in the US suffer from glaucoma due to a mutation in the GLC1A gene, found on chromosome 1. There has been some speculation as to the role of the gene product in the eye. As it is found in the structures of the eye involved in pressure regulation, it may cause increased pressure in the eye by obstructing the aqueous outflow.   With early treatment, serious loss of vision and blindness can be prevented. The cloning of the GLCA1 gene is the first step towards an understanding of the pathology of glaucoma at the molecular level, and may help in the development of tests for the early detection of the disease, as well as providing a basis for research into effective therapies. Link to NCBI page

SEX DETERMING Y GENE WE HAVE COME A LONG WAY in our understanding of sexual dimorphism since 355 BC. In those days, Aristotle suggested that the difference between the two sexes was due to the heat of semen at the time of copulation: hot semen generated males, whereas cold semen made females. Thankfully, we now know a little more about the molecular events of sex determination.   Usually, a woman has two X chromosomes (XX) and a man one X and one Y (XY). However, both male and female characteristics can sometimes be found in one individual, and it is possible to have XY women and XX men. Analysis of such individuals has revealed some of the molecules involved in sex determination, including one called SRY, which is important for testis formation.   SRY (which stands for sex-determining region Y gene) is found of the Y chromosome. In the cell, it binds to DNA and in doing so distorts it dramatically out of shape. This alter the properties of the DNA and likely alters the expression of a number of genes, leading to testis formation. Therefore XX men who lack a Y chromosome also lack SRY and frequently do not develop secondary sexual characteristics in the usual way.   Since human SRY is similar to SRY of mice, a model of SRY function has been developed in mice. This has been particularly important in discovering the interactions of SRY with other genes in male sex determination. Link to NCBI page

5-ALPHA REDUCTASE 5-ALPHA REDUCTASE is an enzyme that was first discovered in the male prostate. Here, it catalyzes the conversion of testosterone to dihydrotestosterone, which in turn binds to the androgen receptor and initiates development of the external genitalia and prostate. The gene for 5-alpha reductase has been mapped to chromosome 5.   More recently, 5-alpha reductase was found in human scalp and elsewhere in the skin, where it carries out the same reaction as in the prostate. It is thought that disturbances in 5-alpha reductase activity in skin cells might contribute to male pattern baldness, acne or hirsutism. The discovery of a plant homolog of human 5-alpha reductase may lead to new drugs, and the race is now on to find inhibitors of 5-alpha reductase. Link to NCBI page

TUBEROUS SCLEROSIS TUBEROUS SCLEROSIS is an hereditary disorder characterized by benign, tumor-like nodules of the brain and/or retinas, skin lesions, seizures and/or mental retardation. Patients may experience a few or all of the symptoms with varying degrees of severity.   Two loci for tuberous sclerosis have been found: TSC1 on chromosome 9, and TSC2 on chromosome 16. It took four years to pin down a specific gene from the TSC1 region of chromosome 9: in 1997, a promising candidate was found. Called hamartin by the discoverers, it is similar to a yeast protein of unknown function, and appears to act as a tumor suppressor: without TSC1, growth of cells proceeds in an unregulated fashion, resulting in tumor formation. TSC2 codes for a protein called tuberin, which, through database searches, was found to have a region of homology to a protein found in pathways that regulate the cell (GAP3, a GTPase-activation protein).   TSC1 has a homolog in yeast, which provides a system in which to model the human disease. Link to NCBI

WAARDENBURG SYNDROME  THE MAIN CHARACTERISTICS of Waardenburg syndrome (WS) include: a wide bridge of the nose; pigmentary disturbances such as two different colored eyes, white forelock and eyelashes and premature graying of the hair; and some degree of cochlear deafness. The disease was named for Petrus Johannes Waardenburg, a Dutch ophthalmologist (1886-1979) who was the first to notice that people with two different colored eyes frequently had hearing problems.   The several types of WS are inherited in dominant fashion, so researchers typically see families with several generations who have inherited one or more of the features.Type I of the disorder is characterized by displacement of the fold of the eyelid, while Type II does not include this feature, but instead has a higher frequency of deafness.   The discovery of the human gene that causes Type I WS came about after scientists speculated that the gene that causes 'splotch mice' (mice with a splotchy coat coloring) might be the same gene that causes WS in humans. They located the human gene to chromosome 2 and found it was the same as mouse Pax3. Pax3 is one of a family of eight mouse Pax genes that are involved in regulating embryonic development at the level of transcription.   With a mouse model to draw from, scientists are learning much about how Pax3 causes Waardenburg syndrome. Link to NCBI page

WERNER SYNDROME WERNER SYNDROME is a premature aging disease that begins in adolescence or early adulthood and results in the appearance of old age by 30-40 years of age. Its physical characteristics may include short stature (common from childhood on) and other features usually developing during adulthood: wrinkled skin, baldness, cataracts, muscular atrophy and a tendency to diabetes mellitus, among others.   The disorder is inherited and transmitted as an autosomal recessive trait. Cells from WS patients have a shorter lifespan in culture than do normal cells. The gene for Werner disease (WRN) was mapped to chromosome 8 and cloned: by comparing its sequence to existing sequences in GenBank, it is a predicted helicase belonging to the RecQ family. However, it has yet to be shown to have real helicase activity (as a DNA unwinder important for DNA replication). The molecular role of WRN in Werner syndrome therefore remains to be proven, as does any role it might have in the aging process in general.   A yeast protein similar to the human WRN protein, called SGS1, has been found. Mutations in SGS1 cause yeast to have a shorter lifespan than yeast cells without the mutation, and shown other signs typical of aging in yeast, such as an enlarged and fragmented nucleolus. Using yeast as a model for human aging in general, may give insight into the mechanisms of Werner syndrome and related diseases. Link to NCBI page

About Notes These notes are derived from the NCBI WWW pages Genes and Disease. They are included here for computers without internet access and for educational purposes only. Where possible use the WWW link at the bottom of each section to see the original pages which include images and many Links to other resources.