The following is a list of definitions and disease descriptions useful in understanding information found in Genetics and Louisiana Families. For further definitions, we recommend the On-line Medical Dictionary (OMD), prepared by Oxford University. You can access the OMD at the following address: http://cancerweb.ncl.ac.uk/omd/. You can also find information on particular topics in the Frequently Asked Questions (FAQs) section of Genetics and Louisiana Families.
One of the features of the science of genetics is that researchers and clinicians are always finding exceptions to rules. In fact, many mutations in themselves illustrate exceptions to rules. Further, with information learned from results of the Human Genome Project, we are continually discovering exceptions and new curiosities about genetic phenomena. In this glossary, we focus on the fundamental concepts underlying genetics without necessarily including the exceptions, because the exceptions may be too numerous to mention. Because each human being is genetically unique, each genetic patient is potentially an exception to an established genetic rule. Exceptions and peculiarities of specific genetic conditions will be addressed by your healthcare provider. However, these rules and definitions remain the most useful concepts in the struggle to diagnose, understand, and remediate genetic disease.
A more complete (but technical) explanation of the particular diseases listed in this glossary may be found at the Online Mendelian Inheritance in Man (OMIM) website, accessible at http://www.ncbi.nlm.nih.gov/Omim/.
New and revised definitions useful to readers of Genetics and Louisiana Families will be added on a regular basis.
ALLELE different forms of a gene. Because sexually reproducing life forms possess two copies of each chromosome, individuals contain two copies of each gene. The two copies, however, may not be identical, and therefore any individual can contain two different forms of the same gene. These different forms are called alleles. We may be able to see the effect of a protein made only by one allele. The allele that is expressed into protein is called dominant. The other allele, whose expression is hidden, or which does not express protein at all, is called recessive.
AGE OF ONSET the period of life when particular symptoms of a disease are first noticeable. Age of onset can vary in different forms of a disease. For instance, in Type I Usher syndrome, the age of onset for blindness is in the first to second decades of life; in Type II Usher syndrome, the age of onset for blindness is later, noticeable in the third to fourth decades of life.
ALSTRÖM SYNDROME a rare autosomal recessive syndrome characterized by blindness, hearing loss, early-onset obesity, and non-insulin-dependent diabetes mellitus. The gene for Alström syndrome (ALMS1) has been found on chromosome 2p13. Mutation in ALMS1 causes the disease in two distinct populations, French-Acadian and North African.
ATAXIA a loss of voluntary control of muscles, especially those used for walking and reaching. Two notable types of hereditary ataxias are Friedreich ataxia and Ataxia telangiectasia.
ATAXIA TELANGIECTASIA a rare genetic disorder characterized by progressive loss of balance control (ataxia), demonstrated by unsteady walking, and the appearance of prominent blood vessels (called telangiectasia), commonly on the whites of the eyes and on the skin of the face. Signs of the disorder usually first become noticeable between 1-4 years of age, and symptoms gradually increase in severity. Speech problems often occur, as well as a gradual loss of power and other coordination problems. Ultimately, generally during adolescence, A-T patients are permanently wheelchair bound. A-T patients also have a compromised immune system and, because of this, they often contract recurrent respiratory tract infections. Additionally, A-T patients have an extremely high likelihood of developing cancer, primarily leukemia or lymphoma. A-T patients show a handful of other maladies, such as premature aging, sterility, diabetes, and growth defects. Owing primarily to either cancer or infection, A-T claims the life of afflicted patients, most in their teens or twenties. It is estimated that between 1 in 40,000 and 1 in 100,000 babies born in the U.S. are afflicted with A-T. Mutation of the ATM gene on chromosome 11 causes A-T. A-T is inherited in an autosomal recessive fashion.
AUTOSOME one of the 22 pairs of chromosomes in human cells not involved in the determination of gender.
AUTOSOMAL DOMINANT INHERITANCE one of the basic patterns of inheritance. In dominant inheritance, a defect in only one of the two copies (alleles) of a gene leads to a disorder. In other words, a person affected with the disorder inherited a defective allele from only one parent. When the defective allele is part of one of the autosomes, the disorder it causes is called autosomal dominant. An autosomal dominant disorder is inherited through generations in a particular pattern: (i) A person affected by the disorder has at least one affected parent; (ii) an affected person and a normal (unaffected) person have an equal number of affected and normal (unaffected) children, on average; (iii) unaffected children of an affected parent have unaffected children and grandchildren; (iv) the risk for occurrence of the disorder among children of an affected person is 50% at each childbirth; (v) males and females are equally likely to be affected.
AUTOSOMAL RECESSIVE INHERITANCE one of the basic patterns of inheritance. In recessive inheritance, a defect in both of the two copies (alleles) of a gene leads to a disorder. In other words, a person affected with the disorder inherited one defective allele from each parent. When the defective alleles are part of one of the autosomes, the disorder it causes is called autosomal recessive. An autosomal recessive disorder is inherited through generations in a particular pattern: (i) If normal parents have an affected child, then both parents are carriers, each carrying one copy of the defective allele; (ii) if two carriers have children, on average one-fourth of their children will be affected, one-fourth will be normal (unaffected), and one-half will be normal but will be carriers; (iii) All children of an affected person and a normal person will be normal but will be carriers; (iv) all children of two affected persons will be affected; (v) males and females are equally likely to be affected. Certain populations may have an increased number of carriers for two reasons: (1) If the population was founded with only a few individuals, one of which was a carrier, then the defective allele will be more frequent in the population of his descendants than in a general population; this situation is called the founder effect, and founder effects are observed in the Louisiana Acadian population for rare disorders like Usher syndrome and Friedreich ataxia. (2) If the defective allele improves a carrier's chances for survival, then the defective allele will be more frequent in the population of his descendants than in a general population; this situation is called selective advantage, and selective advantage is observed in subpopulations of African descendants, where the defect causing sickle-cell anemia protects against infection by the deadly malaria parasite.
CANCER any of a number of diseases caused by the uncontrolled growth of cells and the formation of tumors (abnormal masses of cells). Abnormal cells can arise from any organ, and many different cancers are named after either the affected organ (liver cancer, brain cancer) or the type of abnormal cell (glioma, neuroma). The uncontrolled growth of cancer cells causes problems by displacing and starving normal, healthy cells. Sometimes cancer cells can leave a tumor, enter the blood stream, and cause cancer in other parts of the body; this migration of cancer cells across the body is called metastasis. The DNA of cancer cells shows mutations in not one but several genes, including proto-oncogenes, tumor suppressor genes, and DNA repair genes. Some of these mutations occur in sperm or egg cells and can be inherited by subsequent generations. Other mutations can occur in normal cells undertaking the normal growth and repair processes in the body.
CARRIER FREQUENCY a ratio showing the number of individuals in a group who have inherited ("carry") one mutated copy (allele) of a gene. Carriers are not affected by the disease caused by the mutated gene, but they have a 1 in 2 chance of transmitting that mutation to a child. Carrier frequency is important for genetic counseling. Because an autosomal recessive disease must be inherited from both parents (one mutant allele from each parent), the risk that any carrier will have an affected child partly depends on the carrier frequency of the general population. In some cultural groups, carrier frequencies for a particular disease are much higher than in the general population. For instance, among Ashkenazi Jews in the U.S., the carrier frequency for Tay-Sachs disease is 1 in 30; this means that for every 30 individuals of Ashkenazi Jewish descent there is one who carries the gene mutation responsible for this disease. The carrier frequency for non-Ashkenazi Caucasians in the U.S. is 1 in 170.
CELL the basic unit of all forms of life. Humans are composed of an unknown number of cells predicted to be in the trillions. Humans have different types of cells, like skin cells, liver cells, brain cells, or sex cells, and each type of cell performs a particular function. Cells have several internal structures that serve to separate different types of biochemical reactions. One of these structures is the nucleus. Because the chromosomes are located in the nucleus, the complex biochemical reactions involving the genetic material (DNA) occur in the nucleus.
CHARCOT-MARIE-TOOTH DISEASE one of the most common hereditary peripheral neuropathies (disease that affects the peripheral nerves), characterized by slowly progressive muscle wasting with muscle weakness and loss of sensation primarily affecting the legs. Patients progressively lose the ability to walk and feel. Different forms of CMT can be caused by mutation in any of over twenty different genes, and the disease can be inherited in an autosomal dominant, autosomal recessive, or X-linked pattern. The prevalence of CMT is 40 per 100,000 in the general population.
CHROMOSOME a very long molecule of DNA found in the nucleus of a cell. Genes are small segments of chromosomes, and any chromosome may have hundreds to thousands of genes. Different life forms have different numbers of chromosomes. Life forms that reproduce by sexual reproduction (contributions to the offspring from different parents, i.e., male and female) have two copies of each of their chromosomes. Humans have a total number of 46 chromosomes: 22 pairs of autosomes (chromosomes that contain genes for the various parts and functions of the body) and one pair of sex chromosomes (chromosomes that contain, among other genes, the genes that determine if a life form is male or female). With one exception, each time humans make new cells they must make and place 46 chromosomes (two copies of each chromosome) in each new cell. In the case of making new sex cells (sperm and egg cells), however, humans must place only 23 chromosomes (one copy of each chromosome) into each new cell; in this way, when a sperm cell fertilizes an egg cell the total number of chromosomes will be 46, the normal number of chromosomes in human cells. The special process of making sperm or egg cells with only 23 chromosomes is called meiosis. On rare occasions, an extra copy of one of the chromosomes remains in a sperm or egg cell after meiosis; if this abnormal cell participates in fertilization, the child resulting from that fertilization will have three copies of a particular chromosome, a condition called trisomy. Because an extra chromosome will carry an extra set of genes, trisomy will invariably cause medical problems. Most trisomies are not compatible with life, causing false pregnancies or stillbirths; those that are compatible with life result in cases like Down syndrome, which is a trisomy of chromosome 21. In the same way that an extra chromosome can remain in a sperm or egg cell, a chromosome can be missing from a sperm or egg cell, resulting in a monosomy, where cells contain only one copy of one of the chromosomes.
CLEFT LIP and CLEFT PALATE fissures in the upper lip and the palate (the bony plate between the oral and nasal cavities), caused by incomplete closing of the two sides of the face in the developing, bilateral embryo. Cleft lip and cleft palate often occur together and are often but not always associated with mutations of chromosome number and with chromosome deletions. Both can be repaired surgically.
CONGENITAL any condition present at or before birth. Many congenital conditions are not noticeable until several and sometimes many years after birth.
DIABETES a group of diseases generally characterized by excessive urination and thirst. In the most well known type, diabetes mellitus (DM), these symptoms are caused by the body's inability to remove excess sugar from the blood. Sugars, especially glucose, arrive in the blood either through digestion of foods or from release by the liver, where it is stored for use between meals. Blood transports glucose to all cells of the body, and inside cells glucose is burned to release energy used to keep cells alive and healthy. The hormone insulin, which is made by specific cells in the pancreas and secreted into the blood stream, forces cells to absorb glucose, thereby removing it from the blood. In Type I DM, the pancreas does not produce enough insulin, resulting in high blood glucose levels (hyperglycemia). The Type I disease is also known as Insulin-Dependent Diabetes Mellitus (IDDM), and this is the type most commonly diagnosed in individuals younger than 30 years. Most patients with IDDM have inherited a genetic susceptibility that allows the immune system to destroy insulin-producing cells. The Type II disease, Non-Insulin Dependent Diabetes Mellitus (NIDDM) is the most common type seen in patients over age 30. In NIDDM, there are usually three simultaneous problems: (i) impaired insulin secretion, (ii) a decreased effectiveness of insulin in stimulating absorption of glucose by cells of the body, and (iii) a decreased effectiveness in slowing down glucose release from the liver. There is a close association between NIDDM and obesity, and the late twentieth century epidemic of NIDDM in the U.S. may be related to the high-calorie, low-exercise lifestyle of the general population. In addition, many ethnic groups have high incidences of NIDDM, including Native American Indians. Early symptoms of DM, including fatigue, blurred vision, nausea, and a tendency toward dehydration, are due mainly to hyperglycemia. Later complications of DM include progressive, severe, and sometimes fatal problems with blood vessels (peripheral vascular disease), kidneys (nephropathy), retina (retinopathy), nerves (neuropathy), and skin (ulcers and infections). Fortunately, a variety of insulin preparations and glucose-lowering drugs are available and are effective at increasing the quality of life for affected patients. A different group of diseases known as diabetes insipidus (DI) can be caused by mutations in genes that control the function of anti-diuretic hormone (ADH), the major hormone of water balance in the body.
DNA short for Deoxyribose Nucleic Acid (also written deoxyribonucleic acid). DNA is the chemical that serves as the genetic (or heritable) material. Molecules of DNA are the material passed from parents to offspring, carrying all the information to properly make the new organism. DNA is a very long polymer - a large molecule made of many small, similar molecules (monomers) connected together. The small molecules that make DNA are called nucleotides, and there are four different deoxyribonucleotides in the DNA of all forms of life: adenosine, cytidine, guanosine, and thymidine, better known as A,C,G, and T. It is difficult to imagine how these four small molecules can direct all the structures and behaviors of a life form as complex as a human being until the realization that there are three billion nucleotides in human DNA, each precisely placed in a long sequence. Specific sequences of 1000-100,000 nucleotides that direct the manufacture of specific proteins are called genes. We estimate that humans have about 35,000 genes, and these genes are small parts of very long DNA molecules 50 -250 million nucleotides long) called chromosomes. Each chromosome consists of two DNA molecules twisted around one another in structure known as the double helix. The double helix is coiled tightly around itself, such that about six feet of DNA is tucked and folded inside each cell of the body in a structure called the nucleus, which cannot be seen without a microscope. Changes in the nucleotide sequence of a gene are called mutations, and mutations can sometimes lead to the manufacture of defective proteins, which, in turn, can cause genetic disease.
DOMINANT the form of a gene that is expressed into protein. Because sexually reproducing life forms possess two copies of each chromosome, individuals contain two copies of each gene. The two copies, however, may not be identical, and therefore any individual can contain two different forms of the same gene. These different forms are called alleles. In fact, we may be able to see the effect of a protein made only by one allele. The allele that is expressed into protein is called dominant. The other allele whose expression is hidden, or which does not express protein at all, is called recessive.
DOWN SYNDROME a congenital condition characterized by moderate to severe mental retardation, slanting eyes, a broad and short skull, broad hands, and short fingers. Other abnormalities include heart defects, abnormal opening (atresia) of the esophagus, and an increased incidence of acute lymphocytic leukemia. DS can be detected in the first few months of pregnancy by amniocentesis, the sampling of fluid surrounding the fetus that contains fetal cells and therefore fetal chromosomes. The two major risk factors include (i) having a DS child from a previous pregnancy and (ii) pregnancy after age 40. DS is typically caused by the inheritance of an extra copy of chromosome 21, and for this reason it is commonly called Trisomy 21.
ENZYME a protein whose function is to speed and control a chemical reaction in the body. Because enzymes are proteins, the information to make them is encoded in specific genes.
EXPANSION MUTATION an unusual type of mutation in which a small set of nucleotides is repeated many times in a chromosome, leading to an abnormal gene structure that adversely affects expression of the gene product. The gene defect causing Friedreich ataxia in Acadians, for example, is an expansion mutation in which three nucleotides are repeated hundreds of times, making expression of the frataxin gene impossible.
EXPRESSION the production of a functional protein from a gene. Expression involves many steps and complicated chemical reactions, including those of transcription and translation. In humans and other complex life forms, expression may also include removal of unnecessary sequences of nucleotides from the messenger RNA (a process called splicing) and chemical modification of a newly translated protein (called processing).
FRIEDREICH ATAXIA (FA) a progressive, neurodegenerative disorder that involves both the central and peripheral nervous systems. FA shows an autosomal recessive pattern of inheritance and is characterized by muscle weakness, decreased or absent reflexes of the lower limbs, gait ataxia (inability to coordinate voluntary muscular movements which leads to unstable walking), dysarthria (difficulty in articulating words), and sensory disturbances. The disease in Acadian patients shows a slower progression, a slightly later age of onset, and a later age at death than that in non-Acadians. In addition, patients with the Acadian form of the disease have less marked symptoms and fewer complications than non-Acadian patients. The gene causing Friedreich ataxia has been discovered on chromosome 9 and is called frataxin. The clinical differences in the Acadian disease may be due to a different range of sizes of an expansion mutation in the frataxin gene. The frataxin protein has a function in mitochondria that probably involves the way cells use the mineral iron. The prevalence of this disease in the general population is 1-2/100,000.
GENE the unit of heredity. A gene is a small segment of a very large DNA molecule called a chromosome. Humans contain about 35,000 different genes among their 23 pair of chromosomes. Most genes encode proteins; that is, a gene contains the information to make one or more proteins. Because DNA never leaves the cell nucleus and because proteins are made outside the nucleus, the information contained in a gene must be copied into another molecule - a messenger RNA (mRNA) molecule - before it can direct the manufacture of a protein. mRNA molecules are transported out of the cell nucleus and into the cytoplasm, where proteins are made. The process of converting the information contained in an mRNA molecule into the structure of a protein is called translation. A small number (about 800 in humans) of genes encode small RNA molecules that are essential parts of important and complex biochemical reactions, including translation.
THE GENETIC CODE the rules that govern the conversion of the nucleotide information of a messenger RNA (mRNA) molecule into the amino acid information of a protein (translation). Specific sets of three nucleotides (codons) in a mRNA molecule direct the placement of a single amino acid in a protein. For instance, the sequence of A,U, and G nucleotides in a specific RNA molecule will direct the placement of the amino acid methionine in a protein being made. Because the nucleotide sequence of a mRNA represents the nucleotide sequence of a gene from which it was copied (transcribed), genes are said to encode proteins. A complex of multiple proteins and RNA molecules are involved in the manufacture of proteins. This manufacture, called translation, occurs in the cytoplasm of cells on internal cell structures called ribosomes. The genetic code also contains codons that tell ribosomes where to start and where to stop translating a mRNA molecule. The genetic code is almost universal for all forms of life.
GENOME the complete contents of the genetic material (DNA) of a life form. The human genome contains about 35,000 genes on 23 long DNA molecules, called chromosomes, located in the nucleus of all cells. Together, the long DNA molecules are polymers of about three billion nucleotides, but less than 2% of the nucleotides in these DNA molecules encode proteins. The remaining 98% of the genome (i) is involved in the control of gene expression, (ii) is important for maintaining the structure of the chromosomes and their stability, and (iii) is the result of small segments of nucleotides (called repeats) that have been duplicated repeatedly over millions of years. We predict that the 25,000 genes of the human genome can make about 85,000 different proteins and about 800 different small RNA molecules. Because of their location in the nucleus of the cell, the 23 long chromosomes (which occur in pairs - 46 total) and the genes they contain are called the nuclear genome. Mitochondria also have a genome - a single, much smaller DNA molecule that occurs in many (100-1000) copies inside each mitochondrion. Unlike the nuclear genome, nearly 100% of the mitochondrial genome in humans is made of genes.
HARMONIN the gene mutated in Acadian Usher syndrome (Type Ic Usher syndrome). In Acadians with the Type Ic disease, the mutation prevents cells from making the protein encoded by the harmonin gene. Although the function of the harmonin protein is not yet known, its presence in retinal and inner ear cells suggest that it plays a role in hearing and vision. Because lack of the harmonin protein causes the deafness and blindness of Usher syndrome, the role of the harmonin protein must be an important one.
THE HUMAN GENOME the complete contents of the genetic material (DNA) of in humans. The human genome contains about 35,000 genes on 23 long DNA molecules, called chromosomes, located in the nucleus of all cells. Together, the long DNA molecules are polymers of about three billion nucleotides, but less than 2% of the nucleotides in these DNA molecules encode proteins. The remaining 98% of the genome (i) is involved in the control of gene expression, (ii) is important for maintaining the structure of the chromosomes and their stability, and (iii) is the result of small segments of nucleotides (called repeats) that have been duplicated repeatedly over millions of years. We predict that the 25,000 genes of the human genome can make about 85,000 different proteins and about 800 different small RNA molecules.
MEIOSIS the process of cell division that creates sperm and egg cells with only half the number of chromosomes of a normal cell. In humans, the normal number of chromosomes in the nuclei of all cells is 46-one pair of each of 23 chromosomes. After meiosis, a parent cell in a testis or an ovary will give rise to 1-4 daughter cells, each containing only one chromosome from each pair in the parent cell. Meiosis is essential in maintaining the stability of genetic material in sexually reproducing organisms, allowing genetic contributions from each of two parents while restoring the normal chromosome number at the same time. A special event called crossing over takes place in a parent cell at the beginning of meiosis. Crossing over involves the equivalent exchange of DNA between members of a chromosome pair, resulting in new combinations of slightly different nucleotide sequence. Therefore, each sperm cell or egg cell that derives from meiosis will be genetically unique, ensuring that each child will look different not only from either parent but from siblings as well.
MESSENGER RNA the copy of a gene made by the process of transcription. Because DNA molecules are very large and cannot leave the nucleus of the cell, the information it contains (the genes) must be copied into small molecules that can be transported out of the nucleus and into the cytoplasm where the manufacture of proteins takes place. Messenger RNA (mRNA) molecules are these small molecules. One or more mRNA molecules are transcribed from a specific gene and contain information stored in the gene to direct the manufacture of one or more proteins. mRNA molecules are often much smaller than the genes from which they are transcribed, because genes contain more nucleotides than are necessary to make a protein. RNA molecules are polymers of nucleotides, similar to the nucleotides that comprise DNA. Proteins, however, are polymers of amino acids. Therefore, during the manufacture or proteins from mRNA molecules, the chemical language of nucleotides must be converted to the chemical language of amino acids, a process called translation.
METASTASIS the migration of cancer cells from one site to another site in the body, where a new tumor is formed similar to the original tumor. For instance, a lung tumor cell metastasizes to the brain and forms a new cancer in the brain. In most types of cancer, metastasis of cancer cells occurs through the blood.
MITOCHONDRIA an organelle within a cell that is involved in the production of energy molecules from the remnants of food molecules in the presence of oxygen. Because energy production is such an important part of normal health, particularly for parts of the body that require lots of oxygen, like muscles, kidneys, eyes, ears, and the brain, problems with mitochondria can cause medical problems. A mitochondrion contains its own DNA that directs the manufacture of a few of its own proteins. Mitochondrial DNA is ten times more susceptible to mutations than chromosomal DNA in the nucleus, and some of these mutations can cause complex medical problems that can show symptoms differently in different individuals. Further, different cells of a particular organ can have different numbers of mutated mitochondria, making mitochondrial diseases highly variable. Because sperm cells are unlikely to transmit mitochondria during fertilization, all the mitochondria in each of the cells in a person's body have been inherited from the egg cell of the mother. A mutation in mitochondria therefore shows a unique pattern of inheritance called maternal inheritance.
NEUROFIBROMATOSIS one of several different diseases that results in benign or malignant tumors of the nervous system. Neuofibromatosis Type 1 (also known as classic neurofibromatosis, von Recklinghausen disease, or Elephant Man's Disease) is usually characterized by multiple neurofibromas emerging from the surface of the skin. Many patients also exhibit café-au-lait spots (light-brown patches of skin) and Lisch nodules (small, dark spots on the iris of the eye). Type 1 disease is caused by mutation of the neurofibromin gene on chromosome 17. The neurofibromin protein functions in activating specific types of chemical reactions inside nerve cells. Neurofibromatosis Type 2 (also known as central neurofibromatosis or acoustic neurofibromatosis) causes tumors in one of the cranial nerves (the acoustic nerve; the tumors are sometimes called acoustic neuromas). Type 2 disease is caused by mutation of the schwannomin gene on chromosome 22. Neurofibromatosis Type 1 is one of the most common of the genetic diseases, with a frequency of about 1 in 3000. According to the findings of Lacassie, neurofibromatosis is the most common single-gene genetic disorder seen in clinics in Acadiana. Both disease types show autosomal dominant (AD) inheritance.
NIEMANN-PICK DISEASE an autosomal recessive disease caused by deficiency of the enzyme sphingomyelinase, which leads to accumulation of lipids (fat-like molecules) in organs such as liver, spleen, bone marrow, and brain. The abnormal storage of lipids produces enlargement of the liver and spleen. There is also anemia (reduced number of red blood cells) and thrombocytopenia (reduced number of blood platelets) due to involvement of the bone marrow. Involvement of the nervous system results in muscle weakness that manifests as feeding problems, which in turn causes decreased body weight and growth. Those types of the disease involving the central nervous system cause loss of motor function and deterioration of intellectual capabilities. There are five clinical subtypes of this disease. According to the subtype, the severity and age of onset are variable. In some subtypes, the age at death varies. Certain subtypes of this disease are found more frequently in specific cultural groups. For instance, among Ashkenazi Jews, the carrier frequency is 1 in 80; this means that for every 80 individuals of Ashkenazi Jewish descent there is one who carries the gene mutation responsible for this disease. The incidence of the disease among Ashkenazi Jews is estimated to be about 1 in 25-40,000. This disease is also found among Acadians.
NUCLEUS the part of the cell that contains the chromosomes. The nucleus is a self-contained internal component of the cell (called an organelle) that protects the genetic material from the rest of the cell. The chromosomes are surrounded by a gel-like nucleoplasm that is contained by a double-layered nuclear envelope. The nuclear envelope separates the nucleoplasm from the cytoplasm, the gel-like material of the rest of the cell. Different chemical reactions take place in these two gels, and by separating them the cell can prevent chemical reactions in the cytoplasm from interfering and potentially damaging those inside the nucleus. Furthermore, only certain chemicals can pass into or out of the nucleus. Genes are contained inside the nucleus as parts of chromosomes, but proteins made from the genes are made outside the nucleus in the cytoplasm. The information contained in a gene is transcribed (copied) into one or more messenger RNA molecules and shipped across the nuclear envelope, out of the nucleus and into the cytoplasm where it is translated into protein.
ONCOGENE the mutated form of a gene (a proto-oncogene) that normally promotes the division of cells. Oncogenes cause uncontrolled cell division, leading to the formation of a tumor. Over 100 different oncogenes have been recognized among the human chromosomes.
OSTEOGENESIS IMPERFECTA one of several different diseases characterized by a tendency to bone fractures with minimal trauma, abnormal curvatures of the spine, blue schlerae (the whites of the eyes), and tooth problems. Mutations in seven different genes have been found to cause the disease. Types I-IV are caused by defects in one of the collagen genes. Collagens are a family of proteins important for the proper formation and maintenance of bone structure.
PROTEINS the functional molecules of the cell. Specific proteins undertake specific and important functions of the body: Enzymes, antigens, antibodies, some hormones, and carrier proteins of the blood (albumins) are all proteins. Proteins also make up a large proportion of the structure of each cell. The body makes all these proteins from information stored in genes. (Proteins are encoded by genes.) Proteins are long and complex molecules; they are polymers made of smaller molecules (monomers) called amino acids. Because proteins are polymers of amino acids but genes are polymers of nucleotides, the cell must perform very important and complex reactions to convert information from one form (nucleotides) to the other (amino acids). First, a specific gene, located in the nucleus as part of chromosome, must be transcribed into messenger RNA (mRNA). Both DNA and mRNA are polymers of different forms of the same nucleotides. The specific mRNA, containing the nucleotide sequence of the gene, is transported out of the nucleus and into the cytoplasm, where it is converted into an amino acid polymer (a protein) in a process known as translation. Because the sequence of nucleotides in a mRNA molecule represents the sequence of nucleotides in a gene, a mutation in a gene will also appear in the mRNA molecule, resulting in an abnormal sequence of amino acids in the specific protein. Mutations in genes can cause medical problems because they cause the formation of abnormal proteins, which then cannot perform their specific function in the body. Some mutations are so severe that the specified protein cannot be made at all.
PROTO-ONCOGENE one of several genes that promote the division of cells (also called cell growth). The body grows and repairs because two new cells can be produced from the division of a single cell. (And four cells can be produced from the division of these two cells; in this way, over 1000 cells will be made from just ten sets of divisions.) The division of cells is strictly controlled by the body, but when a cell has a mutation in a proto-oncogene it can grow and divide uncontrollably, leading to the formation of a tumor. Mutated proto-oncogenes are called oncogenes.
RECESSIVE the form of a gene that is hidden by expression of a different form. Because sexually reproducing life forms possess two copies of each chromosome, individuals contain two copies of each gene. The two copies, however, may not be identical, and therefore any individual can contain two different forms of the same gene. These different forms are called alleles. In fact, we may be able to see the effect of a protein made only by one allele. The allele that is expressed into protein is called dominant. The other allele whose expression is hidden, or which does not express protein at all, is called recessive.
RELATIVE RISK the ratio of the risk of a disease in an exposed person compared to the risk in an unexposed person. For instance, if the risk of developing lung cancer is 10 times the risk for someone who does not smoke, then the relative risk is said to be 10. The risk is 10 in the smoker and 1 in the non-smoker. In another example, the risk of developing lung cancer in someone with constant exposure to passive smoke (for example, the spouse of someone who smokes) is about 1.5 times higher than the risk for a non-smoker. The relative risk for developing lung cancer of a spouse of a smoker as compared to a non-smoker who is not exposed to passive smoke is 1.5.
RETINITIS PIGMENTOSA (RP) a degeneration of the retina, characterized by night blindness, narrowing of the visual field, narrowed retinal blood vessels, and retinal pigmentation. Visual acuity is usually preserved until late in the disease. RP represents several distinct diseases, caused by mutation in any of several different genes. Different types of RP are heritable in autosomal dominant, autosomal recessive, and X-linked recessive fashions. The overall frequency in the U.S is 1 in 3,700. The highest incidence known is in the Navajo Indians with 1 in 1,800 affected. Sometimes RP is found together with another disease, like with deafness in Usher syndrome.
SEX CELLS cells contributed by male and female parents during sexual reproduction. In humans, these cells are the sperm cell (manufactured in the testes and contributed by males during reproduction) and the egg cell (manufactured in the ovaries and contributed by females during reproduction). Sex cells contain only half the number of chromosomes (23 in humans) that other cells contain (46, or one pair each, in humans), such that after fertilization (the fusion of sperm and egg cells into a zygote, the single-celled stage of the embryo) cells of the offspring contain normal number of chromosomes (46) found in each of the parents. Because children grow from zygotes containing chromosomes (and therefore genes) from each parent, they will show features of each parent. Children of the same family show different features than each other, however, because each sperm and egg cells contains slightly different gene information in their chromosomes (see crossing over). If one or both parents have a mutation, then that mutation will be carried by the sperm or egg cell and become part of each cell in the child's body.
SEX CHROMOSOMES chromosomes that carry the genes determining gender (maleness or femaleness). In humans, the chromosomes are known as X and Y. Each human has a pair of these chromosomes: females carry two X chromosomes (and are called XX) and males carry one X and one Y (called XY). The Y chromosome is very small and contains only relatively few genes. One of these genes is responsible for the production of testes in the fetus, and, in turn, testes produce hormones like testosterone, which promote the appearance and behavior characteristic of males. The X chromosome is large and contains many genes, and these genes are called X-linked (or sex-linked) genes. Mutations in X-linked genes will have different effects in males and females: Because males have only a single X chromosome, a mutation in an X-linked gene will likely express itself as an abnormality. However, because females have two X chromosomes, a mutation in a gene on one can be counteracted by a normal (unmutated) gene on the other. The expression of a mutated X-linked gene is called X-linked inheritance.
SEX-LINKED INHERITANCE one of the basic patterns of inheritance. Sex-linked inheritance refers to the inheritance of genes that are part of the sex chromosomes, those chromosomes containing genes determining maleness and femaleness in humans. Often, sex-linked inheritance refers to X-linked inheritance, because the X-chromosome is large and, like the autosomes, contains many genes that control normal body structures and reactions. Like autosomal inheritance, X-linked inheritance can be X-linked dominant or X-linked recessive. X-linked inheritance is different in males and females, because females have two X-chromosomes (including two copies of each gene on the X-chromosome) and males have only one X-chromosome (and only one copy of each gene on the X-chromosome). Instead of a second X-chromosome, males have a Y-chromosome, which is a small chromosome containing a small number of genes, all of which seem to be involved in maintaining characteristics of maleness. These genes are called Y-linked, and Y-linked inheritance occurs only among males across generations. For the same reason, X-linked inheritance never occurs between males across generations.
SPLICING the removal of sequences of nucleotides from a messenger RNA (mRNA) molecule that are not involved in translation (the manufacture of a protein from a mRNA molecule). Because mRNA is a copy of a gene, the unnecessary nucleotide sequences are also found in DNA and are therefore susceptible to mutation. Despite the fact that these sequences are not important for the manufacture of a protein, mutation in these sequences can cause genetic problems. Such mutations can change either the structure or abundance of mRNA molecules, which in turn alters the structure or abundance of proteins that can be manufactured, and thereby alters the function or efficiency of the protein in the cell.
TAY-SACHS DISEASE a progressive, neurodegenerative disease characterized by muscle weakness, apathy, increased startle response, developmental retardation, dementia, seizures, deafness, and blindness. The age of onset is between three and six months, and death usually occurs by age 3. The disease is autosomal recessive and is caused by deficiency of the enzyme hexosaminidase due to gene mutation. Tay-Sachs is more common in Ashkenazi Jews, among whom the carrier frequency is 1 in 25. The incidence in Acadians is also increased relative to the general popualtion, with a gene frequency of 1 in 100.
TRANSLATION the set of chemical reactions in the cell cytoplasm that builds proteins from amino acids using directions contained in mRNA molecules. Translation occurs on structures in the cytoplasm called ribosomes, which, during protein building, are responsible for holding in proper positions and all at the same time an mRNA molecule, a fragment of newly-built protein, and new amino acids to be added to the protein fragment. Translation is so named because the process converts or translates the language of DNA (nucleotides) into the language of protein (amino acids).
TRANSCRIPTION the set of chemical reactions in the cell nucleus that copies a small segment of a chromosome containing a gene into a molecule that can travel out of the nucleus for translation. Because DNA and all the genes in it need to be protected from the rest of the cell, only copies made from small segments of chromosomes are allowed out of the nucleus, thereby allowing the chromosomes to remain behind and intact. The small segment copy that travels out of the nucleus is known as a messenger RNA (mRNA) molecule, and a mRNA molecule contains a sequence of nucleotides that represents the sequence of nucleotides of chromosomal DNA that specifies a particular gene. Each gene in the human genome makes one or more mRNAs, and each mRNAs serves as the set of directions for the sequence of amino acids in a particular protein. Transcription is so named because the process copies or transcribes the nucleotide message of a gene into the nucleotide message of an mRNA molecule.
TRISOMY a condition in which the cells of an individual contain an extra copy of one of the chromosomes. Trisomy arises during meiosis when chromosomes fail to separate properly into daughter cells. Having an extra copy of a chromosome implies that an extra copy of each of the genes of that chromosome is present also, and too many copies of certain genes can cause severe medical problems. For this reason, trisomies of large chromosomes, like chromosome 1 in humans, are not seen, because such situations are not compatible with life. (In other words, a zygote containing an extra copy of one of the larger chromosomes does not develop into an embryo or fetus.) However, trisomies of smaller chromosomes, like chromosome 21, are not uncommon in genetics clinics. Trisomy 21 is also known as Down syndrome. Another type of trisomy involves the X chromosome (Triple-X syndrome), where a woman has three copies of the X chromosome in each of her cells rather than the normal pair of X chromosomes. Like Trisomy 21 and other trisomies, Triple-X syndrome is characterized by mental retardation among other medical problems.
TUMOR SUPPRESSOR GENE one of several genes that functions normally to stop cell growth. Mutation in a tumor suppressor gene can lead to uncontrolled cell growth and tumor formation.
USHER SYNDROME a collection of medical problems first described in 1858 that includes both hearing and vision problems. The syndrome is named after British physician Dr. Charles Usher, who in 1914 was the first to note that the hearing and vision problems could be inherited. In Usher syndrome, the hearing problems can range from congenital (occurring from birth) to progressive (worsening over time) and can range from severe, profound deafness to mild deafness. The vision problem, also known as a separate disease called retinitis pigmentosa (RP), is almost always progressive, becoming first noticeable in the second decade of life. Based on the severity and onset of sensory problems, we can recognize three clinical types of Usher Syndrome. In Type I Usher syndrome, children are born profoundly deaf, and the inner ear defect causing deafness is so severe that problems with balance may occur; the RP in the Type I disease is usually noticeable in the first to second decade of life. In Type II Usher syndrome, the hearing problems are less severe, and hearing aids may be useful in these patients; the RP in Type II disease usually noticeable in the third to fourth decades of life. In Type III Usher syndrome, both the hearing and vision problems are progressive, and the time in which RP is noticeable is variable. In Acadiana, Usher syndrome was first reported by Kloepfer in 1966 in a survey of government-sponsored hospitals for the deaf. The majority of Acadians with Usher syndrome have Type I disease, the most severe type. The prevalence of Type I disease in the general population is about 2.4 per 100,000, and a conservative estimate for Type I disease among Acadians is 4.4 per 100,000. Usher syndrome is actually a collection of at least ten distinct diseases, each the result of mutation in a different gene. In the year 2000, the gene causing Type I Usher syndrome in Acadians was discovered. The gene is called harmonin, and the protein encoded by the harmonin gene is found in both inner ear and retinal cells. The mutation in the harmonin gene inherited by patients with Type I disease prevents their cells from making the harmonin protein. The function of the harmonin protein, and how its absence causes Type I Usher syndrome, is not yet known.
VON HIPPEL-LINDAU DISEASE (VHL) an autosomal dominant disease characterized by tumors of blood vessel cells. These tumors can form in the retina, brain, spinal cord, pancreas, kidneys, and other organs. Because it is difficult to predict where (in which organ) and when (at what age) these tumors will cause problems, VHL patients must have regular medical examinations. Mutation in the VHL gene on chromosome 3 causes VHL disease. In addition, most non-heritable kidney cancers also contain mutations in the VHL gene.
X-LINKED DOMINANT INHERITANCE one of the basic patterns of inheritance. In dominant inheritance, a defect in only one of the two copies (alleles) of a gene leads to a disorder. In other words, a person affected with the disorder inherited a defective allele from only one parent. When the defective allele is part of one of the X-chromosome, the disorder it causes is called X-linked dominant. An X-linked dominant disorder is inherited through generations in a particular pattern, and, because females have two X-chromosomes and males only one, females and males are affected differently: (i) Affected males transmit the disorder to all of their daughters but none of their sons; (ii) affected females with one defective gene will transmit the disorder to half of their children, with males and females equally affected; (iii) affected females with both genes defective will transmit the disorder to all of their children; (iv) twice as many females as males will have this disorder, unless the disorder is lethal in males.
X-LINKED RECESSIVE INHERITANCE one of the basic patterns of inheritance. In autosomal recessive inheritance, a defect in both of the two copies (alleles) of a gene leads to a disorder. In other words, a person affected with the disorder inherited one defective allele from each parent. When the defective alleles are part of one of the X-chromosome, the disorder it causes is called X-linked recessive. An X-linked recessive disorder is inherited through generations in a particular pattern, and, because females have two X-chromosomes and males only one, females and males are affected differently: (i) Nearly all affected persons are male; (ii) affected males never transmit the disorder to their sons; (iii) all daughters of an affected male will be carriers; (iv) carrier females transmit the disorder to half of their sons; (v) half the daughters of carrier females will themselves be carriers; (vi) an affected male and a carrier female will, on average, transmit the disorder to half of their daughters and half their sons.