Genetic information is coded within DNA. This information is packaged into chromosomes that are present in cell nuclei. In humans, 46 chromosomes contain an estimated 30,000–50,000 gene pairs. DNA contains four distinct molecules (base pairs). These four base pairs code the information that controls growth, development, and function by providing a template for message molecules called RNA. RNA molecules are involved in the process of transcription (changing a DNA message into a protein) as well as in providing molecules that regulate expression, make the hardware within the cell for building proteins (ribosomes), and also perform many housekeeping functions.
With the exception of red blood cells and egg/sperm cells, there are 23 pairs of chromosomes in human cell nuclei. One of each pair comes from each parent. Twenty-two of these pairs match up and contain copies of the same genes (although the copies may not be identical). These chromosomes are assigned numbers, and they are called autosomes. Then, there are two sex chromosomes: X and Y. Females have two X chromosomes; males have one X and one Y chromosome. The Y chromosome is unique to males and contains genes that determine male structure and function and also affect fertility. The Y chromosome contains very few genes, but its presence or absence determines male or female development. Genes, like chromosomes, come in pairs, except for genes on the sex chromosomes.
Autosomal dominant inheritance. Within one gene pair, an abnormality in a single copy of the gene may produce a disorder. A person with such a gene combination would have a theoretic 50–50 chance of passing this gene on to any offspring. Dominant disorders may therefore be inherited from a parent, or they may arise as a new mutation in an egg or sperm cell that participates in fertilization. For many dominantly inherited conditions, manifestations of the disorder are not consistent. This observation is known as variable expression. Examples of dominantly inherited disorders include Huntington disease, neurofibromatosis, familial hypercholesterolemia, and hereditary colon cancer (Chart 11.2).
One form of diabetes, type 2, is an example of autosomal dominant inheritance, although not all cases are hereditary. Diabetes, a disorder of carbohydrate metabolism, can be divided into two categories: type 1 diabetes (T1D) (juvenile onset or insulin dependent) and type 2 diabetes (T2D) (adult onset or non–insulin dependent). The cause of diabetes is deficient insulin action (insulin action is equal to the product of insulin concentration [B-cell control] and insulin sensitivity [target cell function]). Deficient insulin action leads to disordered carbohydrate, lipid, and protein metabolism. T1D results from insulin deficiency; T2D results from a combination of insulin resistance and relative insulin deficiency.
About 7%–10% of breast cancers show an autosomal dominant inheritance pattern. Mutations of the BRCA1 (breast cancer 1) and BRCA2 (breast cancer 2) genes, found on chromosomes 17 and 13, respectively, account for most breast cancers. Individuals who test positive for mutations should be monitored closely (monthly self-breast examinations and annual or semiannual clinic follow-up), consider chemoprevention (e.g., tamoxifen), and possibly undergo prophylactic surgery (controversial).
T1D: Autoimmune diabetes may result from an interaction of genetics and the environment and results in an absolute insulin deficiency. T1D resulting from autoimmune destruction of pancreatic B cells is not inherited, but susceptibility to type 1 disease is. The major genetic loci indicative of susceptibility to type 1 are located in the HLA complex: DRBI, DQAI, and DQBI.
T2D: Patients with T2D (due to insulin resistance and B-cell failure) often have a first-degree relative with the disease and a genetic predisposition to T2D resulting in a restricted ability of the B cells to secrete insulin. T2D is inherited as a dominant gene, although not all cases are hereditary. Persons at risk include those with a family history and those who develop gestational diabetes. T2D has been associated with metabolic syndrome. Metabolic syndrome is defined as having at least three of the following conditions: hypertension, obesity, hyperglycemia, hypertriglyceridemia, and low high-density lipoprotein cholesterol.
Autosomal recessive inheritance. Both copies of the gene pair must not function correctly for a problem to be apparent. If both parents carry the same nonfunctional gene, there is a one-in-four chance that any child could inherit two nonfunctional copies, leading to possible disease. Examples of autosomal recessively inherited diseases include cystic fibrosis, sickle cell disease, Tay-Sachs disease, some nonsyndromic early-onset hearing loss, and recurrent pyogenic infections. Primary hemochromatosis, an example of an inherited autosomal recessive disease, is caused by a mutation of the HFE gene. This disorder is characterized by excessive absorption and accumulation of iron resulting in tissue damage and subsequently organ damage, such as liver dysfunction. This disorder, treated by phlebotomy at regular intervals (about 500 mL of blood per week, which equates to about 250 mg of iron), is fatal if not diagnosed early. Genotyping is done of the HFE gene to include the C2824 and H63D mutations.
X-linked recessive inheritance. Males have only one X chromosome, so that abnormal genes on the X chromosome can cause problems. Females have a second X chromosome, which usually masks the effects of an abnormal gene, although not always completely. A woman with a disease-causing gene on one X chromosome would have a 50–50 chance of passing this gene to any child, and this is independent of their 50–50 chance of having a son. Examples of X-linked disorders include hemophilia and Duchenne muscular dystrophy.
Multifactorial inheritance. Some developmental processes, as well as some adult disease states, are influenced by the interactions of many genes associated with environmental factors. Examples of multifactorial disorders include pyloric stenosis, cleft lip and palate, spina bifida, and schizophrenia.
Cytogenic inheritance. Chromosomal abnormalities may include abnormal numbers of chromosomes (e.g., Down syndrome is caused by three copies of chromosome 21). Chromosomal rearrangements, called translocations, can be unbalanced, causing multiple congenital abnormalities. A molecular abnormality within a single gene can cause structural differences like fragile X syndrome. Submicroscopic deletions of chromosomes can be studied using fluorescent in situ hybridization. Examples of human syndromes caused by microdeletions include Williams syndrome and DiGeorge syndrome.
Mitochondrial inheritance. Separate from the nucleus of the cell are the energy-processing organelles called mitochondria. These organelles possess a unique set of genes on a single chromosome. Mutations in these genes can cause a wide variety of disorders, including neuromuscular disorders. Examples include Kearns–Sayre syndrome and Leber hereditary optic neuropathy. Mitochondria are inherited exclusively from the mother.
Nontraditional inheritance. Some human genes are sensitive to modification (known as imprinting or methylation) that alters gene expression, depending on the gender of the parent in which the gene originates. Some human syndromes are caused by the presence of two copies of a gene or chromosome originating from one parent and none from the other (called uniparental disomy). Examples include Beckwith–Wiedemann syndrome and Prader–Willi syndrome.