In most cases, EDMD is inherited as an X-linked recessive trait. EDMD may also be inherited as an autosomal dominant trait. Autosomal recessive inheritance is extremely rare, but has been reported in at least one family. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xq28” refers to band 28 on the long arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and manifest mostly in males. Females that have a defective gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the defective gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a defective gene he will develop the disease.
Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.
If a male with an X-linked disorder is able to reproduce, he will pass the defective gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.
Investigators have determined that the X-linked form of EDMD is caused by disruption or changes (mutations) of the EMD (also known as STA) gene located on the long arm of the X chromosome (Xq28). The EMD gene encodes a muscle protein known as emerin. Emerin is found in most cell types of the body and skeletal and cardiac muscle have particularly high expression levels.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals typically carry a number of abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Investigators have determined that the autosomal dominant and autosomal recessive forms of EDMD are caused by mutations of the same gene located on the long arm of the chromosome 1 (1q21.2). The gene is known as the LMNA gene and encodes the proteins lamin A and lamin C. Interestingly, mutations in this gene also cause a variety of other human diseases, including limb-girdle muscular dystrophy, dilated cardiomyopathy, Dunnigan-type familial partial lipodystrophy, and the premature aging disease Hutchinson-Gilford progeria syndrome.
EDMD can also result from mutations in the nuclear envelope proteins nesprin-1 and -2, which also directly interact with emerin. Mutations in the SUN-domain proteins SUN1 and SUN2, which form a complex with nesprins to connect the nucleus to the cytoskeleton, can also cause EDMD. These findings suggest that disruption in the LINC (Linker between nucleoskeleton and cytoskeleton) complex can contribute to the muscular phenotype in EDMD.
Lastly, some cases of EDMD have been attributed to mutations in the FHL1 gene, also known as LUMA, a nuclear membrane protein that binds to emerin At the same time, more than half of all EDMD patients have no identifiable mutations in the above genes, suggesting that additional genes/mutations must be responsible for EDMD. Consequently, substantial efforts are underway to identify additional genes that cause EDMD and the underlying disease mechanism.