Adams-Oliver syndrome ... (Adams-Oliver syndrome) - Genes ARHGAP31, DLL4, DOCK6, EOGT, NOTCH1 and RBPJ
Syndrome Adams-Oliver is a rare congenital condition characterized by an abnormality in the development of skin called cutaneous aplasia and limb defects. In addition to these features, affected individuals may exhibit other signs.
Most people with Adams-Oliver syndrome have cutaneous aplasia, a condition characterized by the absence of skin areas that are normally produced at the vertex of the skull. In some cases, the bone beneath the skin is also underdeveloped. As a result, affected individuals often have scars and no growth of hair in the affected area. In addition to aplasia cutis congenita, they are also frequent anomalies of the hands and feet. These abnormalities involve more often fingers and may include abnormal nails, and brachydactyly syndactyly or oligodactyly. In some cases, other bones of the hands, feet or lower limbs are malformed or absent.
Some affected children have congenital cutis marmorata telangiectasia, an abnormality in blood vessels causing a pattern shaped network of red or purple skin. Furthermore, people with Adams-Oliver syndrome of may develop pulmonary hypertension or other problems of blood vessels and heart defects. In some cases, people with Adams-Oliver syndrome have neurological problems, such as developmental delays, learning disabilities or abnormalities in brain structure.
This process is due to mutations in the ARHGAP31 (Rho GTPase activating protein 31), DLL4 (delta-like 4 (Drosophila)), DOCK6 (dedicator of cytokinesis 6), EOGT (EGF domain specific O-linked N-acetylglucosamine transferase) gene , NOTCH1 (Notch 1) and rbpj (recombination signal binding protein for immunoglobulin kappa J region). Because some affected individuals have mutations in one of these genes, it is likely that other genes have not been identified also participate in the development of this condition.
The ARHGAP31 gene (Rho GTPase activating protein 31), located on the long arm of chromosome 3 (3q13.33), encoding the protein ARHGAP31 which is classified as a protein Rho GTPase activating (GAP) protein. GAPs inactivate the GTPases proteins, which play an important role in chemical signaling inside cells. GTPases are active when they are attached to one molecule of GTP , and inactivated when they are attached to a GDP molecule. The ARHGAP31 protein inactivates Cdc42 GTPases known as Rac1 and by stimulating a reaction that binds GTP to GDP. When active, Cdc42 and Rac1 transmit signals that are critical to many aspects of embryonic development. The ARHGAP31 protein appears to regulate these GTPases specifically for the development of limbs, skull and heart. They have identified at least three mutations in the gene ARHGAP31 in people with Adams-Oliver syndrome. These mutations result in the synthesis of an abnormally short ARHGAP31 protein is more active than normal. Increased GAP activity causes a reduction in Cdc42 and Rac1 signaling, altering the proper development of the skin at the top of the head and bones of the hands and feet.
The DLL4 gene (delta-like 4 (Drosophila)), located on the long arm of chromosome 15 (15q14), encoding the DLL4 protein, which is part of the Notch signaling pathway, important for the normal development of many tissues throughout the organism. The DLL4 protein binds to Notch 1 receptor protein, to activate a series of signaling pathways affecting cell functions. In particular, stimulated by DLL4 signaling plays a role in angiogenesis throughout life. They found at least nine DLL4 genetic mutations in people with Adams-Oliver syndrome. Some of these mutations result in the synthesis of an abnormally short protein probably decomposes rapidly, causing a deficiency DLL4. Other mutations change amino acids in the DLL4 protein. It is thought that these changes alter the protein structure, affecting its ability to function. This loss of function may be the basis of abnormal blood vessels in persons with Adams-Oliver syndrome; However, some people with Adams-Oliver syndrome associated with DLL4 not have these abnormalities. Although it is unclear how the loss of DLL4 function leads to anomalies of the scalp and extremities, it is believed to be due to abnormal development of blood vessels before birth.
The DOCK6 gene (dedicator of cytokinesis 6), located on the short arm of chromosome 19 (19p13.2) encoding the protein factor guanine nucleotide exchange (GEF). As the protein encoded by the ARHGAP31 gene, the GEF protein regulates GTPases, specifically during the development of the extremities, skull, and heart. DOCK6 also plays a role in the development of axons extending from nerve cells. Most DOCK6 gene mutations identified in people with Adams-Oliver syndrome, leading to the synthesis of an abnormally short, nonfunctional protein DOCK6. Other mutations change DOCK6 amino acids in protein, which alters the normal function of the protein. The inability to activate DOCK6 Cdc42 Rac1 or causes a reduction in signaling, disrupting the proper development of certain tissues, including the skin on top of the head and bones of the hands and feet. Neurological disorders such as cerebral malformations and mental retardation, are more prevalent in people with Adams-Oliver syndrome associated with mutations in the gene DOCK6 that in cases associated with other genes.
The EOGT (EGF domain specific O-linked N-acetylglucosamine transferase) gene, located on the short arm of chromosome 3 (3p14.1), encodes a protein that modifies certain other proteins by transferring a molecule called N-acetylglucosamine. This change, called O-GlcNAc modification may affect protein stability and regulation of several cellular processes such as cell signaling and transcription processes. Little is known about the proteins altered by EOGT protein or how changes O-GlcNAc has on them. Studies suggest that Notch proteins can be modified by EOGT. At least three mutations found in the EOGT gene in individuals with Adams-Oliver syndrome. The most common genetic alteration EOGT is in the Arab population and results in an abnormally short protein. The other mutations change the amino acids in protein EOGT. It is believed that mutations in the gene EOGT reduce or eliminate the ability of the protein to transfer N-acetylglucosamine. However, the effect this has on the deterioration of cells or how leads to the characteristics of Adams-Oliver syndrome is unknown.
NOTCH1 (Notch 1) gene, located on the long arm of chromosome 9 (9q34.3), encoding the Notch1 protein, a member of the family of Notch receptors. The binding of a ligand to Notch1 receptor sends signals that are important for the normal development of many tissues throughout the body, both before and after birth. Notch1 signaling helps determine cell fate. Also plays a role in growth, proliferation, differentiation and apoptosis. The protein encoded from NOTCH1 gene has such various functions that the gene is considered both an oncogene and a tumor suppressor gene. At least 15 mutations have been identified in the NOTCH1 gene as responsible for Adams-Oliver syndrome. These mutations are inherited and are present in every cell of the body. Some of the mutations result in the synthesis of an abnormally short protein probably decomposes rapidly, causing a deficiency of Notch1. Other mutations change the amino acids in Notch1 protein. It is thought that these changes alter the protein structure, affecting its ability to function. Loss Notch1 signaling may underlie the abnormal blood vessels and heart in people with Adams-Oliver syndrome. However, although such anomalies are more common in individuals affected with NOTCH1 gene mutations than in those with a different genetic mutation, some people with Adams-Oliver syndrome associated with Notch1 not have these abnormalities. It is unclear how the loss of Notch1 function leads to anomalies of the scalp and extremities.
The rbpj gene (recombination signal binding protein for immunoglobulin kappa J region), located on the short arm of chromosome 4 (4p15.2), encodes a protein that is part of the Notch signaling pathway. Signaling through Notch pathway stimulates RBP-J protein to bind to specific DNA regions and control the activity of genes that play a role in cell development. Mutations in the gene rbpj consist of amino acid changes in the rbpj protein, disrupting the region of the protein normally binds to DNA. The altered proteins are unable to bind DNA, thus preventing the activation of particular genes. Although these changes in gene activity alter the proper development of skin on top of the head and bones of the hands and feet, it is not clear why this change mainly affects the development of these tissues.
The Adams-Oliver syndrome can have different inheritance patterns. When due to mutations in the ARHGAP31, DLL4, NOTCH1 or rbpj gene is inherited in an autosomal dominant pattern. Autosomal dominant inheritance means that a copy of the altered gene in each cell is sufficient to express the disease. The altered gene is usually inherited from an affected parent. Some cases associated with NOTCH1 gene mutations 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. When the syndrome is due to mutations in the gene or EOGT DOCK6 is inherited with an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
Tests in IVAMI: in IVAMI perform the detection of mutations associated with syndrome Adams-Oliver, by complete PCR amplification of the exons of the ARHGAP31, DLL4, DOCK6, EOGT, NOTCH1 and rbpj genes, respectively, and subsequent sequencing.
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).