Activating mutations of the stimulatory G protein in the McCune-Albright syndrome

Article Abstract:

Patients with McCune-Albright syndrome develop areas of abnormal fibrous tissue structure in some bones, 'cafe au lait' areas of pigmentation in the skin, and a host of hormonal abnormalities, which generally include precocious puberty. The distribution of abnormalities in affected patients have suggested to researchers that a somatic mutation may be involved. In contrast with a germ-line mutation, which is passed from generation to generation, a somatic mutation occurs in a cell in the early embryonic stage after the fertilized egg has divided. As a result, all the body tissues that descend from the mutant cell carry the genetic abnormality, while other cells of the body are genetically normal. Genetic studies have implicated a component of the cyclic AMP transduction pathway as the site of the critical mutation in McCune-Albright syndrome. Many cells respond to hormonal stimulation by means of a cell-surface receptor specific for that hormone. For some hormones, the cell-surface receptor is connected to a complex of several proteins, which stimulates the formation of cAMP (cyclic adenosine monophosphate). Under normal circumstances, the enzymatic complex is rapidly returned to an inactive state, and thus the accumulation of cAMP in the cell is an indicator of the repeated stimulation by hormones outside the cell. This regulatory protein complex is very intricate, and contains a set of proteins called G proteins, which catalyze the breakdown of GTP (guanosine triphosphate), a critical step in the return of the complex to its inactive state. The gene for one of the proteins, Gs-alpha, contains a mutation can result in an inappropriate amino acid substitution. In the four patients investigated, normal tissues not containing the mutation could also be identified, confirming that the mutation is indeed somatic and not a germ-line mutation. The mutation in Gs-alpha appears to result in a hormone receptor complex that remains active in catalyzing the formation of cAMP. As a result, the cell responds as though it were being stimulated by massive amounts of hormone, resulting in the symptoms of McCune-Albright syndrome. (Consumer Summary produced by Reliance Medical Information, Inc.)

Hormone receptors, Fibrous dysplasia of bone

---

Mutation in the gene encoding the stimulatory G protein of adenylate cyclase in Albright's hereditary osteodystrophy

Article Abstract:

Albright's hereditary osteodystrophy is an inherited disorder characterized by abnormal fibrous development of bone, and results in shortness in height and of the fingers and toes, and bony growths under the skin. Patients also have pseudohypoparathyroidism; their symptoms indicate that they have low levels of parathyroid hormone, which is involved in maintaining levels of calcium necessary for bone formation. It has been found that patients with Albright's hereditary osteodystrophy have decreased function of the G protein, which is associated with adenylate cyclase, an enzyme involved in transmitting a signal from outside of a cell to the inside. G proteins bind cellular receptors, such as hormone receptors, to enzyme systems, such as adenylate cyclase, which transmit signals and cause cells to become active. The genes encoding the G proteins were examined at the molecular level in two patients with Albright's hereditary osteodystrophy who were from the same family. A technique known as the polymerase chain reaction was used to amplify the DNA from the patients so that it could be examined. The G protein encoding gene from the patients was abnormal, as seen by the pattern produced by restriction digest analysis (which indicates that there are changes in a gene by comparing it to the gene of normal individuals). This genetic change was further analyzed by sequencing the patients' DNA (establishing the order of the nucleotides). A change was seen in one nucleotide; the altered gene encodes the synthesis of a shorter molecule. These findings indicate that changes in the G protein, due to a change in one DNA nucleotide, can cause Albright's hereditary osteodystrophy. The analysis of this defect will allow the understanding of the mechanism of this disease. (Consumer Summary produced by Reliance Medical Information, Inc.)

---

Albright's hereditary osteodystrophy and defective G proteins

Article Abstract:

G proteins are molecules that act as go-betweens, serving as a bridge between cellular receptors, which come in contact with extracellular signals, and enzyme systems inside of cells, which cause cell activation. Modification of G proteins can lead to disease. One example is pseudohypoparathyroidism, in which there is a resistance to the parathyroid hormone, rather than a lack of the hormone, because of a defect in G proteins. One form of pseudohypoparathyroidism is Albright's hereditary osteodystrophy, in which patients have abnormal physical features. Patients are resistant to parathyroid hormone as well as other hormones, which utilize G proteins and cyclic AMP, an intracellular enzyme system, as the mechanism to transmit signals for activating cells. A recent study has shown that there is a mutation in the gene that codes for a subunit of the G protein in two related patients with Albright's hereditary osteodystrophy. As seen in many human inherited diseases, there may be various mutations responsible for defective G proteins. Three distinct mutations in G proteins have been identified in another laboratory in three unrelated families. The mutations explain the defect in function of the parathyroid hormone in pseudohypoparathyroidism, but do not explain why there are so many clinical manifestations of the disease. The role of the G protein in this disease is still not understood. The finding of the defective G protein in Albright's hereditary osteodystrophy has started a search for other diseases caused by defective G proteins, such as acromegaly, in which excessive growth hormone is secreted by the pituitary gland. With further research, other diseases caused by defective G proteins will also be identified. (Consumer Summary produced by Reliance Medical Information, Inc.)

Causes of, Acromegaly, editorial

Similar abstracts:

• Abstracts: Evaluation of the cost-effectiveness of home monitoring of uterine contractions
• Abstracts: A study of cyproheptadine in the treatment of metastatic carcinoid tumor and the malignant carcinoid syndrome
• Abstracts: Phenotypic variation in colorectal adenoma/cancer expression in two families: hereditary flat adenoma syndrome
• Abstracts: Comparing outcomes of care before and after implementation of the DRG-based prospective payment system. The effects of the DRG-based prospective payment system on quality of care for hospitalized Medicare patients: an introduction to the series
• Abstracts: Quality of care before and after implementation of the DRG-based prospective payment system: a summary of effects

This website is not affiliated with document authors or copyright owners. This page is provided for informational purposes only. Unintentional errors are possible.