DGCR8 microprocessor
DGCR8 microprocessor
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About the
Microprocessor syndrome
The microprocessor is a protein complex responsible for the proper production of microRNAs (miRNAs) in the cells of the body. DGCR8 and DROSHA are the two genes involved in the formation of this complex.
Mutations in these microprocessor genes affect the accurate production of miRNAs resulting in aberrant regulation of several biological processes in the cells, which in turn leads to the development of a tumor.
DGCR8-microprocessor syndrome is an ultra rare familial tumor predisposition syndrome characterized by germline genetic mutations in a gene called DGCR8.
Patients with DGCR8 syndrome can be diagnosed with benign lesions such as multinodular goiter (an enlargement of the thyroid gland due to the irregular growth of multiple lumps (nodules) in the gland) and peripheral schwannomas (nerve tumors located in the limbs) but can also be diagnosed with serious diseases such as thyroid cancer.
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Other benign tumors like a choroid plexus papilloma (a benign brain tumor seen in children) and benign tumors of the ovary have each been seen in one patient but whether those are associated with DGCR8 syndrome is still unclear.
About the DGCR8 gene
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Where is DGCR8 located?
DGCR8 (named after DiGeorge Critical Region 8) localizes within the 22q11 deletion syndrome (DS) associated region (OMIM 611867) next to the 3 established schwannoma disease-causing genes LZTR1, SMARCB1 and NF2 in chromosome 22.
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What is the function of DGCR8?
In partner with another protein called Drosha, the DGCR8 protein forms what is known as the microprocessor complex.
This microprocessor complex plays a key role in the processing of miRNA that affect the regulation of other genes through the miRNAs biogenesis pathway.
MicroRNAs (miRNAs) are small 21-22 nucleotides long noncoding RNAs that control gene expression and play an essential role in different processes from development to cancer. The canonical pathway for miRNA processing involves a subgroup of proteins that cooperate to cleave and assemble a mature miRNA into their target mRNA. In the nucleus a primary miRNA is cleaved by the microprocessor complex (composed of DROSHA-DGCR8) to a pre-miRNA that will be exported to the cytoplasm and further processed by DICER1 into a duplex miRNA of 21-22 nucleotides. One of the duplex strands is then degraded and the mature 22 nucleotides miRNA is loaded into the RISC complex together with the target mRNA by ARGONAUTE proteins.
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What happens when DGCR8 does not work properly?
When DGCR8 is mutated and it doesn´t work properly, it leads to a miRNA processing defect (miRNAs that are wrongly cleaved) that then goes to modify the expression of other genes. This leads to changes in biological processes that in turn promote the development of tumors.
Thyroid nodules and thyroid cancer
Thyroid nodules, which are lumps in the thyroid gland, are a common disease affecting up to 60% of individuals over age 60. Although they are non-life threatening in the majority of cases, about 5% of these nodules are cancerous. In children, however, thyroid nodules, although rare and seen in only 1%–2% of children, are more likely to lead to cancer.
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Multinodular goiter (MNG) is an enlargement of the thyroid gland due to the irregular growth of multiple nodules in the gland. Patients with DGCR8 syndrome have euthyroid MNG meaning that their levels of thyroid hormones are normal. Euthyroid MNG is also the most common disease in patients of another syndrome characterized by defects in miRNA production (DICER1 syndrome). Somatic mutations in the DICER1 gene have also been reported in about 1.5% of adult thyroid nodules and a dozen of adult thyroid cancers.
Wilms Tumors
Wilms tumor (WT), also called nephroblastoma, is the most common kidney tumor in children, affecting around 1 in every 10,000 children worldwide. Usually it occurs in kids aged 3 to 4 years old and is a little more common in girls than in boys. We and others have showed that mutations in the microprocessor genes DROSHA and DGCR8, two genes that regulate the production of microRNAs in the cells, are related to WT development. In most cases, mutations occur only in the tumor tissue (somatic), but some germline (inherited) variants have also been identified.
Also, mutations usually occur in two recurrent locations that have an important activity in the protein (DROSHA E1147K and DGCR8 E518K). These alterations affect processing of microRNA, ultimately leading to deregulation of several biological processes in the cells and tumor formation. Understanding the role of these mutations in WT may lead to a better risk stratification of patients and to more tailored and effective treatments.
Schwannomas
A schwannoma is an overgrowth of tissue surrounding the nerve that leads to a lump under the skin that can be painless or painful. It grows from cells called Schwann cells. Schwann cells protect and support the nerve cells of the nervous system.
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​Although usually painful in DGCR8 syndrome patients, schwannomas are typically non-cancerous tumors that once surgically removed are very rarely likely to grow back.
Although it is a rare disease, Schwannoma is the most common type of peripheral nerve tumors in adults, and it can occur in people of all ages.
