TOPIC: New genes involved in thyroid disease
Title: A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome.
Authors: Risheg H, Graham JM Jr, Clark RD, Rogers RC, Opitz JM, Moeschler JB, Peiffer AP, May M, Joseph SM, Jones JR, Stevenson RE, Schwartz CE, & Friez MJ.
Reference: Nature Genetics 39: 451-453, 2007
The -Opitz-Kaveggia- syndrome (also known as FG syndrome) is an X-linked disorder characterized by mental retardation, relative macrocephaly, hypotonia and constipation. Previously, the molecular basis of this condition was unknown.
The authors report here the molecular basis for the FG syndrome from the original family and its prevalence.
A total of six families were evaluated for DNA and real-time PCR to evaluate candidate genes for this condition.
A recurrent mutation (2881C4T, leading to R961W) in MED12 (also called TRAP230 or HOPA), a gene located at Xq13 that functions as a thyroid receptor-associated protein in the Mediator complex.
Other cases of Optiz-Kaveggia syndrome with findings that overlap with X-linked mental retardation should be considered for MED12 mutations.
A form of mental retardation associated with motor abnormalities was described in 1944 and subsequently named the Allan-Herndon-Dudley (A-H-D) syndrome. This condition was further mapped to a locus on chromosome X: Xq13-q215 and Xq12-q13.6. In 2004, two laboratories independently identified mutations in the MCT8 gene in 7 unrelated families, in which males presented with high serum T3, and low T4 and rT3 concentrations, together with psychomotor abnormalities reminiscent of the A-H-D syndrome. The following year, families previously identified as suffering from the A-H-D syndrome, including the family first reported in 1944, were found to harbour mutations in the MCT8 gene with high serum T3 levels.
The monocarboxylate transporter 8 ( MCT8 ) gene belongs to a family of genes officially named – SLC16- , the products of which catalyze proton-linked transport of monocarboxylates (such as lactate, pyruvate, & ketone bodies). The rat homolog was found to be a specific transporter of thyroid hormone (TH) into cells. This and other TH transporters, together with iodothyronine deiodinases, regulate the level of active hormone at the cell level.
MED12 encodes for a subunit of the macromolecular complex known as a Mediator, which is required for thyroid hormone-dependent activation and repression of transcription by RNA polymerase II. Specifically, it functions as a co-repressor in combination with the TH receptor. The MED12 protein is a program with more than 25 subunits and this is the first report associating a Mediator subunit with mental retardation.
We now have two endocrine/thyroid genes, one involved in TH transport and the other involved in mediating TH action as a transcription protein. In both instances, the gene mutation is believed to be the cause of X-linked mental retardation. In the MCT8 males, their thyroid tests showed elevated serum T3, but low T4 and reverse T3. In the affected males, thyroid tests are reportedly normal but 2 of 4 hemizygous females became hyperthyroid in adulthood. Summary and commentary prepared by Roy Weiss (related to Chapter 3 of TDM)