The Role of TOM1L2 in Smith-Magenis Syndrome
Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation syndrome that affects ~1:20,000-25,000. This disorder is characterized by several craniofacial and skeletal features such as brachycephaly, midface hypoplasia, brachydactyly, and microcephaly in infancy progressing to prognathism with age. Key behavioral abnormalities include the attention-seeking, self-hugging, and self-injurious behaviors such as onychotillomania, polyembolokoilomania, hand-biting, and head-banging. Neurological defects include mental retardation, sleep disturbance, speech and motor delay. Features that are less frequently seen in individuals with SMS include frequent infections, hearing loss, cleft lip or palate, scoliosis, synophrys, and ocular, cardiovascular, and renal abnormalities. Most patients with SMS have an interstitial deletion of chromosome 17p11.2, which includes TOM1L2. Although the function of the TOM1L2 protein is unknown, the presence of GAT and VHS domains suggest that TOM1L2 is involved in protein trafficking. To understand the cellular function of TOM1L2 and its role in SMS, expression studies were performed. Northern analysis indicates that TOM1L2 is expressed in the heart, brain, skeletal muscle and kidney and at lower levels in the placenta, lung, liver and pancreas. Tom1L2 is also detected in the brain, heart, liver, spleen, muscle, lung and kidney by western blotting. Immunohistochemistry of mouse embronic tissues shows that Tom1L2 is expressed in the liver and distal appendages. Tom1L2 gene-trapped mice with decreased levels of Tom1L2 expression have been created and evaluated. These mice have undergone physiological and behavioral analyses, careful skeletal and craniofacial measurements, histological assessments, and a battery of behavioral tests. Preliminary data indicate that Tom1L2 mutant mice have increased risk for infection. The importance of TOM1L2 for the immune response in SMS is currently being investigated.