Three M syndrome 3 (3M3)

Three M syndrome 1, 2 and 3

Three M syndrome 1 (3M1; MIM 273750) , 2 (3M2; MIM 612921) and 3 (3M3; MIM 614205) are autosomal recessive disorders characterized by pre- and postnatal growth retardation, large head circumference, and a characteristic facial appearance including a pointed triangular shaped face, frontal bossing, midface hypoplasia, a short upturned nose with anteverted nares and full lips. Additional findings include slender long bones, tall vertebral bodies, delayed bone age and prominent heels. Intracranial aneurysms have also been rarely reported. To date, mutations in the CUL7 (cullin 7), OBSL1 (obscurin-like 1) and CCDC8 (coiled-coil domain-containing protein 8) genes have been linked to 3M1, 3M2 and 3M3, respectively. There are no apparent phenotypic differences between patients with mutations in CUL7, OBSL1 or CCDC8. 3M1, gloomy face syndrome and Yakut short stature syndrome are allelic disorders. The product of CUL7 assembles an E3 ubiquitin ligase complex involved in the ubiquitin-proteasome pathway. This complex promotes ubiquitination of cyclin D1 and insulin receptor substrate 1. Studies have also indicated binding to p53. Obscurin-like 1 is a cytoskeletal adaptor protein, which interacts with the giant cytoskeletal proteins titin and myomesin. The molecular link between CUL7, OBSL1 and CCDC8 is speculative but OBSL1 may act as an adapter protein linking CUL7 and CCDC8. These molecules are thought to participate in a common pathway vital to growth control.