Three M syndrome 2 (3M2)

Three M syndrome 1 and 2

Three M syndrome 1 (3M1; MIM 273750) and 2 (3M2; MIM 612921) are autosomal recessive disorders characterized by pre- and postnatal growth retardation, a large head circumference, and a characteristic facial appearance including a pointed triangular shaped face, frontal bossing, 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) and OBSL1 (obscurin-like 1) genes have been linked to 3M1 and 3M2, respectively. There are no apparent phenotypic differences between patients with mutations in CUL7 or OBSL1. 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 protein 1 is a cytoskeletal adaptor protein, the function of which is unknown. The molecular link between CUL7 and OBSL1 is speculative and is not clearly defined.