A postnatal role for embryonic myosin revealed by MYH3 mutations that alter TGF beta signaling and cause autosomal dominant spondylocarpotarsal synostosis

作者：Zieba Jennifer; Zhang Wenjuan; Chong Jessica X; Forlenza Kimberly N; Martin Jorge H; Heard Kelly; Grange Dorothy K; Butler Merlin G; Kleefstra Tjitske; Lachman Ralph S; Nickerson Deborah; Regnier Michael; Cohn Daniel H; Bamshad Michael; Krakow Deborah^*

来源：Scientific Reports, 2017, 7(1): 41803.

DOI：10.1038/srep41803

Spondylocarpotarsal synostosis (SCT) is a skeletal disorder characterized by progressive vertebral, carpal and tarsal fusions, and mild short stature. The majority of affected individuals have an autosomal recessive form of SCT and are homozygous or compound heterozygous for nonsense mutations in the gene that encodes the cytoskeletal protein filamin B (FLNB), but a subset do not have FLNB mutations. Exome sequence analysis of three SCT patients negative for FLNB mutations identified an autosomal dominant form of the disease due to heterozygosity for missense or nonsense mutations in MYH3, which encodes embryonic myosin. Cells transfected with the MYH3 missense mutations had reduced TGF beta signaling, revealing a regulatory role for embryonic myosin in the TGF beta signaling pathway. In wildtype mice, there was persistent postnatal expression of embryonic myosin in the small muscles joining the neural arches of the spine suggesting that loss of myosin function in these muscles contribute to the disease. Our findings demonstrate that dominant mutations in MYH3 underlie autosomal dominant SCT, identify a postnatal role for embryonic myosin and suggest that altered regulation of signal transduction in the muscles within the spine may lead to the development of vertebral fusions.

• 出版日期2017-2-16
• 单位UCLA