@article {349,
	title = {A postnatal role for embryonic myosin revealed by MYH3 mutations that alter TGFβ signaling and cause autosomal dominant spondylocarpotarsal synostosis.},
	journal = {Sci Rep},
	volume = {7},
	year = {2017},
	month = {2017 02 16},
	pages = {41803},
	abstract = {<p>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 TGFβ signaling, revealing a regulatory role for embryonic myosin in the TGFβ signaling pathway. In wild-type 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.</p>},
	keywords = {Abnormalities, Multiple, Alleles, Bone Morphogenetic Proteins, Cytoskeletal Proteins, Female, Genes, Dominant, Genotype, Humans, Lumbar Vertebrae, Male, Musculoskeletal Diseases, Mutation, Myosins, Phenotype, Radiography, Scoliosis, Signal Transduction, Synostosis, Thoracic Vertebrae, Transforming Growth Factor beta, Whole Exome Sequencing},
	issn = {2045-2322},
	doi = {10.1038/srep41803},
	author = {Zieba, Jennifer and Zhang, Wenjuan and Chong, Jessica X and Forlenza, Kimberly N and Martin, Jorge H and Heard, Kelly and Grange, Dorothy K and Butler, Merlin G and Kleefstra, Tjitske and Lachman, Ralph S and Nickerson, Deborah and Regnier, Michael and Cohn, Daniel H and Bamshad, Michael and Krakow, Deborah}
}
@article {70,
	title = {Recessive Inactivating Mutations in TBCK, Encoding a Rab GTPase-Activating Protein, Cause Severe Infantile Syndromic Encephalopathy.},
	journal = {Am J Hum Genet},
	volume = {98},
	year = {2016},
	month = {2016 Apr 07},
	pages = {772-81},
	abstract = {<p>Infantile encephalopathies are a group of clinically and biologically heterogeneous disorders for which the genetic basis remains largely unknown. Here, we report a syndromic neonatal encephalopathy characterized by profound developmental disability, severe hypotonia, seizures, diminished respiratory drive requiring mechanical ventilation, brain atrophy, dysgenesis of the corpus callosum, cerebellar vermis hypoplasia, and facial dysmorphism. Biallelic inactivating mutations in TBCK (TBC1-domain-containing kinase) were independently identified by whole-exome sequencing as the cause of this condition in four unrelated families. Matching these families was facilitated by the sharing of phenotypic profiles and WES data in a recently released web-based tool (Geno2MP) that links phenotypic information to rare variants in families with Mendelian traits. TBCK is a putative GTPase-activating protein (GAP) for small GTPases of the Rab family and has been shown to control cell growth and proliferation, actin-cytoskeleton dynamics, and mTOR signaling. Two of the three mutations (c.376C>T [p.Arg126(*)] and c.1363A>T [p.Lys455(*)]) are predicted to truncate the protein, and loss of the major TBCK isoform was confirmed in primary fibroblasts from one affected individual. The third mutation, c.1532G>A (p.Arg511His), alters a conserved residue within the TBC1 domain. Structural analysis implicated Arg511 as a required residue for Rab-GAP function, and in~silico homology modeling predicted impaired GAP function in the corresponding mutant. These results suggest that loss of Rab-GAP activity is the underlying mechanism of disease. In contrast to other disorders caused by dysregulated mTOR signaling associated with focal or global brain overgrowth, impaired TBCK function results in progressive loss of brain volume. </p>},
	keywords = {Adolescent, Alleles, Amino Acid Sequence, Brain Diseases, Child, Child, Preschool, Corpus Callosum, Female, GTPase-Activating Proteins, Humans, Magnetic Resonance Imaging, Male, Molecular Sequence Data, Mutation, Pedigree, Protein Conformation, Protein-Serine-Threonine Kinases, Signal Transduction, TOR Serine-Threonine Kinases},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2016.01.016},
	author = {Chong, Jessica X and Caputo, Viviana and Phelps, Ian G and Stella, Lorenzo and Worgan, Lisa and Dempsey, Jennifer C and Nguyen, Alina and Leuzzi, Vincenzo and Webster, Richard and Pizzuti, Antonio and Marvin, Colby T and Ishak, Gisele E and Ardern-Holmes, Simone and Richmond, Zara and Bamshad, Michael J and Ortiz-Gonzalez, Xilma R and Tartaglia, Marco and Chopra, Maya and Doherty, Dan}
}
