title: A postnatal role for embryonic myosin revealed by MYH3 mutations that alter TGFβ signaling and cause autosomal dominant spondylocarpotarsal synostosis.
abstract: 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.
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, California, 90095, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Zieba
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, California, 90095, USA.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.|Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, 98195, USA.|Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA.
authors.forename: Jessica X
authors.initials: JX
authors.lastname: Chong
authors.affiliation: Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, 90095, USA.
authors.forename: Kimberly N
authors.initials: KN
authors.lastname: Forlenza
authors.affiliation: Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, 90095, USA.
authors.forename: Jorge H
authors.initials: JH
authors.lastname: Martin
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, California, 90095, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Heard
authors.affiliation: Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, Saint Louis, Missouri, USA.
authors.forename: Dorothy K
authors.initials: DK
authors.lastname: Grange
authors.affiliation: Departments of Psychiatry &Behavioral Sciences and Pediatrics, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Merlin G
authors.initials: MG
authors.lastname: Butler
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.affiliation: International Skeletal Dysplasia Registry, University of California Los Angeles, Los Angeles, California, 90095, USA.
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Lachman
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Nickerson
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, WA, USA.|Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, USA.|Center for Cardiovascular Biology, University of Washington, Seattle, WA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Regnier
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, California, 90095, USA.|Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, 90095, USA.|International Skeletal Dysplasia Registry, University of California Los Angeles, Los Angeles, California, 90095, USA.|Orthopaedic Institute for Children, University of California Los Angeles, Los Angeles, California, 90095, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Cohn
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.|Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, 98195, USA.|Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bamshad
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at UCLA, California, 90095, USA.|Department of Orthopaedic Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California, 90095, USA.|International Skeletal Dysplasia Registry, University of California Los Angeles, Los Angeles, California, 90095, USA.|Orthopaedic Institute for Children, University of California Los Angeles, Los Angeles, California, 90095, USA.|Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, California, 90095, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Krakow
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D000483:Alleles; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant; D005838:Genotype; D006801:Humans; D008159:Lumbar Vertebrae / Q000002:abnormalities* / Q000378:metabolism; D008297:Male; D009140:Musculoskeletal Diseases / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D009218:Myosins / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D011859:Radiography; D012600:Scoliosis / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013580:Synostosis / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D013904:Thoracic Vertebrae / Q000002:abnormalities* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000073359:Exome Sequencing
chemical_list: D019485:Bone Morphogenetic Proteins; D003598:Cytoskeletal Proteins; C510594:MYH3 polypeptide, human; D016212:Transforming Growth Factor beta; D009218:Myosins