Autosomal-Dominant Multiple Pterygium Syndrome Is Caused by Mutations in MYH3.

TitleAutosomal-Dominant Multiple Pterygium Syndrome Is Caused by Mutations in MYH3.
Publication TypeJournal Article
Year of Publication2015
AuthorsChong, JX, Burrage, LC, Beck, AE, Marvin, CT, McMillin, MJ, Shively, KM, Harrell, TM, Buckingham, KJ, Bacino, CA, Jain, M, Alanay, Y, Berry, SA, Carey, JC, Gibbs, RA, Lee, BH, Krakow, D, Shendure, J, Nickerson, DA, Bamshad, MJ
Corporate Authors
JournalAm J Hum Genet
Volume96
Issue5
Pagination841-9
Date Published2015 May 7
ISSN1537-6605
KeywordsArthrogryposis, Cytoskeletal Proteins, Exome, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Humans, Mutation, Myosins, Osteogenesis
Abstract

Multiple pterygium syndrome (MPS) is a phenotypically and genetically heterogeneous group of rare Mendelian conditions characterized by multiple pterygia, scoliosis, and congenital contractures of the limbs. MPS typically segregates as an autosomal-recessive disorder, but rare instances of autosomal-dominant transmission have been reported. Whereas several mutations causing recessive MPS have been identified, the genetic basis of dominant MPS remains unknown. We identified four families affected by dominantly transmitted MPS characterized by pterygia, camptodactyly of the hands, vertebral fusions, and scoliosis. Exome sequencing identified predicted protein-altering mutations in embryonic myosin heavy chain (MYH3) in three families. MYH3 mutations underlie distal arthrogryposis types 1, 2A, and 2B, but all mutations reported to date occur in the head and neck domains. In contrast, two of the mutations found to cause MPS in this study occurred in the tail domain. The phenotypic overlap among persons with MPS, coupled with physical findings distinct from other conditions caused by mutations in MYH3, suggests that the developmental mechanism underlying MPS differs from that of other conditions and/or that certain functions of embryonic myosin might be perturbed by disruption of specific residues and/or domains. Moreover, the vertebral fusions in persons with MPS, coupled with evidence of MYH3 expression in bone, suggest that embryonic myosin plays a role in skeletal development.

DOI10.1016/j.ajhg.2015.04.004
Alternate JournalAm. J. Hum. Genet.
PubMed ID25957469
PubMed Central IDPMC4570285
Grant ListK99 HG004316 / HG / NHGRI NIH HHS / United States
U54 HG006493 / HG / NHGRI NIH HHS / United States
RC2 HG005608 / HG / NHGRI NIH HHS / United States
T32GM07526 / GM / NIGMS NIH HHS / United States
1R01HD048895 / HD / NICHD NIH HHS / United States
1RC2HG005608 / HG / NHGRI NIH HHS / United States
U54HG003273 / HG / NHGRI NIH HHS / United States
R00 HG004316 / HG / NHGRI NIH HHS / United States
U54HD061221 / HD / NICHD NIH HHS / United States
T32 GM007526 / GM / NIGMS NIH HHS / United States
HD024064 / HD / NICHD NIH HHS / United States
U54 HD083092 / HD / NICHD NIH HHS / United States
U54 HD061221 / HD / NICHD NIH HHS / United States
U54 U54HG006542 / HG / NHGRI NIH HHS / United States
P01HD070394 / HD / NICHD NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
P30 HD024064 / HD / NICHD NIH HHS / United States
P30 DK056338 / DK / NIDDK NIH HHS / United States
R01 HD048895 / HD / NICHD NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
5R000HG004316 / HG / NHGRI NIH HHS / United States
R01AR066124 / AR / NIAMS NIH HHS / United States
1U54HG006493 / HG / NHGRI NIH HHS / United States
R01 AR066124 / AR / NIAMS NIH HHS / United States
P01 HD070394 / HD / NICHD NIH HHS / United States