title: Unregulated smooth-muscle myosin in human intestinal neoplasia.
abstract: A recent study described a recessive ATPase activating germ-line mutation in smooth-muscle myosin (smmhc/myh11) underlying the zebrafish meltdown (mlt) phenotype. The mlt zebrafish develops intestinal abnormalities reminiscent of human Peutz-Jeghers syndrome (PJS) and juvenile polyposis (JP). To examine the role of MYH11 in human intestinal neoplasia, we searched for MYH11 mutations in patients with colorectal cancer (CRC), PJS and JP. We found somatic protein-elongating frameshift mutations in 55% of CRCs displaying microsatellite instability and in the germ-line of one individual with PJS. Additionally, two somatic missense mutations were found in one microsatellite stable CRC. These two missense mutations, R501L and K1044N, and the frameshift mutations were functionally evaluated. All mutations resulted in unregulated molecules displaying constitutive motor activity, similar to the mutant myosin underlying mlt. Thus, MYH11 mutations appear to contribute also to human intestinal neoplasia. Unregulated MYH11 may affect the cellular energy balance or disturb cell lineage decisions in tumor progenitor cells. These data challenge our view on MYH11 as a passive differentiation marker functioning in muscle contraction and add to our understanding of intestinal neoplasia.
authors.affiliation: Department of Medical Genetics and Division of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and Genome Scale Biology Program, Biomedicum Helsinki, University of Helsinki, 00014, Helsinki, Finland.
authors.forename: Pia
authors.initials: P
authors.lastname: Alhopuro
authors.forename: Denis
authors.initials: D
authors.lastname: Phichith
authors.forename: Sari
authors.initials: S
authors.lastname: Tuupanen
authors.forename: Heli
authors.initials: H
authors.lastname: Sammalkorpi
authors.forename: Miranda
authors.initials: M
authors.lastname: Nybondas
authors.forename: Juha
authors.initials: J
authors.lastname: Saharinen
authors.forename: James P
authors.initials: JP
authors.lastname: Robinson
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Yang
authors.forename: Li-Qiong
authors.initials: LQ
authors.lastname: Chen
authors.forename: Torben
authors.initials: T
authors.lastname: Orntoft
authors.forename: Jukka-Pekka
authors.initials: JP
authors.lastname: Mecklin
authors.forename: Heikki
authors.initials: H
authors.lastname: Järvinen
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
authors.forename: Gabriela
authors.initials: G
authors.lastname: Moeslein
authors.forename: Darryl
authors.initials: D
authors.lastname: Shibata
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
authors.forename: Anneke
authors.initials: A
authors.lastname: Lucassen
authors.forename: Ian P M
authors.initials: IP
authors.lastname: Tomlinson
authors.forename: Virpi
authors.initials: V
authors.lastname: Launonen
authors.forename: Ari
authors.initials: A
authors.lastname: Ristimäki
authors.forename: Diego
authors.initials: D
authors.lastname: Arango
authors.forename: Auli
authors.initials: A
authors.lastname: Karhu
authors.forename: H Lee
authors.initials: HL
authors.lastname: Sweeney
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics; D000595:Amino Acid Sequence; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics; D004252:DNA Mutational Analysis; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics*; D024462:Myosin Type II / Q000235:genetics*; D010580:Peutz-Jeghers Syndrome / Q000235:genetics; D024745:Smooth Muscle Myosins / Q000235:genetics* / Q000502:physiology
chemical_list: C509903:MYH11 protein, human; D024462:Myosin Type II; D024745:Smooth Muscle Myosins; D018995:Myosin Heavy Chains