Unregulated smooth-muscle myosin in human intestinal neoplasia.
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.
Alhopuro
Pia
P
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.
Phichith
Denis
D
Tuupanen
Sari
S
Sammalkorpi
Heli
H
Nybondas
Miranda
M
Saharinen
Juha
J
Robinson
James P
JP
Yang
Zhaohui
Z
Chen
Li-Qiong
LQ
Orntoft
Torben
T
Mecklin
Jukka-Pekka
JP
Järvinen
Heikki
H
Eng
Charis
C
Moeslein
Gabriela
G
Shibata
Darryl
D
Houlston
Richard S
RS
Lucassen
Anneke
A
Tomlinson
Ian P M
IP
Launonen
Virpi
V
Ristimäki
Ari
A
Arango
Diego
D
Karhu
Auli
A
Sweeney
H Lee
HL
Aaltonen
Lauri A
LA
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
C509903:MYH11 protein, human; D024462:Myosin Type II; D024745:Smooth Muscle Myosins; D018995:Myosin Heavy Chains