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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.

Original publication

DOI

10.1073/pnas.0801213105

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

08/04/2008

Volume

105

Pages

5513 - 5518

Keywords

Adenomatous Polyposis Coli, Amino Acid Sequence, Case-Control Studies, Colorectal Neoplasms, DNA Mutational Analysis, Gene Expression Regulation, Neoplastic, Humans, Intestinal Neoplasms, Molecular Sequence Data, Mutation, Myosin Heavy Chains, Myosin Type II, Peutz-Jeghers Syndrome, Smooth Muscle Myosins