A novel functionally deficient MYH variant in individuals with colorectal adenomatous polyposis.

Pia Alhopuro, Antony R. Parker, Rainer Lehtonen, Susa Enholm, Heikki J. Järvinen, Jukka Pekka Mecklin, Auli Karhu, James R. Eshleman, Lauri A. Aaltonen

Research output: Contribution to journalArticlepeer-review


Inherited biallelic mutations in the base excision repair gene MYH confer susceptibility to colorectal adenomas and carcinoma. Approximately 85% of Caucasians with MYH mutations carry the (c.494A>G) p.Y165C and (c.1145G>A) p.G382D variants. Only a few other clearly pathogenic mutations have been identified, and mutation analyses tend to focus on the two founder mutations rather than the whole coding region of the gene. We sequenced the entire coding region of MYH in a population-based series of 24 Finnish APC-mutation negative polyposis patients in order to identify novel pathogenic MYH variants. A population-based series of 1,042 Finnish colorectal cancer patients and 85 cancer-free controls were available for further evaluation. A functional cleavage assay was designed to evaluate consequences of possible novel variants to protein function. Three novel MYH variants, (c.270C>T) p.Y90Y, (c.1376C>A) p.A459D, and (c.1389G>C) p.T469T, were observed. p.A459D variant in exon 14 was identified in two patients from the polyposis series, once in homozygosity and once in compound heterozygosity with p.Y165C. In the population-based series of 1,042 colorectal cancer patients, the p.A459D mutation was identified once, in homozygosity (allele frequency 0.1%). No p.A459D mutations were identified in the control individuals. In vitro cleavage assay showed significantly reduced repair activity in p.A459D cells. Interestingly, another variant in the same codon has previously been described in a British study, supporting a key role for the codon 459 in MYH function. We therefore suggest that screening of mutations in MYH exon 14 should be added to the molecular analysis at-risk individuals.

Original languageEnglish (US)
Pages (from-to)393
Number of pages1
JournalHuman mutation
Issue number4
StatePublished - Oct 2005
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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