Dominant versus recessive traits conveyed by allelic mutations - To what extent is nonsense-mediated decay involved?

S. Ben-Shachar, M. Khajavi, M. A. Withers, C. A. Shaw, H. Van Bokhoven, H. G. Brunner, James R. Lupski*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Mutations in ROR2, encoding a receptor tyrosine kinase, can cause autosomal recessive Robinow syndrome (RRS), a severe skeletal dysplasia with limb shortening, brachydactyly, and a dysmorphic facial appearance. Other mutations in ROR2 result in the autosomal dominant disease, brachydactyly type B (BDB1). No functional mechanisms have been delineated to effectively explain the association between mutations and different modes of inheritance causing different phenotypes. BDB1-causing mutations in ROR2 result from heterozygous premature termination codons (PTCs) in downstream exons and the conveyed phenotype segregates as an autosomal dominant trait, whereas heterozygous missense mutations and PTCs in upstream exons result in carrier status for RRS. Given that the distribution of PTC mutations revealed a correlation between the phenotype and the mode of inheritance conveyed, we investigated the potential role for the nonsense-mediated decay (NMD) pathway in the abrogation of possible aberrant effects of selected mutant alleles. Our experiments show that triggering or escaping NMD may cause different phenotypes with a distinct mode of inheritance. We generalize these findings to other disease-associated genes by examining PTC mutation distribution correlation with conveyed phenotype and inheritance patterns. Indeed, NMD may explain distinct phenotypes and different inheritance patterns conveyed by allelic truncating mutations enabling better genotype-phenotype correlations in several other disorders.

Original languageEnglish
Pages (from-to)394-400
Number of pages7
JournalClinical Genetics
Issue number4
StatePublished - 2009
Externally publishedYes


  • Brachydactyly type B genotype/phenotype correlation
  • Mode of inheritance
  • Nonsense-mediated decay
  • Premature termination codons
  • ROR2
  • Robinow syndrome


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