title: Dominant versus recessive traits conveyed by allelic mutations - to what extent is nonsense-mediated decay involved?
abstract: 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.
authors.affiliation: Department of Molecular and Human Genetic, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ben-Shachar
authors.forename: M
authors.initials: M
authors.lastname: Khajavi
authors.forename: M A
authors.initials: MA
authors.lastname: Withers
authors.forename: C A
authors.initials: CA
authors.lastname: Shaw
authors.forename: H
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: H G
authors.initials: HG
authors.lastname: Brunner
authors.forename: J R
authors.initials: JR
authors.lastname: Lupski
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000483:Alleles; D001848:Bone Diseases, Developmental / Q000235:genetics; D002478:Cells, Cultured; D005799:Genes, Dominant; D005808:Genes, Recessive; D006801:Humans; D040582:Inheritance Patterns; D017880:Limb Deformities, Congenital / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D011956:Receptors, Cell Surface / Q000235:genetics; D013577:Syndrome
chemical_list: D011956:Receptors, Cell Surface; C078717:ROR2 protein, human; D057050:Receptor Tyrosine Kinase-like Orphan Receptors