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Published on: August 15, 2019
Dominant versus recessive traits conveyed by allelic mutations - to what extent is nonsense-mediated decay involved?
S Ben-Shachar1, M Khajavi, M A Withers
1Department of Molecular and Human Genetic, Baylor College of Medicine, Houston, TX 77030, USA.
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.
Insights
Nonsense-mediated decay (NMD) explains how different ROR2 mutations cause distinct genetic disorders, Robinow syndrome (RRS) and brachydactyly type B (BDB1), by influencing inheritance patterns and phenotypes.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- Mutations in ROR2 cause autosomal recessive Robinow syndrome (RRS) and autosomal dominant brachydactyly type B (BDB1).
- The distinct phenotypes and inheritance patterns associated with different ROR2 mutations remain mechanistically unexplained.
- Premature termination codons (PTCs) are implicated in both RRS and BDB1, but their precise role and the influence of their location are unclear.
Purpose of the Study:
- To investigate the functional mechanisms underlying the differential phenotypes and inheritance patterns of ROR2 mutations.
- To explore the role of the nonsense-mediated decay (NMD) pathway in modulating the effects of PTC-containing ROR2 alleles.
- To determine if NMD can explain genotype-phenotype correlations in other genetic disorders caused by allelic mutations.
Main Methods:
- Analysis of PTC mutation distribution in ROR2 and correlation with phenotype and inheritance.
- Experimental investigation of the nonsense-mediated decay (NMD) pathway's involvement with specific ROR2 mutant alleles.
- Generalization of findings to other disease-associated genes with PTC mutations.
Main Results:
- The location of PTCs in ROR2 correlates with distinct phenotypes and modes of inheritance (autosomal dominant vs. recessive carrier status).
- Triggering or escaping NMD by specific ROR2 mutations leads to different disease phenotypes and inheritance patterns.
- NMD activity significantly influences the phenotypic outcome of PTC-containing alleles.
Conclusions:
- The nonsense-mediated decay (NMD) pathway is a key determinant of phenotype and inheritance patterns for ROR2 mutations.
- NMD provides a unifying mechanism to explain how allelic truncating mutations in a single gene can lead to distinct genetic disorders.
- Understanding NMD's role can improve genotype-phenotype correlations for ROR2-related disorders and potentially others involving PTC mutations.
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