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Mutation of a gene essential for ribosome biogenesis, EMG1, causes Bowen-Conradi syndrome

Joy Armistead1, Sunita Khatkar, Britta Meyer

  • 1Department of Biochemistry and Medical Genetics, University of Manitoba, MB, Canada.

American Journal of Human Genetics
|May 26, 2009
PubMed

Insights

Bowen-Conradi syndrome (BCS) is caused by a mutation in the EMG1 gene, leading to reduced protein levels and severe developmental issues. This genetic disorder primarily affects the Hutterite population.

Area of Science:

  • Genetics and Molecular Biology
  • Human Disease Pathogenesis

Background:

  • Bowen-Conradi syndrome (BCS) is a severe autosomal-recessive disorder with significant growth impairment and psychomotor retardation, predominantly observed in the Hutterite community.
  • Previous research localized the BCS-associated gene to a specific interval on human chromosome 12p13.3.

Purpose of the Study:

  • To identify the specific genetic mutation responsible for Bowen-Conradi syndrome (BCS).
  • To elucidate the molecular mechanism by which the identified mutation leads to BCS.

Main Methods:

  • Candidate gene sequencing within the 1.9 Mbp chromosomal interval linked to BCS.
  • Segregation analysis and population screening of the identified variant in Hutterite and non-Hutterite populations.
  • Structural modeling, mRNA expression analysis, protein level assessment, and in vitro functional assays (mammalian cell overexpression, yeast two-hybrid).

Main Results:

  • A specific variant, c.400A-->G (p.D86G), in the 18S ribosome assembly protein EMG1 gene was identified as the probable cause of BCS.
  • The mutation segregated with the disease in affected families and was absent in control populations, indicating its causative role.
  • The D86G substitution disrupts a conserved salt bridge, leading to EMG1 protein aggregation, reduced soluble protein levels, and altered protein interactions.

Conclusions:

  • The identified mutation in the EMG1 gene is the likely cause of Bowen-Conradi syndrome (BCS).
  • The pathogenic mechanism involves protein aggregation due to the mutation, resulting in a functional deficiency of EMG1 protein.
  • This finding provides critical insight into the molecular basis of BCS and its impact on early childhood development.

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