title: Mutation of a gene essential for ribosome biogenesis, EMG1, causes Bowen-Conradi syndrome.
abstract: Bowen-Conradi syndrome (BCS) is an autosomal-recessive disorder characterized by severely impaired prenatal and postnatal growth, profound psychomotor retardation, and death in early childhood. Nearly all reported BCS cases have been among Hutterites, with an estimated birth prevalence of 1/355. We previously localized the BCS gene to a 1.9 Mbp interval on human chromosome 12p13.3. The 59 genes in this interval were ranked as candidates for BCS, and 35 of these, including all of the best candidates, were sequenced. We identified variant NM_006331.6:c.400A-->G, p.D86G in the 18S ribosome assembly protein EMG1 as the probable cause of BCS. This mutation segregated with disease, was not found in 414 non-Hutterite alleles, and altered a highly conserved aspartic acid (D) residue. A structural model of human EMG1 suggested that the D86 residue formed a salt bridge with arginine 84 that would be disrupted by the glycine (G) substitution. EMG1 mRNA was detected in all human adult and fetal tissues tested. In BCS patient fibroblasts, EMG1 mRNA levels did not differ from those of normal cells, but EMG1 protein was dramatically reduced in comparison to that of normal controls. In mammalian cells, overexpression of EMG1 harboring the D86G mutation decreased the level of soluble EMG1 protein, and in yeast two-hybrid analysis, the D86G substitution increased interaction between EMG1 subunits. These findings suggested that the D-to-G mutation caused aggregation of EMG1, thereby reducing the level of the protein and causing BCS.
authors.affiliation: Department of Biochemistry and Medical Genetics, University of Manitoba, MB, Canada.
authors.forename: Joy
authors.initials: J
authors.lastname: Armistead
authors.forename: Sunita
authors.initials: S
authors.lastname: Khatkar
authors.forename: Britta
authors.initials: B
authors.lastname: Meyer
authors.forename: Brian L
authors.initials: BL
authors.lastname: Mark
authors.forename: Nehal
authors.initials: N
authors.lastname: Patel
authors.forename: Gail
authors.initials: G
authors.lastname: Coghlan
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Lamont
authors.forename: Shuangbo
authors.initials: S
authors.lastname: Liu
authors.forename: Jill
authors.initials: J
authors.lastname: Wiechert
authors.forename: Peter A
authors.initials: PA
authors.lastname: Cattini
authors.forename: Peter
authors.initials: P
authors.lastname: Koetter
authors.forename: Klaus
authors.initials: K
authors.lastname: Wrogemann
authors.forename: Cheryl R
authors.initials: CR
authors.lastname: Greenberg
authors.forename: Karl-Dieter
authors.initials: KD
authors.lastname: Entian
authors.forename: Teresa
authors.initials: T
authors.lastname: Zelinski
authors.forename: Barbara
authors.initials: B
authors.lastname: Triggs-Raine
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics*; D006224:Cricetinae; D012321:DNA-Directed RNA Polymerases / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005808:Genes, Recessive; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D001678:Organelle Biogenesis; D010375:Pedigree; D011487:Protein Conformation; D011596:Psychomotor Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; D020798:Two-Hybrid System Techniques
chemical_list: D012333:RNA, Messenger; C409038:nucleus-encoded phage-type RNA polymerase; D012321:DNA-Directed RNA Polymerases