Mutation of a gene essential for ribosome biogenesis, EMG1, causes Bowen-Conradi syndrome.
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.
Armistead
Joy
J
Department of Biochemistry and Medical Genetics, University of Manitoba, MB, Canada.
Khatkar
Sunita
S
Meyer
Britta
B
Mark
Brian L
BL
Patel
Nehal
N
Coghlan
Gail
G
Lamont
Ryan E
RE
Liu
Shuangbo
S
Wiechert
Jill
J
Cattini
Peter A
PA
Koetter
Peter
P
Wrogemann
Klaus
K
Greenberg
Cheryl R
CR
Entian
Karl-Dieter
KD
Zelinski
Teresa
T
Triggs-Raine
Barbara
B
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
D012333:RNA, Messenger; C409038:nucleus-encoded phage-type RNA polymerase; D012321:DNA-Directed RNA Polymerases