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Mystery behind Bowen–Conradi syndrome solved: a novel ribosome biogenesis defect

In the 1870s approximately 100 individuals from an Anabaptist sect in Switzerland migrated to the North American prairie, forming a community known as the Hutterite Brethren (1). Following the traditions and beliefs of their founders, the Hutterites still live in small isolated communities and rarely form familial ties with non-Hutterites. The current Hutterite population is estimated to be approximately 40,000 individuals, all descendants of the original 100 founders. Due to the high rate of consanguinity within the Hutterite population, many individuals suffer from genetic conditions that are rarely found in the North American general population. Bowen–Conradi syndrome (BCS) is one of the more serious conditions afflicting this population with a sobering incidence of 1 in 355 live births. BCS is a lethal autosomal recessive disease, causing death usually within the first 2 years. It is primarily characterized by preand postnatal growth retardation, microcephally, micrognathia, a prominent nose with a noticeable lack of glabellar angle, flexion contraction of joints, rockerbottom feet, camptodactyly and severe psychomotor delay (1). The rapid decline and demise of BCS patients is primarily the result of failure to thrive due to feeding difficulties which commonly leads to aspiration and repeated bouts of pneumonia. Although the high rate of consanguinity among Hutterites has led the prevalence of BCS, it also provides a clue for researchers looking for the genetic cause of BCS, identity by decent at a linked locus. By conducting a genome-wide scan looking both for linkage and homozygosity a previous study identified a 3.5 cM (1.9 Mbp) region located on chromosome 12p13.3 predicted to contain the causative BCS gene (2). This region contains 59 known or suspected genes and it was the aim of this current study to identify the affected BCS gene. Initial transcription expression assays of the 59 candidate genes revealed no differences in levels or transcript lengths between affected and unaffected subjects, indicating that the BCS mutation did not affect transcriptional activation or splicing of the affected gene. Sequencing of the candidate genes revealed 59 known and 6 novel single nucleotide polymorphisms (SNPs). Of the 59 known SNPs, only 6 were non-synonymous changes or did not reside in introns, however, all 59 SNPs were excluded due to their known presence in the known SNP database. Of the six novel SNPs five were found in intronic regions and the final SNP c.400A→G, p.D86G resides in the coding sequence of essential for mitotic growth 1 (EMG1 ). This SNP segregated completely with disease and was not found in any unaffected family members nor was it found in control individuals from the general population. Sequence alignment of several orthologs of EMG1 revealed it to be highly conserved, and the identified SNP resides within one of the most conserved regions. EMG1 is more commonly known by the name of its yeast ortholog, nucleolar essential protein 1 (NEP1). Several yeast studies have revealed NEP1 to be involved in pre-rRNA processing during ribosomal biogenesis (3, 4). Specifically, NEP1 is thought to be involved in the maturation process of 18S rRNA, a component of the 40S subunit of eukaryotic ribosomes. NEP1 is believed to be involved in methylation of the rRNA, which is thought to aid in attaining the correct conformation of the rRNA as well as protein or RNA interactions. The authors of this study used the sequence homology of EMG1 orthalogs as well as previous graphic models of EMG1 to graphically model both monomeric and homodimeric EMG1 (5). The monomeric EMG1 was found to contain a core α/β knot fold, a characteristic feature of SPOUT super family of methyltransferases, which are known to methylate tRNA and rRNA. The dimeric model identified a methyl donor binding pocket. The graphic model indicated that D86 (which is changed to a G in the identified SNP) forms hydrogen bonds with R84, these hydrogen bonds stabilize R84, which is positioned in the RNA binding grove of the EMG1 dimer. The authors found EMG1 to be expressed in most tissues, with slightly stronger expression found in the heart, liver, stomach, kidney and brain of normal individuals. Using semi-quantitative PCR, upregulation in fetal brain over adult brain was found. This is consistent with the finding in