| Shwachman-Diamond syndrome (OMIM 260400) is a rare, autosomal recessive disorder characterized by pancreatic exocrine insufficiency, hematological dysfunction, and skeletal abnormalities. Clinical diagnosis of SDS can be challenging due to the variable and intermittent nature of phenotypic components. Diagnosis would be facilitated by identification of the SDS gene, and development of a rapid molecular test.;Eighteen positional candidate genes were identified in extant sequences and prioritised for mutation screening based on ascribed functions and expression profiling. Disease-associated mutations were identified in the SBDS gene, which was locally duplicated at 7q11. Sixty percent of mutations were gene conversions that arose due to recombination between SBDS and a highly homologous pseudogene. Patient mutation data and model organism studies suggested the gene is essential, with symptoms arising due to hypomorphic alleles. Indirect evidence suggests that SBDS functions in RNA metabolism or ribosome assembly or function.;SBDS is ubiquitously expressed, and highly conserved, with homologues in all sequenced archaeal and eukaryotic genomes. The recent crystal structure of an archaeal homologue revealed a three domain arrangement. Alignment of homologues revealed that domain one was the most highly conserved across species, followed by domains two and three, respectively. A functional complementation assay was developed in Saccharomyces cerevisiae and used to assess chimeric proteins. Domain one was functionally interchangeable between distantly related Eukaryotes. Domain two imparted species specificity, while domain three was non-essential.;Elucidation of the molecular etiology of SDS should lead to improved treatments, including pharmacological and gene-based therapies.;Genetic studies in multiplex families identified a single 1.9 cM co-segregating locus at 7q11, but had exhausted informative families and genetic markers. Physical mapping was initiated as part of a positional cloning approach to gene identification. A partial map of the interval was constructed from available genomic sequences. This was comprised of 3.5 Mb and four gaps of unknown size. Features of the region were typical of other characterised pericentromeric loci. For example, a proximal region was composed of a mosaic of recent segmental duplications. |
