Recently, a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 was reported as the cause of chromosome 9p21-linked frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS). We here report the prevalence of the expansion in a hospital-based cohort and associated clinical features indicating a wider clinical spectrum of C9ORF72 disease than previously described. We studied 280 patients previously screened for mutations in genes involved in early onset autosomal dominant inherited dementia disorders. A repeat-primed polymerase chain reaction amplification assay was used to identify pathogenic GGGGCC expansions. As a potential modifier, confirmed cases were further investigated for abnormal CAG expansions in ATXN2. A pathogenic GGGGCC expansion was identified in a total of 14 probands. Three of these presented with atypical clinical features and were previously diagnosed with clinical olivopontocerebellar degeneration (OPCD), atypical Parkinsonian syndrome (APS) and a corticobasal syndrome (CBS). Further, the pathogenic expansion was identified in six FTD patients, four patients with FTD-ALS and one ALS patient. All confirmed cases had normal ATXN2 repeat sizes. Our study widens the clinical spectrum of C9ORF72 related disease and confirms the hexanucleotide expansion as a prevalent cause of FTD-ALS disorders. There was no indication of a modifying effect of the ATXN2 gene.

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The homeodomain protein PDX-1 is critical for pancreas development and is a key regulator of insulin gene expression. PDX-1 nullizygosity and haploinsufficiency in mice and humans results in pancreatic agenesis and diabetes, respectively. At embryonic day (e) 10.5, PDX-1 is expressed in all pluripotential gut-derived epithelial cells destined to differentiate into the exocrine and endocrine pancreas. At e15, PDX-1 expression is downregulated in exocrine cells, but remains high in endocrine cells. The aim of this study was to determine whether targeted overexpression of PDX-1 to the exocrine compartment of the developing pancreas at e15 would allow for respecification of the exocrine cells. Transgenic (TG) mice were generated in which PDX-1 was expressed in the exocrine pancreas using the exocrine-specific elastase-1 promoter. These mice exhibited a marked dysmorphogenesis of the exocrine pancreas, manifested by increased rates of replication and apoptosis in acinar cells and a progressive fatty infiltration of the exocrine pancreas with age. Interestingly, the TG mice exhibited improved glucose tolerance, but absolute ␤-cell mass was not increased. These findings indicate that downregulation of PDX-1 is required for the proper maintenance of the exocrine cell phenotype and that upregulation of PDX-1 in acinar cells affects ␤-cell function. The mechanisms underlying these observations remain to be elucidated. Diabetes 50: 1553-1561, 2001 P DX-1 (also known as IDX-1/STF-1/IPF-1) is a homeodomain transcription factor evolutionarily derived from the Parahox amphilox three-gene cluster and is a critical determinant of pancreas development in higher vertebrates (1-4). The early embryonic expression of PDX-1 demarcates the dorsal and ventral regions of the primitive mouse gut from which the two pancreatic buds emerge. As development proceeds, PDX-1 is expressed in the pancreas, the posterior portion of the developing primitive stomach epithelium, the anterior region of the duodenum, and the yolk sac (5). In the fully developed adult pancreas, PDX-1 expression is restricted predominantly to the endocrine pancreas (islets of Langerhans) in the insulin-producing ␤-cells and in a fraction of the somatostatin-producing ␦-cells, as well as in a subpopulation of cells in the pancreatic ducts that are pluripotential progenitors for ␤-cells (6,7). PDX-1 is a transcriptional activator of the insulin, somatostatin, glucokinase, and GLUT2 genes (2-4), and is involved in regulating glucose responsiveness of the insulin promoter (8,9).The importance of PDX-1 in pancreatic development is demonstrated by the consequences of the loss of PDX-1 function. Targeted disruption of the pdx-1 gene in mice and an inactivating mutation of pdx-1 (ipf-1) in a human infant (10) manifest as agenesis of the pancreas (11,12). Conditional disruption of the pdx-1 gene selectively in ␤-cells of mice using the Cre/Lox approach results in a progressive loss of ␤-cells and the development of diabetes in mice by age 5-6 months (13). Mice (14) and humans (10)...