Familial platelet disorder with predisposition to acute myelogenous leukaemia (FPD/AML, MIM 601399) is an autosomal dominant disorder characterized by qualitative and quantitative platelet defects, and propensity to develop acute myelogenous leukaemia (AML). Informative recombination events in 6 FPD/AML pedigrees with evidence of linkage to markers on chromosome 21q identified an 880-kb interval containing the disease gene. Mutational analysis of regional candidate genes showed nonsense mutations or intragenic deletion of one allele of the haematopoietic transcription factor CBFA2 (formerly AML1) that co-segregated with the disease in four FPD/AML pedigrees. We identified heterozygous CBFA2 missense mutations that co-segregated with the disease in the remaining two FPD/AML pedigrees at phylogenetically conserved amino acids R166 and R201, respectively. Analysis of bone marrow or peripheral blood cells from affected FPD/AML individuals showed a decrement in megakaryocyte colony formation, demonstrating that CBFA2 dosage affects megakaryopoiesis. Our findings support a model for FPD/AML in which haploinsufficiency of CBFA2 causes an autosomal dominant congenital platelet defect and predisposes to the acquisition of additional mutations that cause leukaemia.

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Caused by the presence of an extra copy of human chromosome 21 (trisomy 21), Down syndrome (DS) is the most common genetic disorder with an incidence of one in 800 live births. DS patients suffer various symptoms, including mental retardation and an early-onset of Alzheimer's disease (AD). The brains of both DS and AD patients show increased amounts of b-amyloid (Ab), which leads to the formation of amyloid plaques, a hallmark of AD pathogenesis (Mann and Esiri 1989). Although the cause of an early-onset AD in DS patients is not clearly understood (Wisniewski et al. 1985), one potential mechanism is overexpression of the gene for b-amyloid precursor protein (APP) located on chromosome 21. Three copies of the APP gene are necessary for DS-affected individuals to develop AD pathology (Prasher et al. 1998). However, this genetic background does not sufficiently account for the full spectrum of pathologies seen in AD patients; over-expres- Abbreviations used: aa, amino acids; AD, Alzheimer's disease; APP, amyloid precursor protein; APPct, C-terminal fragment of APP; Ab, b-amyloid; BACE1, b-secretase APP Cleaving Enzyme 1; DS, Down syndrome; DYRK1A, dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A; GFP, green fluorescent protein; GST, glutathione S-transferase; NGF, nerve growth factor; p-AICD, phospho-APP intracellular domain; PBS, phosphate-buffered saline; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; TG, transgenic; WT, wild-type; YF, Y321F kinase-inactive mutant. AbstractMost individuals with Down Syndrome (DS) show an earlyonset of Alzheimer's disease (AD), which potentially results from the presence of an extra copy of a segment of chromosome 21. Located on chromosome 21 are the genes that encode b-amyloid (Ab) precursor protein (APP ), a key protein involved in the pathogenesis of AD, and dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A (DYRK1A ), a proline-directed protein kinase that plays a critical role in neurodevelopment. Here, we describe a potential mechanism for the regulation of AD pathology in DS brains by DYRK1A-mediated phosphorylation of APP. We show that APP is phosphorylated at Thr668 by DYRK1A in vitro and in mammalian cells. The amounts of phospho-APP and Ab are increased in the brains of transgenic mice that over-express the human DYRK1A protein. Furthermore, we show that the amounts of phospho-APP as well as those of APP and DYRK1A are elevated in human DS brains. Taken together, these results reveal a potential regulatory link between APP and DYRK1A in DS brains, and suggest that the overexpression of DYRK1A in DS may play a role in accelerating AD pathogenesis through phosphorylation of APP.

Down syndrome (DS) is associated with a variety of symptoms, such as incapacitating mental retardation and neurodegeneration (i.e., Alzheimer's disease), that prevent patients from leading fully independent lives. These phenotypes are a direct consequence of the overexpression of chromosome 21 genes, which are present in duplicate due to non-disjunction of chromosome 21. Accumulating data suggest that the chromosome 21 gene product, dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (Dyrk1A), participates in the pathogenic mechanisms underlying the mental and other physical symptoms of DS. In this review, we summarize the evidence supporting a role for Dyrk1A in DS, especially DS pathogenesis. Recently, several natural and synthetic compounds have been identified as Dyrk1A inhibitors. Understanding the function and regulation of Dyrk1A may lead to the development of novel therapeutic agents aimed at treating DS.

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