Endoglin (CD105) is expressed on the surface of endothelial and haematopoietic cells in mammals and binds TGFbeta isoforms 1 and 3 in combination with the signaling complex of TGFbeta receptors types I and II. Endoglin expression increases during angiogenesis, wound healing, and inflammation, all of which are associated with TGFbeta signaling and alterations in vascular structure. The importance of endoglin for normal vascular architecture is further indicated by the association of mutations in the endoglin gene with the inherited disorder Hereditary Haemorrhagic Telangiectasia Type 1 (HHT1), a disease characterised by bleeding from vascular malformations. In order to study the role of endoglin in vivo in more detail and to work toward developing an animal model of HHT1, we have derived mice that carry a targeted nonsense mutation in the endoglin gene. Studies on these mice have revealed that endoglin is essential for early development. Embryos homozygous for the endoglin mutation fail to progress beyond 10.5 days postcoitum and fail to form mature blood vessels in the yolk sac. This phenotype is remarkably similar to that of the TGFbeta1 and the TGFbeta receptor II knockout mice, indicating that endoglin is needed in vivo for TGFbeta1 signaling during extraembryonic vascular development. In addition, we have observed cardiac defects in homozygous endoglin-deficient embryos, suggesting endoglin also plays a role in cardiogenesis. We anticipate that heterozygous mice will ultimately serve as a useful disease model for HHT1, as some individuals have dilated and fragile blood vessels similar to vascular malformations seen in HHT patients.

Alström syndrome (OMIM 203800) is an autosomal recessive disease, characterized by cone-rod retinal dystrophy, cardiomyopathy and type 2 diabetes mellitus, that has been mapped to chromosome 2p13 (refs 1-5). We have studied an individual with Alström syndrome carrying a familial balanced reciprocal chromosome translocation (46, XY,t(2;11)(p13;q21)mat) involving the previously implicated critical region. We postulated that this individual was a compound heterozygote, carrying one copy of a gene disrupted by the translocation and the other copy disrupted by an intragenic mutation. We mapped the 2p13 breakpoint on the maternal allele to a genomic fragment of 1.7 kb which contains exon 4 and the start of exon 5 of a newly discovered gene (ALMS1); we detected a frameshift mutation in the paternal copy of the gene. The 12.9-kb transcript of ALMS1 encodes a protein of 4,169 amino acids whose function is unknown. The protein contains a large tandem-repeat domain comprising 34 imperfect repetitions of 47 amino acids. We have detected six different mutations (two nonsense and four frameshift mutations causing premature stop codons) in seven families, confirming that ALMS1 is the gene underlying Alström syndrome. We believe that ALMS1 is the first human disease gene characterized by autosomal recessive inheritance to be identified as a result of a balanced reciprocal translocation.Alström syndrome was initially mapped to an interval of 6.1 cM between loci D2S286 and D2S327 (refs 3-5). Although several candidate genes have been investigated, no mutations have previously been identified [6][7][8] . We have shown that the 2p13 breakpoint in the individual with the 46,XY,t(2;11)(p13;q21)mat translocation is between these loci by metaphase fluorescence in situ hybridization (FISH) analysis using the BACs RP11-355F16 (containing D2S286) and RP11-480F1 (located 150 kb proximal to D2S327) as probes. The BAC RP11-582H21 crosses the translocation breakpoint (Fig. 1a,b) and is overlapped by RP11-79N18, which contains CCT7, a member of a chaperonin gene

Alströ m syndrome is a rare autosomal recessive disorder caused by mutations in a novel gene of unknown function, ALMS1. Central features of Alströ m syndrome include obesity, insulin resistance, and type 2 diabetes, and therefore investigating ALMS1 function stands to offer new insights into the pathogenesis of these common conditions. To begin this process, we have analyzed the subcellular localization and tissue distribution of ALMS1 by immunofluorescence. We show that ALMS1 is widely expressed and localizes to centrosomes and to the base of cilia. Fibroblasts with disrupted ALMS1 assemble primary cilia and microtubule cytoskeletons that appear normal, suggesting that the Alströ m syndrome phenotype results from impaired function rather than abnormal development. Coupled with recent data on the complex phenotype of Bardet-Biedl syndrome, our findings imply an unexpected central role for basal body and centrosome dysfunction in the pathogenesis of obesity, insulin resistance, and type 2 diabetes. Unraveling the molecular mechanisms underlying the Alströ m syndrome phenotype will be important in the search for new therapeutic targets for these conditions. Diabetes

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