).Mutations in BRCA1 and BRCA2 confer a high risk of breast and ovarian cancer 1 , but account for only a small fraction of breast cancer susceptibility 1,2 . To find additional genes conferring susceptibility to breast cancer, we analyzed CHEK2 (also known as CHK2), which encodes a cell-cycle checkpoint kinase that is implicated in DNA repair processes involving BRCA1 and p53 (refs 3-5). We show that CHEK2*1100delC, a truncating variant that abrogates the kinase activity 6 , has a frequency of 1.1% in healthy individuals. However, this variant is present in 5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P=0.00000003), including 13.5% of individuals from families with male breast cancer (P=0.00015). We estimate that the CHEK2*1100delC variant results in an approximately twofold increase of breast cancer risk in women and a tenfold increase of risk in men. By contrast, the variant confers no increased cancer risk in carriers of BRCA1 or BRCA2 mutations. This suggests that the biological mechanisms underlying the elevated risk of breast cancer in CHEK2 mutation carriers are already subverted in carriers of BRCA1 or BRCA2 mutations, which is consistent with participation of the encoded proteins in the same pathway.

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Abstract-The Fibulins are a 6-member protein family hypothesized to function as intermolecular bridges that stabilize the organization of extracellular matrix structures. Here, we show that reduced expression of Fibulin-4 leads to aneurysm formation, dissection of the aortic wall and cardiac abnormalities. Fibulin-4 knockdown mice with a hypomorphic expression allele arose from targeted disruption of the adjacent Mus81 endonuclease gene. Mice homozygous for the Fibulin-4 reduced expression allele (Fibulin-4 R/R ) show dilatation of the ascending aorta and a tortuous and stiffened aorta, resulting from disorganized elastic fiber networks. They display thickened aortic valvular leaflets that are associated with aortic valve stenosis and insufficiency. Strikingly, already a modest reduction in expression of Fibulin-4 in the heterozygous ϩ/R mice occasionally resulted in small aneurysm formation. To get insight into the underlying molecular pathways involved in aneurysm formation and response to aortic failure, we determined the aorta transcriptome of ϩ/R and Fibulin-4 R/R animals and identified distinct and overlapping biological processes that were significantly overrepresented including cytoskeleton organization, cell adhesion, apoptosis and several novel gene targets. Transcriptome and protein expression analysis implicated perturbation of TGF-␤ signaling in the pathogenesis of aneurysm in fibulin-4 deficient mice. Our results show that the dosage of a single gene can determine the severity of aneurysm formation and imply that disturbed TGF-␤ signaling underlies multiple aneurysm phenotypes. (Circ Res. 2007;100:738-746.)Key Words: aneurysm Ⅲ aortic valve Ⅲ mouse model E xtracellular elastic fibers supply structure and mechanical elasticity to organs such as large arteries, lungs and skin. 1 Elastic fibers are assembled through polymerization of tropoelastin monomers and loss of elastin is associated with aneurysmal degeneration of the aorta. 2 The 6-member protein family of Fibulins, which are prominently expressed in blood vessels are hypothesized to function as intermolecular bridges that stabilize the organization of extracellular structures such as elastic fibers and basement membranes. 3 Fibulin-4 is found in the medial layers of arteries and heart valves. 4 Whereas complete Fibulin-4 knockout mice have recently been generated 5 and showed embryonic lethality (E12.5), we generated a Fibulin-4 allele with reduced expression by transcriptional interference through placement of a TKneo targeting construct in a downstream gene (Mus81). Mus81 knockout mice have been generated previously. 6,7 In the targeting strategy of Dendouga et al, exons 9 to 12 were replaced by a PGKneo marker flanked by loxP sites and subsequently the marker was excised using Cre-recombinase expressing mice. Mus81 knockout mice from which the selectable marker was removed were born at expected Mendelian frequencies and were indistinguishable from WT littermates in terms of development, growth, immune function and fertility. 6 To examine ...

We identified, by homozygosity mapping, a novel locus on 10q21.3-q22.1 for Goldberg-Shprintzen syndrome (GOSHS) in a consanguineous Moroccan family. Phenotypic features of GOSHS in this inbred family included microcephaly and mental retardation, which are both central nervous system defects, as well as Hirschsprung disease, an enteric nervous system defect. Furthermore, since bilateral generalized polymicogyria was diagnosed in all patients in this family, this feature might also be considered a key feature of the syndrome. We demonstrate that homozygous nonsense mutations in KIAA1279 at 10q22.1, encoding a protein with two tetratrico peptide repeats, underlie this syndromic form of Hirschsprung disease and generalized polymicrogyria, establishing the importance of KIAA1279 in both enteric and central nervous system development.