Incidence and clinical features of X-linked Cornelia de Lange syndrome due to SMC1L1 mutations

Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder characterized by facial dysmorphism, growth and mental retardation, microcephaly, and various malformations. Heterozygous mutations in the NIPBL gene have been detected in approximately 45% of affected individuals. Recently, a second CdLS gene, mapping to the X chromosome, has been identified: SMC1L1 (structural maintenance of chromosomes 1-like 1; or SMC1A). In order to estimate the incidence and refine the clinical presentation of X-linked CdLS, we have screened a series of 11 CdLS boys carrying no NIPBL anomaly. We have identified two novel de novo SMC1L1 missense mutations (c.587G>A [p.Arg196His] and c.3254A>G [p.Tyr1085Cys]). Our results confirm that SMC1L1 mutations cause CdLS and support the view that SMC1L1 accounts for a significant fraction of boys with unexplained CdLS. Furthermore, we suggest that SMC1L1 mutations have milder effects than NIPBL mutations with respect to pre- and postnatal growth retardation and associated malformations. If confirmed, these data may have important implications for directing mutation screening in CdLS.     

From the Cover: Bacillus subtilis chromosome organization oscillates between two distinct patterns

Bacterial chromosomes have been found to possess one of two distinct patterns of spatial organization. In the first, called “ori-ter” and exemplified by Caulobacter crescentus, the chromosome arms lie side-by-side, with the replication origin and terminus at opposite cell poles. In the second, observed in slow-growing Escherichia coli (“left-ori-right”), the two chromosome arms reside in separate cell halves, on either side of a centrally located origin. These two patterns, rotated 90° relative to each other, appear to result from different segregation mechanisms. Here, we show that the Bacillus subtilis chromosome alternates between them. For most of the cell cycle, newly replicated origins are maintained at opposite poles with chromosome arms adjacent to each other, in an ori-ter configuration. Shortly after replication initiation, the duplicated origins move as a unit to midcell and the two unreplicated arms resolve into opposite cell halves, generating a left-ori-right pattern. The origins are then actively segregated toward opposite poles, resetting the cycle. Our data suggest that the condensin complex and the parABS partitioning system are the principal driving forces underlying this oscillatory cycle. We propose that the distinct organization patterns observed for bacterial chromosomes reflect a common organization–segregation mechanism, and that simple modifications to it underlie the unique patterns observed in different species.Central to reproduction is the faithful segregation of replicated chromosomes to daughter cells. In eukaryotes, DNA replication, chromosome condensation, and sister chromatid segregation are separated into distinct steps in the cell cycle that are safeguarded by checkpoint pathways. In bacteria, these processes occur concurrently, posing unique challenges to genome integrity and inheritance (1, 2). In the absence of temporal control, bacteria take advantage of spatial organization to promote faithful and efficient chromosome segregation. The organization of the chromosome dictates where the chromosome is replicated, and the factors that organize and compact the newly replicated DNA play a central role in its segregation (1, 2).Studies in different bacteria have revealed strikingly distinct patterns of chromosome organization that appear to arise from different segregation mechanisms. In Caulobacter crescentus and Vibrio cholerae chromosome I, the origin and terminus are located at opposite cell poles, with the two replication arms between them, in a pattern referred to as “ori-ter” (3–5). After replication initiation, one of the sister origins is held in place and the other is actively translocated to the opposite cell pole, regenerating the ori-ter organization in both daughter cells (5–11). By contrast, in slow-growing Escherichia coli, the origin is located in the middle of the nucleoid and the two replication arms reside in opposite cell halves, in a “left-ori-right” pattern (12, 13). Replication initiates at midcell, and the duplicated origins segregate to the quarter positions followed by the left and right arms on either side, regenerating the left-ori-right pattern in the two daughter cells.Although chromosome organization was first analyzed in the Gram-positive bacterium Bacillus subtilis, our understanding of the replication–segregation cycle in this bacterium has remained elusive. In pioneering studies, it was shown that during spore formation, the replicated origins reside at opposite cell poles and the termini at midcell in an ori-ter ter-ori organization (14–18). A similar ori-ter pattern was observed during vegetative growth (15, 19). However, in separate studies, DNA replication was found to initiate at a midcell-localized origin (20, 21). How these disparate patterns fit into a coherent replication–segregation cycle has never been addressed and motivated this study. Our analysis has revealed that the B. subtilis chromosome follows an unexpected and previously unidentified choreography during vegetative growth in which the organization alternates between ori-ter and left-ori-right patterns. Our data further suggest that the highly conserved partitioning system (parABS) and the structural maintenance of chromosomes (SMC) condensin complex, in conjunction with replication initiation, function as the core components for this oscillating cycle. We propose that this cycle enhances the efficiency of DNA replication and sister chromosome segregation and provides a unifying model for the diverse patterns of chromosome organization observed in bacteria.     

天鹅记忆加压接骨器治疗肱骨骨折加载应力的选择

目的:分析天鹅记忆加压接骨器(swan-likememoryconnector,SMC)固定肱骨时不同应力加载的选择,为今后肱骨骨折治疗时内固定器械的放置部位、载荷的施加方向及大小等提供力学依据。方法:选择湿肱骨标本行CT成像得到肱骨每层横截面图像,采用大型有限元分析软件ANSYS5.6建立肱骨、SMC以及SMC固定肱骨的三维模型。结果:所构建SMC固定肱骨三维模型,逼真反映真实解剖形态及生物力学行为,同时获得不同加载方式下肱骨的受力情况。结论:SMC固定肱骨三维有限元模型的构建,可以为肱骨正常力学行为以及骨折后内固定的力学基础研究提供精确模型。     

Spectrum and consequences of SMC1A mutations: The unexpected involvement of a core component of cohesin in human disease

SMC1A encodes a structural component of the cohesin complex, which is necessary for sister chromatid cohesion. In addition to its canonical role, cohesin has been shown to be involved in gene expression regulation and maintenance of genome stability. Recently, it has been demonstrated that mutations in the SMC1A gene are responsible for Cornelia de Lange syndrome (CdLS). CdLS is a genetically heterogeneous multisystem developmental disorder with variable expressivity, typically characterized by consistent facial dysmorphia, upper extremity malformations, hirsutism, cardiac defects, growth and cognitive retardation, gastrointestinal abnormalities, and other systemic involvement. SMC1A mutations have also been identified in colorectal cancers. So far a total of 26 different mutations of the SMC1A gene have been reported. All mutations reported to date are either missense or small in‐frame deletions that maintain the open reading frame and presumably result in a protein with residual function. The mutations involve all domains of the protein but appear to cluster in key functional loci. At the functional level, elucidation of the effects that specific SMC1A mutations have on cohesin activity will be necessary to understand the etiopathology of CdLS and its possible involvement in tumorigenesis. In this review, we summarize the current knowledge of SMC1A mutations. Hum Mutat 30:1–6, 2009. © 2009 Wiley‐Liss, Inc.     

Effects of vitamin D on aortic smooth muscle cells in culture

Earlier investigations on vitamin-induced experimental atherosclerosis in rats suggested that smooth muscle cells (SMCs) play a pivotal role in development of these vascular abnormalities. This study demonstrates the effects of vitamin D (ergocalciferol) on SMCs of rat aorta in tissue culture. SMCs were obtained from aortas of newborn rats by enzymatic digestion and maintained for 6 wk in primary culture with vitamin D (1.2 n ) in the culture medium. The effects of vitamin D on SMCs, as compared with control SMCs cultures, were evaluated by light and electron microscopy. Growth of SMCs was characterized by cell counting, measurement of DNA and protein content, and by analysis of the nucleolar organizing regions. Vitamin D had no effect on proliferation of SMCs but stimulated synthesis and intercellular deposition of elastic fibres and had a stabilizing effect on the musculo-elastic multilayer formed by the cultured cells. In addition, it prevented degeneration of SMCs, with long-term preservation of the typical phenotype in primary culture.