The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous autosomal recessive disorder characterized by recurrent infections of the respiratory tract associated with the abnormal function of motile cilia. Approximately half of individuals with PCD also have alterations in the left-right organization of their internal organ positioning, including situs inversus and situs ambiguous (Kartagener's syndrome). Here, we identify an uncharacterized coiled-coil domain containing a protein, CCDC40, essential for correct left-right patterning in mouse, zebrafish and human. In mouse and zebrafish, Ccdc40 is expressed in tissues that contain motile cilia, and mutations in Ccdc40 result in cilia with reduced ranges of motility. We further show that CCDC40 mutations in humans result in a variant of PCD characterized by misplacement of the central pair of microtubules and defective assembly of inner dynein arms and dynein regulatory complexes. CCDC40 localizes to motile cilia and the apical cytoplasm and is required for axonemal recruitment of CCDC39, disruption of which underlies a similar variant of PCD.     

Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2

A combined genome-wide association and linkage study was used to identify loci causing variation in cystic fibrosis lung disease severity. We identified a significant association (P = 3.34 × 10(-8)) near EHF and APIP (chr11p13) in p.Phe508del homozygotes (n = 1,978). The association replicated in p.Phe508del homozygotes (P = 0.006) from a separate family based study (n = 557), with P = 1.49 × 10(-9) for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family based study identified a significant quantitative trait locus on chromosome 20q13.2 (log(10) odds = 5.03). Our findings provide insight into the causes of variation in lung disease severity in cystic fibrosis and suggest new therapeutic targets for this life-limiting disorder.     

A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation

Autosomal dominant polycystic liver disease results from mutations in PRKCSH or SEC63. The respective gene products, glucosidase IIβ and SEC63p, function in protein translocation and quality control pathways in the endoplasmic reticulum. Here we show that glucosidase IIβ and Sec63p are required in mice for adequate expression of a functional complex of the polycystic kidney disease gene products, polycystin-1 and polycystin-2. We find that polycystin-1 is the rate-limiting component of this complex and that there is a dose-response relationship between cystic dilation and levels of functional polycystin-1 following mutation of Prkcsh or Sec63. Reduced expression of polycystin-1 also serves to sensitize the kidney to cyst formation resulting from mutations in Pkhd1, the recessive polycystic kidney disease gene. Finally, we show that proteasome inhibition increases steady-state levels of polycystin-1 in cells lacking glucosidase IIβ and that treatment with a proteasome inhibitor reduces cystic disease in orthologous gene models of human autosomal dominant polycystic liver disease.     

MODELLING RANDOM CONVEX SETS

A model is developed for convex-set valued data,which are the Minkowski sum of aconvex parameter set and a convex noise set.This model is generalized to include location and scaleparameters.A further generalization results in a model for convex sets which is analogous to aone-way analysis of variance models.In each case,estimators of the parameters are given which,under certain conditions,are shown to be consistent.Data generated from the model and theestimators are studied.An outlier detection method is examined.     

Some new data concerning effect of actinomycin D on early chick embryos

Zusammenfassung Actinomycin D führte beim Hühnerembryo zu einer deutlichen Hemmung der Herzentwicklung nach Inkubation im Nährmedium während der Entwicklungsstadien 3 und 3⁺. Nach Vorbehandlung der Stadien 3–7 und anschliessender Kultur in actinomycin D-freiem Medium fanden sich Fehlbildungen von Herz, ZNS und Somiten, die in ihrer Häufigkeit von den betroffenen Entwicklungsphasen abhängig sind.

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This study was supported by a grant from the Rutgers University Research Council No. 07-2189.     

Histone hydrolase in tadpole liver

Résumé Le cytoplasme du foie de têtard contient une enzyme qui hydrolyse spécifiquement les protéines basiques telle que la polylysine, la protamine et les histones. L'addition d'autres protéines telles que l'albumine, la globuline et l'acide polyglutamique inhibe l'activité de cette enzyme. Les résultats obtenus montrent que cette hydrolysase extraite du foie de têtard diffère des cathépsines ou de l'histone-hydrolase du rein de rat.

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This work was supported by research grants from the National Institute of Arthritis and Metabolic Diseases No. AM 09602, National Science Foundation No. GB-22663 and from the National Cancer Institute No. CA 07174.