REVIEWS

Book reviewed in this article:
The Shape of Things that Come.: Sexual Selection and Animal Genitalia .—William G. Eberhard.
Die Art in Raum und Zeit: Das Artkonzept in der Biologie und Palaontologie .—Rainer Willmann     

Retracted: Established and emerging pathogens in Ixodes ricinus ticks collected from birds on a conservation island in the Baltic Sea

The following article from Medical and Veterinary Entomology, ‘Established and emerging pathogens in Ixodes ricinus ticks collected from birds on a conservation island in the Baltic Sea’ by J. Franke, F. Meier, A. Moledenhauer, E. Straube, W. Dorne and A. Hildebrandt, published online on 26 September 2010 in Wiley Online Library ( wileyonlinelibrary.com ), has been retracted by agreement between the journal Editors, Doug D. Colwell, Mary Cameron, Domenico Otranto and Hilary Ranson and Blackwell Publishing Ltd. and with the knowledge of the authors. The retraction has been agreed due to overlap between this article and the following articles published in the journal Ticks and Tick‐borne Diseases: ‘The potential role of migratory birds in transmission cycles of Babesia spp., Anaplasma phagocytophilum, and Rickettsia spp.’ by Anke Hildebrandt, Jan Franke, Frank Meier, Svea Sachse, Wolfram Dorn and Eberhard Straube. Ticks and Tick‐Bourne Diseases, Volume 1 Issue 2, 2010, pages 105–107 DOI: 10.1016/j.ttbdis.2009.12.003 http://www.sciencedirect.com/science/article/pii/S1877959X10000105 and Are birds reservoir hosts for Borrelia afzelii? By Jan Franke, Anja Moldenhauer, A., Anke Hildebrandt, Wolfram Dorn, Ticks and Tick‐Borne Diseases, Volume 1 Issue 2, 109–112 DOI: 10.1016/j.ttbdis.2010.03.001 http://www.sciencedirect.com/science/article/pii/S1877959X10000336     

Mechanical stretch increases CCN2/CTGF expression in anterior cruciate ligament-derived cells

Wolfram syndrome (WFS) is a rare hereditary disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). It is a heterogeneous disease and full characterization of all clinical and biological features of this disorder is difficult. The wide spectrum of clinical expression, affecting several organs and tissues, and the similarity in phenotype between patients with Wolfram syndrome and those with certain types of respiratory chain diseases suggests mitochondrial DNA (mtDNA) involvement in Wolfram syndrome patients. We report a Tunisian patient with clinical features of moderate Wolfram syndrome including diabetes, dilated cardiomyopathy and neurological complications. The results showed the presence of the mitochondrial ND1 m.3337G>A mutation in almost homoplasmic form in 3 tested tissues of the proband (blood leukocytes, buccal mucosa and skeletal muscle). In addition, the long-range PCR amplifications revealed the presence of multiple deletions of the mitochondrial DNA extracted from the patient’s skeletal muscle removing several tRNA and protein-coding genes. Our study reported a Tunisian patient with clinical features of moderate Wolfram syndrome associated with cardiomyopathy, in whom we detected the ND1 m.3337G>A mutation with mitochondrial multiple deletions.     

Homozygosity mapping identifies an additional locus for Wolfram syndrome on chromosome 4q

Wolfram syndrome, which is sometimes referred to as "DIDMOAD" (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness), is an autosomal recessive neurodegenerative disorder for which only insulin-dependent diabetes mellitus and optic atrophy are necessary to make the diagnosis. Researchers have mapped Wolfram syndrome to chromosome 4p16.1, and, recently, a gene encoding a putative transmembrane protein has been cloned and mutations have been identified in patients. To pursue the possibility of locus heterogeneity, 16 patients from four different families were recruited. These patients, who have the Wolfram syndrome phenotype, also have additional features that have not previously been reported. There is an absence of diabetes insipidus in all affected family members. In addition, several patients have profound upper gastrointestinal ulceration and bleeding. With the use of three microsatellite markers (D4S432, D4S3023, and D4S2366) reported to be linked to the chromosome 4p16.1 locus, we significantly excluded linkage in three of the four families. The two affected individuals in one family showed homozygosity for all three markers from the region of linkage on chromosome 4p16.1. For the other three families, genetic heterogeneity for Wolfram syndrome was verified by demonstration of linkage to chromosome 4q22-24. In conclusion, we report the unique clinical findings and linkage-analysis results of 16 patients with Wolfram syndrome and provide further evidence for the genetic heterogeneity of this disorder. We also provide data on a new locus that plays a role in the etiology of insulin-dependent diabetes mellitus.     

Clinical and Molecular Genetic Analysis of 19 Wolfram Syndrome Kindreds Demonstrating a Wide Spectrum of Mutations in WFS1

Wolfram syndrome is an autosomal recessive neurodegenerative disorder characterized by juvenile-onset diabetes mellitus and progressive optic atrophy. mtDNA deletions have been described, and a gene (WFS1) recently has been identified, on chromosome 4p16, encoding a predicted 890 amino acid transmembrane protein. Direct DNA sequencing was done to screen the entire coding region of the WFS1 gene in 30 patients from 19 British kindreds with Wolfram syndrome. DNA was also screened for structural rearrangements (deletions and duplications) and point mutations in mtDNA. No pathogenic mtDNA mutations were found in our cohort. We identified 24 mutations in the WFS1 gene: 8 nonsense mutations, 8 missense mutations, 3 in-frame deletions, 1 in-frame insertion, and 4 frameshift mutations. Of these, 23 were novel mutations, and most occurred in exon 8. The majority of patients were compound heterozygotes for two mutations, and there was no common founder mutation. The data were also analyzed for genotype-phenotype relationships. Although some interesting cases were noted, consideration of the small sample size and frequency of each mutation indicated no clear-cut correlations between any of the observed mutations and disease severity. There were no obvious mutation hot spots or clusters. Hence, molecular screening for Wolfram syndrome in affected families and for Wolfram syndrome-carrier status in subjects with psychiatric disorders or diabetes mellitus will require complete analysis of exon 8 and upstream exons.     

Wolfram syndrome-associated mutations lead to instability and proteasomal degradation of wolframin

Wolfram syndrome is caused by mutations in WFS1 encoding wolframin, a polytopic membrane protein of the endoplasmic reticulum. Here, we investigated the molecular pathomechanisms of four missense and two truncating mutations in WFS1. Expression in COS-7 cells as well as direct analysis of patient cells revealed that WFS1 mutations lead to drastically reduced steady-state levels of wolframin. All mutations resulted in highly unstable proteins which were delivered to proteasomal degradation. No wolframin aggregates were found in patient cells suggesting that Wolfram syndrome is not a disease of protein aggregation. Rather, WFS1 mutations cause loss-of-function by cellular depletion of wolframin.     

Maternal filarial infection - a persistent risk factor for microfilaremia in offspring?

The observation that children born to mothers that are infected with Wuchereria bancrofti ore more susceptible to filarial infection than those born to uninfected mothers, raises many questions, particularly regarding immune mechanisms. In this article, Allen Hightower, Patrick Lommie and Mark Eberhard discuss these issues and their implications for the epidemiology of filarial infection.     

Evidence of an increased risk of hearing loss in heterozygous carriers in a Wolfram syndrome family

Wolfram syndrome (MIM 222300) is characterized by juvenile-onset diabetes mellitus and optic atrophy. Previous linkage analyses in the United States and UK families have indicated that the gene for Wolfram syndrome (WFS) is localized on the short arm of chromosome 4. We herein confirm the linkage of the WFS locus to D4S3023 on 4p with a two-point LOD score of 3.42 in a large Japanese family with Wolfram syndrome. Multipoint linkage analysis revealed the maximum LOD score of 4.82 between D4S3023 and D4S394. We also evaluated putative health risks in carriers by multiple logistic analysis with independent variables, age, gender, and numbers of affected haplotypes and with dependent variables, such as hearing loss, diabetes mellitus, polyuria, incontinence, psychological illness, and visual acuity. The results showed that the putative disease haplotype increased a risk of hearing loss (odds ratio =35.68, 95% confidence interval =4.12–308.95) and diabetes mellitus (odds ratio =7.57, 95% confidence interval =2.03–28.23) independently. This is the first report of an increased health risk of illness in carriers, other than for psychiatric disease. Received: 23 June 1998 / Accepted: 15 August 1998     

Linkage of Wolfram syndrome to chromosome 4p16.1 and evidence for heterogeneity.

Wolfram syndrome (DIDMOAD syndrome; MIM 222300) is an autosomal recessive neurodegenerative disorder characterized by juvenile-onset diabetes mellitus and bilateral optic atrophy. Previous linkage analysis of multiply affected families indicated that the gene for Wolfram syndrome is on chromosome 4p, and it produced no evidence for locus heterogeneity. We have investigated 12 U.K. families with Wolfram syndrome, and we report confirmation of linkage to chromosome 4p, with a maximum two-point LOD score of 4.6 with DRD5, assuming homogeneity, and of 5.1, assuming heterogeneity. Overlapping multipoint analysis using six markers at a time produced definite evidence for locus heterogeneity: the maximum multipoint LOD score under homogeneity was <2, whereas when heterogeneity was allowed for an admixture a LOD of 6.2 was obtained in the interval between D4S432 and D4S431, with the peak close to the marker D4S3023. One family with an atypical phenotype was definitely unlinked to the region. Haplotype inspection of the remaining 11 families, which appear linked to chromosome 4p and had typical phenotypes, revealed crossover events during meiosis, which also placed the gene in the interval D4S432 and D4S431. In these families no recombinants were detected with the marker D4S3023, which maps within the same interval.     

Identification, characterization and comparative analysis of a novel chorismate mutase gene in Arabidopsis thaliana

Phenylalanine, tyrosine, and tryptophan have a dual biosynthetic role in plants; they are required for protein synthesis and are also precursors to a number of aromatic secondary metabolites critical to normal development and stress responses. Whereas much has been learned in recent years about the genetic control of tryptophan biosynthesis in Arabidopsis and other plants, relatively little is known about the genetic regulation of phenylalanine and tyrosine synthesis. We have isolated, characterized and determined the expression of Arabidopsis thaliana genes encoding chorismate mutase, the enzyme catalyzing the first committed step in phenylalanine and tyrosine synthesis. Three independent Arabidopsis chorismate mutase cDNAs were isolated by functional complementation of a Saccharomyces cerevisiae mutation. Two of these cDNAs have been reported independently (Eberhard et al., 1993. FEBS 334, 233-236; Eberhard et al., 1996. Plant J. 10, 815-821), but the third (designated CM-3) represents a novel gene. The different organ-specific expression patterns of these cDNAs, their regulation in response to pathogen infiltration, as well as the different enzymatic characteristics of the proteins they encode are also described. Together, these data suggest that each isoform may play a distinct physiological role in coordinating chorismate mutase activity with developmental and environmental signals.     

WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells

In Wolfram syndrome, a rare form of juvenile diabetes, pancreatic beta-cell death is not accompanied by an autoimmune response. Although it has been reported that mutations in the WFS1 gene are responsible for the development of this syndrome, the precise molecular mechanisms underlying beta-cell death caused by the WFS1 mutations remain unknown. Here we report that WFS1 is a novel component of the unfolded protein response and has an important function in maintaining homeostasis of the endoplasmic reticulum (ER) in pancreatic beta-cells. WFS1 encodes a transmembrane glyco-protein in the ER. WFS1 mRNA and protein are induced by ER stress. The expression of WFS1 is regulated by inositol requiring 1 and PKR-like ER kinase, central regulators of the unfolded protein response. WFS1 is normally up-regulated during insulin secretion, whereas inactivation of WFS1 in beta-cells causes ER stress and beta-cell dysfunction. These results indicate that the pathogenesis of Wolfram syndrome involves chronic ER stress in pancreatic beta-cells caused by the loss of function of WFS1.     

Emerging data on pollen tube growth and fertilization in flowering plants, 1990–1995

Summary Since its discovery at the end of the last century, double fertilization remains of central interest in plant reproductive biology research. Although the sequence of events leading to fertilization is well known from cytological studies, the underlying mechanisms remain to be elucidated. This now seems feasible by the diversification and refinement of recently developed technologies presented in this review. The progress made during the last five years in understanding pollen tube guidance, discharge into the embryo sac, and gametic fusion are described. Future directions are also discussed.Dedicated to Prof. Dr. Dr. h.c. Eberhard Schnepf on the occasion of his retirement     

Mathematica packages for simulation of experimental genetics

This note describes add-on packages for the Mathematica software system (Wolfram 1996) which allow simulation and analysis of both Mendelian and complex genetic traits in experimental crosses of plants or animals. AVAILABILITY: The add-on packages are freely available at http://www.mathsource.com/cgi-bin/msitem?0209-30 4. SUPPLEMENTARY INFORMATION: A tutorial notebook file is included with the packages at the mathsource site.     

Role of Mitochondrial Dynamics in Neuronal Development: Mechanism for Wolfram Syndrome

Deficiency of the protein Wolfram syndrome 1 (WFS1) is associated with multiple neurological and psychiatric abnormalities similar to those observed in pathologies showing alterations in mitochondrial dynamics. The aim of this study was to examine the hypothesis that WFS1 deficiency affects neuronal function via mitochondrial abnormalities. We show that down-regulation of WFS1 in neurons leads to dramatic changes in mitochondrial dynamics (inhibited mitochondrial fusion, altered mitochondrial trafficking, and augmented mitophagy), delaying neuronal development. WFS1 deficiency induces endoplasmic reticulum (ER) stress, leading to inositol 1,4,5-trisphosphate receptor (IP₃R) dysfunction and disturbed cytosolic Ca²⁺ homeostasis, which, in turn, alters mitochondrial dynamics. Importantly, ER stress, impaired Ca²⁺ homeostasis, altered mitochondrial dynamics, and delayed neuronal development are causatively related events because interventions at all these levels improved the downstream processes. Our data shed light on the mechanisms of neuronal abnormalities in Wolfram syndrome and point out potential therapeutic targets. This work may have broader implications for understanding the role of mitochondrial dynamics in neuropsychiatric diseases.     

Late results of primary veloplasty: the Marburg Project

Forty-five randomly selected patients with unilateral cleft lip, alveolus, and palate, all operated upon by Dr. Wolfram Schweckendiek were evaluated by three American specialists to assess the validity of primary veloplasty. Examination revealed an unusually high incidence of short palate and poor mobility of the soft palate. Facial growth was found to be highly acceptable in the majority of the patients. Unusually high incidence of velopharyngeal incompetence was found in these patients.     

Molecular characterization of WFS1 in an Iranian family with Wolfram syndrome reveals a novel frameshift mutation associated with early symptoms

Wolfram syndrome (WS) is a rare autosomal recessive neurodegenerative disorder that represents a likely source of childhood diabetes especially among countries in the consanguinity belt. The main responsible gene is WFS1 for which over one hundred mutations have been reported from different ethnic groups. The aim of this study was to identify the molecular etiology of WS and to perform a possible genotype–phenotype correlation in Iranian kindred.     

Mutations in mitochondrial tRNA genes: non-linkage with syndromes of Wolfram and chronic progressive external ophthalmoplegia.

We have recently identified a point mutation in the mitochondrially encoded tRNA(Leu(UUR)) gene which associates with a combination of type II diabetes mellitus and sensorineural hearing loss in a large pedigree. To extend this finding to other syndromes which exhibit a combination of diabetes mellitus and hearing loss we have sequenced all mitochondrial tRNA genes from two patients with the Wolfram syndrome, a rare congenital disease characterized by diabetes mellitus, deafness, diabetes insipidus and optic atrophy. In each patient, a single different mutation was identified. One is an A to G transition mutation at np 12,308 in tRNA(Leu(CUN)) gene in a region which is highly conserved between species during evolution. This mutation has been described by Lauber et al. (1) as associating with chronic progressive external ophthalmoplegia (CPEO). The other is a C to T transition mutation at np 15,904 in tRNA(Thr) gene. Both mutations are also present in the general population (frequency tRNA(Leu(CUN)) mutation 0.16, tRNA(Thr) mutation 0.015). These findings suggest that evolutionarily conserved regions in mitochondrial tRNA genes can exhibit a significant polymorphism in humans, and that the mutation at np 12,308 in the tRNA(Leu(CUN)) gene is unlikely to be associated with CPEO and Wolfram syndrome.     

Male mice with deleted Wolframin (Wfs1) gene have reduced fertility

Background  

Wolfram Syndrome (WS) is an autosomal recessive disorder characterised by non-autoimmune diabetes mellitus, optic atrophy, cranial diabetes insipidus and sensorineural deafness. Some reports have described hypogonadism in male WS patients. The aim of our study was to find out whether Wfs1 deficient (Wfs1KO) male mice have reduced fertility and, if so, to examine possible causes.     

Toward a more International and Reputable Journal

Editors in 2004 In 2004 I, Hiroo Fukuda (University of Tokyo), was appointedto be the Editor-in-Chief of Plant and Cell Physiology (PCP).As my first task I have added four overseas and four domesticEditors: John Harada (University of California, Davis), FumihikoKatagiri (University of Minnesota, from July), Jiayang Li (ChineseAcademy of Science), Eberhard Schäfer (Freiburg University,from July), Ikuko Hara-Nishimura (Kyoto University), FumihikoSato (Kyoto University), Ichiro Terashima (Osaka University)and Hideyuki Takahashi (Tohoku University, from July). I would like to take