Magnetic Ground States of the Rare-Earth Tripod Kagome Lattice Mg_{2}RE_{3}Sb_{3}O_{14} (RE=Gd,Dy,Er).

We present the structural and magnetic properties of a new compound family, Mg_{2}RE_{3}Sb_{3}O_{14} (RE=Gd,Dy,Er), with a hitherto unstudied frustrating lattice, the "tripod kagome" structure. Susceptibility (ac, dc) and specific heat exhibit features that are understood within a simple Luttinger-Tisza-type theory. For RE=Gd, we found long-ranged order (LRO) at 1.65 K, which is consistent with a 120° structure, demonstrating the importance of diople interactions for this 2D Heisenberg system. For RE=Dy, LRO at 0.37 K is related to the "kagome spin ice" physics for a 2D system. This result shows that the tripod kagome structure accelerates the transition to LRO predicted for the related pyrochlore systems. For RE=Er, two transitions, at 80 mK and 2.1 K are observed, suggesting the importance of quantum fluctuations for this putative XY system.

Extremely correlated Fermi-liquid description of normal-state ARPES in cuprates.

The normal-state single particle spectral function of the high temperature superconducting cuprates, measured by the angle-resolved photoelectron spectroscopy (ARPES), has been considered both anomalous and crucial to understand. Here, we report an unprecedented success of the new extremely correlated Fermi liquid theory by one of us [B. S. Shastry, Phys. Rev. Lett. 107, 056403 (2011)] to describe both laser and conventional synchrotron ARPES data (nodal cut at optimal doping) on Bi(2)Sr(2)CaCu(2)O(8+δ) and synchrotron data on La(1.85)Sr(0.15)CuO(4). It fits all data sets with the same physical parameter values, satisfies the particle sum rule and successfully addresses two widely discussed kink anomalies in the dispersion.

Evaluation of the CYP1B1 gene as a candidate gene in beagles with primary open-angle glaucoma (POAG).

PURPOSE: In humans, primary open-angle glaucoma (POAG) is a complex genetic disorder and is the leading cause of visual impairment. Although all relevant genes were not identified, a small subset of the condition is found to be caused by mutations in the MYOC and CYP1B1 genes. Inherited glaucoma also occurs in several breeds of dogs including beagles. Primary glaucoma in beagles is inherited as an autosomal recessive trait. The purpose of this study is to investigate the role of the CYP1B1 gene in beagles with POAG. METHODS: For the purpose of genetic analysis, total RNAs from the spleen of the canines were isolated and CYP1B1 cDNA was prepared. Genomic DNA from five affected, two carriers, and 13 randomly selected normal beagles with no sign of glaucoma was amplified by the polymerase chain reaction (PCR) using four pairs of primers. The amplified products were directly sequenced using BigDye terminator cycle sequencing. RESULTS: Genomic DNA analyses have identified a substitution polymorphism (109A-->C) in the 5'-untranslated region (UTR) as well as a missense mutation (P93R) in exon 2 of the gene. Three affected, two carriers, and nine normal dogs are heterozygous while two affected and three normal dogs are homozygous for the missense mutation. One normal dog did not show this alteration. Normal dogs also contain the substitution polymorphism in the 5'-UTR. Similar experiments with exon 3 did not identify any additional mutation in the gene. CONCLUSIONS: The above results suggest that CYP1B1 alterations in the coding and UTR are not the primary cause of glaucoma in beagles by possible monogenic association. They may be classified as polymorphisms or they may modify glaucoma phenotype.

Assessment of the contribution of insulin-like growth factor I receptor 3174 G-->A polymorphism to the progression of advanced retinopathy of prematurity.

PURPOSE: Retinopathy of prematurity (ROP) is a leading cause of blindness in children with short gestational age and low birthweight. The condition can cause abnormal vessel development that can lead to retinal detachment and blindness. It has been recently reported that a low level of insulin-like growth factor I (IGF-I) is associated with ROP. However, the most prevalent polymorphism of IGF-I receptor (IGF-IR 3174 G-->A) that was reported to be producing low level of IGF-I was not found to be associated with ROP in a certain population. In order to reproduce this data in a different cohort and to learn more about the contribution of IGF-IR polymorphism to ROP, the authors hypothesized that it is possible that such a polymorphism would occur more frequently in a different cohort of infants with advanced ROP than those children with mild or no disease. METHODS: For genetic analysis, eligible patients were selected consecutively by experienced pediatric ophthalmologists and leukocyte DNA from affected (n=52) and normal patients (n=33) were amplified by polymerase chain reaction. The amplified products were subjected to restriction enzyme digestion with 10 units of MnlI enzyme. The digested products were analyzed by polyacrylamide gel electrophoresis followed by ethidium bromide staining to visualize the restriction fragment length polymorphism. RESULTS: The analysis suggests that there is no statistically significant difference in allelic frequency of the most prevalent IGF-IR gene polymorphism between normal subjects and patients with ROP in this cohort. The G-->A polymorphism did not occur more frequently in patients with ROP. CONCLUSIONS: The results do not support the association of the most prevalent IGF-IR gene polymorphism and the risk of advanced ROP in a different cohort, confirming the earlier report.

Recent developments in certain X-linked genetic eye disorders.

Over the past few years, genetic diseases of the ocular system have become very active and fast-growing research areas in the vision field. The rapid development of the recombinant DNA techniques together with somatic cell genetics, during the last two decades has fueled this progress. As a result, many genetic disease genes have been localized in the human chromosome and several of them have been isolated and characterized. These and other studies have profoundly enriched our basic understanding of genetic eye disorders. Although gene replacement therapy, prenatal diagnosis and carrier detection have not been extensively tried for genetic eye diseases, such attempts will now be feasible. Molecular analyses made it clear that there are many challenging problems that need attention. This report highlights some of these initial developments, particularly on the X-linked major genetic eye diseases. In order to help the beginners and general audience, a brief description of the clinical pathology and the molecular probes used to locate the genetic defects of certain disorders are presented. Disorders are arranged according to their linkage from telomere to telomere on the chromosome to give a coherent structure. It is hoped that this information is useful and of general interest for the beginners, established investigators and ophthalmologists.

Xenopus transcription factor IIIA (XTFIIIA): after a decade of research.

Xenopus transcription factor IIIA (XTFIIIA) is the first eukaryotic transcription factor purified to homogeneity and is specifically required for the 5S RNA gene transcription. It contains two structural domains and nine zinc finger motifs through which it recognizes the promoter region of the 5S RNA gene. It also binds to 5S RNA and serves to store 5S RNA in the form of 7S ribonucleoprotein particles in oocytes. Additionally, it forms a metastable complex with 5S DNA and promotes the formation of stable and competent transcription complexes. Its expression is developmentally controlled at the level of transcription and translation. Moreover, it participates in the assembly of active chromatin templates and at least, in part, is responsible for the developmental regulation of two kinds of 5S RNA genes in Xenopus.

Cosegregation of two unlinked mutant alleles in some cases of autosomal dominant familial exudative vitreoretinopathy.

Familial exudative vitreoretinopathy (FEVR) is a bilateral, clinically and genetically heterogeneous hereditary eye disorder that affects both the retina and the vitreous body. The condition has a high degree of penetrance and variable expressivity. In some cases of autosomal dominant FEVR (AD FEVR), mutations in the frizzled-4 gene (FZD-4) have been shown to be involved in FEVR pathology. In this study, we report that a second unlinked gene (Factor V) is also mutated (Leiden mutation) in the same family, which harbors the FZD-4 gene mutation. These results show for the first time that some families with FEVR could be digenic. While this is unlikely to be a widespread problem, the occurrence of digenic disorders with apparently simple Mendelian inheritance patterns renders the current method of analysis of monogenic disorders by linkage and mutation screening incomplete.

The assembly of functional preinitiation complexes and transcription of 5S RNA-encoding genes containing point mutations.

The transcription of several Syrian hamster 5S RNA-encoding genes (5S genes) containing single and multiple point mutations in and around the intragenic control region has been analyzed in a HeLa cell-free system. Although most genes with point mutations displayed normal levels of transcription, several exhibited a three- to fivefold reduction in transcription. These mutations interfere with the interaction between the 5S genes and the soluble factors. The above studies help to establish the importance of specific nucleotides within the 5S gene for productive interactions of individual transcription factors in vitro.

Light, sight and fight for insight.

The visual processes in the human retina begin with absorption of photons from light. This light energy is converted into electrical stimuli in a series of enzymatic steps which initiates neural responses to light. Therefore, any structural and functional abnormalities in these molecules will likely interfere with signal transduction which may ultimately lead to blindness. A new era began in 1990 with an ultimate goal of redefining and developing new treatments for the photoreceptor disorders by identifying mutations in the genes encoding phototransduction cascade enzymes. As a result of this intense investigation around the world, mutations have now been identified in eight genes, in several retinal dystrophies. Almost all of these genes encode signal transduction enzymes and all are highly expressed in photoreceptor cells. This effort has been further aided by gene disruption technology. Although there are many puzzles that need to be solved, these approaches have given some insight into the genetic eye disorders and will undoubtedly improve our understanding of inherited eye disorders in the future. This improved knowledge may eventually lead to prevention or a cure.

Analysis of eye lens-specific genes in congenital hereditary cataracts and microphthalmia of the miniature schnauzer dog.

The congenital hereditary cataracts and microphthalmia in the miniature schnauzer dog are inherited by an autosomal recessive mode. To understand the genetic basis of these diseases, the authors purified and analyzed leukocyte deoxyribonucleic acid (DNA) from affected and normal animals using a candidate gene approach. Because the genes that encode the lens-specific proteins, specifically, alpha, beta, and gamma crystallins and the membrane protein (MP26), are known to maintain the structure and function of the lens, the authors used complimentary DNA (cDNA) fragments that corresponded to the above genes to search for the mutations at their loci in the affected animals. They found no evidence of the gene deletion and rearrangement in any of the five loci. In addition, the hybridizable sequences of the dog DNA to the specific probes for the human chromosome 4 and 18 loci, which are reported to be involved in the abnormality of the human eye, seem to be unaffected. These data support the notion that the hereditary cataracts and microphthalmia in the dog may be associated with genes other than those reported for several animal systems.

Retinitis pigmentosa and related disorders: phenotypes of rhodopsin and peripherin/RDS mutations.

Retinitis pigmentosa comprises a group of clinically variable and genetically heterogeneous inherited disorders of the retina. It is estimated that approximately 1.5 million people throughout the world are affected by this disease. It is a slowly progressive disorder and causes loss of night vision and peripheral visual field in adolescence. It can be inherited through an autosomal dominant, recessive, or X-linked mode; the autosomal dominant form is considered to be the mildest form. Molecular genetic studies on the autosomal dominant disorder have shown that, in some families, genes encoding the rhodopsin and peripherin/RDS map very close to the disease loci identified previously by the systematic linkage analyses. These results, together with the observation that a recessive nonsense mutation in the Drosophila opsin gene causes photoreceptor degeneration, prompted an extensive search for the alterations in the human rhodopsin and peripherin/RDS genes in families with autosomal dominant retinitis pigmentosa. As a result, several distinct rhodopsin and peripherin/RDS mutations have been found in approximately 30% of all autosomal dominant cases. A wide variety of clinical expression of the disorder even within a family with the same mutation, its late onset, slow progression, and cone degeneration clearly suggest that some other factors or genes in addition to rhodopsin are responsible for the phenotypic expression of the disorder. In this article, an attempt is made to highlight some of these recent developments and to correlate the various mutations and the phenotypes.

Identification of missense mutations in the Norrie disease gene associated with advanced retinopathy of prematurity.

BACKGROUND: Retinopathy of prematurity (ROP) is a retinal vascular disease occurring in infants with short gestational age and low birth weight and can lead to retinal detachment (ROP stages 4 and 5). X-linked familial exudative vitreoretinopathy is phenotypically similar to ROP and has been associated with mutations in the Norrie disease (ND) gene in some cases. OBJECTIVE: To determine if similar mutations in the ND gene may play a role in the development of advanced ROP. METHODS: Clinical examination and molecular genetic analysis were performed on 16 children, including 2 dizygotic and 1 monozygotic twin pairs, and their parents from 13 families. RESULTS: Sequencing of the amplified products revealed missense mutations (R121W and L108P) in the third exon of the ND gene in 4 patients. These mutations were not present in an unaffected premature twin, 2 children with regressed stage 3 ROP, the parents, or in 50 unrelated healthy control subjects. CONCLUSION: These findings suggest that mutations in the ND gene may play a role in the development of severe ROP in premature infants.

Molecular genetics of Rett syndrome.

Rett syndrome is a neurodevelopmental disorder affecting almost exclusively females. It affects approximately one in 15000 females and is characterized by a loss of purposeful hand use, autism, ataxia and seizure. The disorder is usually sporadic, but rare familial cases have also been reported. Recently it has been shown that familial cases are an X-linked dominant disorder and the disease locus maps to Xq28. A candidate gene called methyl-CpG-binding protein 2 was identified from the Xq28 region and was shown to contain mutations in about 77% of Rett syndrome patients. Since the encoded protein was previously shown to be a global transcriptional repressor, undesired expression of yet unidentified genes that are normally repressed is considered to be pathogenic in Rett syndrome.

Parkinson disease: etiology, pathogenesis and future of gene therapy.

Parkinson disease (PD) is a progressive neurological disorder with a prevalence of 1-2% in people over the age of 50. It has a world-wide distribution and has no gender preference. The neurological hallmark of PD is the presence of Lewy bodies and is characterized by the degeneration of nigrostriatal dopaminergic neurons. The causes of PD are unknown but considerable evidence suggests a multifactorial etiology involving genetic and environmental factors. A molecular genetic approach identified three genes and at least two additional loci in rare familial forms of PD. Two of these genes are involved in the ubiquitin mediated pathway of protein degradation and the third one is a highly expressed protein in the synaptic terminal and is called alpha-synuclein. In animal models, it has been shown that use of the household pesticide which is known to contain rotenone, causes PD. Thus, a combined action of genetic and environmental factors is responsible for the pathogenesis of PD. Although use of levodopa or dopamine agonists can substantially reduce clinical symptoms, and transplantation of fetal nerve tissue still remains as an alternative therapy (although it has been recently shown to be having no overall benefit), directed delivery of glial cell derived neurotrophic factor (known to have trophic effects on dopaminergic neurons) may also be a beneficial therapeutic option for PD patients.

X-linked recessive familial exudative vitreoretinopathy.

Familial exudative vitreoretinopathy is an inherited disorder characterized by retinal traction, peripheral vitreous opacities, and subretinal and intraretinal exudates. We observed a family in which four boys (the children of three sisters) were affected with this disorder and an X-linked recessive inheritance was apparent. The differential diagnosis includes retinopathy of prematurity, primary hyperplastic primary vitreous, Coats' disease, peripheral uveitis, retinoblastoma, and Norrie's disease, but this differentiation can usually be made on the basis of clinical findings alone. Knowledge of X-linked recessive transmission is important for correct diagnosis and for genetic counseling.

Genes and susceptible loci of Alzheimer's disease.

Alzheimer's disease (AD) is the most common and devastating neurodegenerative disease of the elderly. Many research findings on familial AD suggest that the mechanisms of the pathogenesis of the disorder is more complex although the overall neuropathology of all cases of AD is surprisingly very similar. Genetic studies on some families have shown that mutations in the genes encoding beta-amyloid precursor protein and presenilins 1 and 2 are responsible for early-onset AD. In addition, apolipoprotein E gene allele E4 and the bleomycin hydrolase locus are shown to be genetic risk factors for late-onset AD in certain sporadic cases. Mitochondrial dysfunctions and age-related oxidative stress may also contribute to degenerative processes in AD. Although several studies support the amyloid cascade hypothesis as the mechanism of the disease, transgenic experiments and recent findings on a variant form of an AD family suggest that A beta deposition may not be sufficient to cause AD. Identification in the future of other genetic, environmental, and age-related factors, may provide additional targets for therapies.

Localization of the Norrie disease gene mRNA by in situ hybridization.

Norrie disease is a rare X-linked recessive neurodevelopmental disorder. The affected males manifest congenital blindness, which is often associated with hearing loss, mental retardation and psychiatric problems. Genetic linkage studies have localized the gene to the short arm of the X-chromosome and the gene has been isolated recently. The encoded protein is a member of the superfamily of growth factors containing a cystine knot motif and may be involved in cell adhesion and neurodevelopment. Molecular genetic analysis revealed a large number of missense, nonsense, deletion, and splice-site mutations among Norrie patients. In order to further determine the role of the Norrie disease gene, we studied the distribution pattern of its mRNA in the retina and in brain by in situ hybridization. The results show abundant hybridization signals in outer nuclear, inner nuclear, and ganglion cell layers of the retina in all three species (mice, rabbit, and human) examined. There was no significant expression in the vitreous body, lens, and rod outer segment. High expression levels were also observed in the cerebellar granular layer, hippocampus, olfactory bulb, cortex, and epithelium of the rabbit brain. These data suggest that the Norrie disease gene could play a critical role in the differentiation or maintenance of the differentiated state of the retina.

A Colombian family with X-linked juvenile retinoschisis with three affected females finding of a frameshift mutation.

X-linked retinoschisis (XLRS) is a vitreoretinal disease responsible for most cases of juvenile macular degeneration in males. Retinoschisis carrier females generally manifest no pathological symptoms. However, a large affected family from Colombia presented three affected females with typical RS phenotype similar to their 27 affected male relatives. Fundus examination as well as electroretinograms (ERG) indicate that the disease in these three affected females is as severe as in their affected male counterparts. DNA sequence analysis of the XLRS1 gene in the affected members of this family indicates a single base (G) deletion at the 639 base position (639delG). This deletion causes a frameshift during translation and results in a larger (235 amino acids) than normal peptide (224 amino acids) with grossly altered discoidin domain, which is considered critical for the cellular function of the protein. The co-segregation of this gene mutation with the RS phenotype and the RS carrier status as well as its complete absence in normal controls indicates that this genetic change is responsible for the RS pathology in this family. This (639delG) is a novel RS mutation and reported here for the first time. Furthermore, the analysis of the three affected females indicates that the RS pathology in affected females (a very rare occurrence) is due to XLRS1 mutations carried on both of their X chromosomes.

Factor V Leiden mutation (R506Q) and the risk of advanced retinopathy of prematurity.

The coagulation factor V Leiden mutation was reported to be a significant (10.7%) risk factor for pre-term deliveries. It is also well known that a portion (10%) of very low birth weight premature babies develop advanced retinopathy of prematurity (ROP) which is a leading cause of blindness in children. However, the relationship between the Leiden mutation and development of advanced ROP is not known. In order to understand this relationship as well as genetic contribution to ROP, in this study, we have analyzed 100 pre-term infants with advanced ROP (stage 4B/5), 20 term babies with a clinically similar disease called familial exudative vitreoretinopathy (FEVR) and 16 normal babies from four different ethnic backgrounds. Our extensive analysis has identified a heterozygous Leiden mutation in four patients (4%) with advanced ROP and in one patient (5%) with sporadic FEVR. DNA sequence analysis has further confirmed this base change as well as heterozygosity. However, the frequency observed in the patients analyzed in our study is lower than reported frequency in the general population (5.4%). Therefore, statistically factor V mutation on its own is not a major risk factor for the above two disorders. However, it may be associated with other additive factors as might be expected for a complex genetic trait.

Evaluation of the prothrombin gene polymorphism in patients with advanced retinopathy of prematurity.

It has been reported recently that a common genetic variant in the 3'-untranslated region of the prothrombin gene is associated with a significant fraction of premature births. The purpose of this study is to evaluate the prothrombin gene polymorphism in a large cohort of patients with preterm birth and advanced retinopathy of prematurity. For this purpose, the leukocyte DNAs were analyzed for the mutation (20210A) in the 3'-untranslated region of the prothrombin gene by PCR amplification, followed by restriction analysis and DNA sequencing. Our extensive analysis revealed a normal genotype (GG) in all patients as well as controls. These results suggest that the common genetic variant in the 3'-untranslated region of the prothrombin gene is not associated with advanced retinopathy of prematurity. Although more patients' samples should be evaluated, this genetic test does not support a relationship between prothrombin gene mutation and retinopathy of prematurity.