Genetic variants of frizzled-4 gene in familial exudative vitreoretinopathy and advanced retinopathy of prematurity.
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Amino Acid Sequence↗
Biomedical subjects
B S Shastry
Publications and source records attributed to B S Shastry.
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.
Alleles↗
Hubbard model on decorated lattices.
We introduce a family of lattices for which the Hubbard model and its natural extensions can be quasiexactly solved, i.e., solved for the ground and low energy states. In particular, we show rigorously that the ground state of the Hubbard model with off-site Coulomb repulsions on a decorated Kagomè lattice is an ordered array of local currents. The low energy theory describing this chiral state is an S=1 / 2 XY model, where each spin degree of freedom represents the two possible chiralities of each local current.
Journal Article↗
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.
Base Sequence↗
Multiple field-induced phase transitions in the geometrically frustrated dipolar magnet: Gd(2) Ti(2)O(7).
Field-driven phase transitions generally arise from competition between Zeeman energy and exchange or crystal-field anisotropy. Here we present the phase diagram of a frustrated pyrochlore magnet Gd(2)Ti(2)O(7), where crystal-field splitting is small compared to the dipolar energy. We find good agreement between zero-temperature critical fields and those obtained from a mean-field model. Here, dipolar interactions couple real space and spin space, so the transitions in Gd(2)Ti(2)O(7) arise from field-induced "cooperative anisotropy," reflecting the broken spatial symmetries of the pyrochlore lattice.
Journal Article↗
Spin dynamics of Sr14Cu24O41 two-leg ladder studied by Raman spectroscopy.
The two-magnon (2M) excitation at 3000 cm(-1) in Sr14Cu24O41 two-leg ladder is studied by Raman scattering. A slight anisotropy of the superexchange coupling J(perpendicular)/J(parallel) approximately 0.8 with J(parallel) = 110+/-20 meV is proposed from the analysis of the magnetic scattering. The resonant coupling across the charge transfer gap increases the 2M intensity by orders of magnitude. The anisotropy of Raman scattering is dependent upon the excitation energy. The 2M relaxation is found to be correlated with the temperature dependent electronic Raman continuum at low frequencies.
Journal Article↗
Molecular and cell biological aspects of Alzheimer disease.
Alzheimer disease (AD) is one of several types of chronic and very common dementing disorders, affecting individuals aged 65 years or older. During the last five years, an enormous growth in the field has enriched our understanding of this complex condition. Molecular genetic studies have identified at least three genes that, when mutated, cause the autosomal dominant, early-onset familial form of the disease. The late-onset, most common forms of the disease are likely to be associated with various genetic susceptibility factors. The application of cell biological techniques has given insight into basic aspects of the functions of important proteins involved in disease progression, and transgenic animal studies have further enriched our knowledge of the pathophysiological aspects of the disease. More efficient therapeutic drugs to retard its progression have been developed, as well as techniques to identify the preclinical phase of the disorder. Although we are still lacking the molecular basis and order of events involved in the disease process, the future for AD research, as well as for AD patients, is more promising than ever before.
Alzheimer Disease↗
Insertion and deletion mutations in the dinucleotide repeat region of the Norrie disease gene in patients with advanced retinopathy of prematurity.
Retinopathy of prematurity (ROP) is a leading cause of blindness in premature children. It is a multifactorial disorder which causes fibrovascular tissue changes that affect the retina in low birth-weight and short gestational age infants. To determine the prevalence of Norrie disease (ND) gene mutations, clinical examination and molecular genetic analyses were performed in 100 pre-term babies of different ethnic backgrounds who developed advanced ROP. The leukocyte DNA was extracted, amplified by the polymerase chain reaction (PCR), and analyzed by single-strand conformation polymorphism (SSCP), G/T and C/A scanning, and by DNA sequencing. All three exons, including splice sites and the 3'-untranslated region, were screened. Of the 100 patients analyzed, 2 patients with advanced ROP showed a mobility shift in the DNA. In 1 patient, this mobility shift was caused by the insertion of an additional 12-bp CT repeat in exon 1, and in the second patient, there was a 14-bp deletion in the same exon of the ND gene, as evidenced by direct sequencing of the amplified products. Similar analyses of exons 2 and 3 and the 3'-untranslated region failed to detect additional mutations in the gene. None of the 130 normal, unrelated controls revealed similar changes. Taking into account the above results, as well as those of other studies, it appears that the ND gene mutations can account for 3% of cases of advanced ROP. Although the ND gene is not frequently involved in advanced ROP, the present large-scale study further supports the hypothesis that genetic influences may play an important role in the development of severe ROP in some premature infants.
Child↗
Evaluation of RP2 and RP3 genes in an X-linked RP family manifesting loss of central vision and preserved peripheral function.
X-Linked retinitis pigmentosa is a most severe and heterogeneous disorder of the retina. Recently, genes (RP2 and RPGR) from two X-linked loci have been positionally cloned and mutations have been identified in many families. To further evaluate allelic and non-allelic heterogeneity and the genotype--phenotype relationships, and to determine the prevalence of mutations in the gene, we have analyzed one previously unreported X-linked retinitis pigmentosa family, using a combination of haplotype analysis and DNA sequencing. Our extensive analysis of the RP2 gene failed to detect any disease--causing or polymorphic mutations. In the case of the RP3 gene, the alleles of the dinucleotide repeat marker did not segregate with the disease. Although we cannot completely exclude the possibility of the RP2 and RP3 genes as candidate genes, the above results suggest that structural and functional changes associated with the RP2 gene are not responsible for the phenotype in the family analyzed. Further identification of the X-linked genes may facilitate the elucidation of the molecular basis of the disorder in the family analyzed.
Alleles↗
X-linked juvenile retinoschisis: mutations at the retinoschisis and Norrie disease gene loci?
Juvenile retinoschisis (RS) and Norrie disease (ND) are X-linked recessive retinal disorders. Both disorders, in the majority of cases, are monogenic and are caused by mutations in the RS and ND genes, respectively. Here we report the identification of a family in which mutations in both the RS and ND genes are segregating with RS pathology. Although the mutations identified in this report were not functionally characterized with regard to their pathogenicity, it is likely that both of them are involved in RS pathology in the family analyzed. This suggests the complexity and digenic nature of monogenic human disorders in some cases. If this proves to be a widespread problem, it will complicate the strategies used to identify the genes involved in diseases and to develop methods for intervention.
Base Sequence↗
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.
Environmental Exposure↗
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.
Chromosome Mapping↗
X-Linked juvenile retinoschisis associated with a 4-base pair insertion at codon 55 of the XLRS1 gene.
X-linked juvenile retinoschisis (RS) is a bilateral vitreoretinal disorder with no known cure. The gene responsible for the disease was recently isolated by positional cloning methods and a spectrum of mutations has been described in families with RS pathology. In this report, we screened six sporadic cases of RS for mutations in the RS gene to understand the etiology of isolated cases. Our extensive studies revealed a novel 4 bp insertion in one family and the remaining families did not show mutations in the RS gene. This mutation altered the reading frame including codon 55 resulting in nine aberrant amino acid residues. The unaffected mother did not contain this mutation. Additionally, it was not found in 60 normal control chromosomes, suggesting that the insertion mutation is disease related in the family analyzed.
Amino Acid Sequence↗
A 5-base insertion in the gammaC-crystallin gene is associated with autosomal dominant variable zonular pulverulent cataract.
A seven-generation family with 30 members affected by highly variable autosomal dominant zonular pulverulent cataracts has been previously described. We have localized the cataracts to a 19-cM interval on chromosome 2q33-q35 including the gamma-crystallin gene cluster. Maximum lod scores are 4.56 (theta=0.02) with D2S157, 3.66 (theta=0.12) with D2S72, and 3.57 (theta=0.052) with CRYG. Sequencing and allele-specific oligonucleotide analysis of the pseudo gammaE-crystallin promoter region from individuals in the pedigree suggest that activation of the gammaE-crystallin pseudo gene is unlikely to cause the cataracts in the family. In addition, base changes in the TATA box but not the Sp1-binding site have been found in unaffected controls and can be excluded as a sole cause of cataracts. In order to investigate the underlying genetic mechanism of cataracts in this family further, exons of the highly expressed gammaC- and gammaD-crystallin genes have been sequenced. The gammaD-crystallin gene shows no abnormalities, but a 5-bp duplication within exon 2 of the gammaC-crystallin gene has been found in one allele of each affected family member and is absent from both unaffected family members and unaffected controls. This mutation disrupts the reading frame of the gammaC-crystallin coding sequence and is predicted to result in the synthesis of an unstable gammaC-crystallin with 38 amino acids of the first "Greek key" motif followed by 52 random amino acids. This finding suggests that the appropriate association of mutant betagamma-crystallins into oligomers is not necessary to cause cataracts and may give us new insights into the genetic mechanism of cataract formation.
Alleles↗
Recent progress in the genetics of incontinentia pigmenti (Bloch-Sulzberger syndrome).
Incontinentia pigmenti (IP) is a rare disorder which affects organs and tissues of ectodermal and mesodermal origin. It is characterized by swirled patterns of hyperpigmentation. In some cases, the condition is also associated with malformations of the teeth, nails, skeleton, hair, eyes, and the central nervous system. The disorder is inherited as an X-linked dominant trait and mostly affects females. However, there have been several cases of IP in males that survived to birth. While IP in females could be caused by a skewed pattern of X-inactivation, three mechanisms: namely, the half-chromatid hypothesis, unstable premutation, and a higher rate of de-novo germline mutations, have been proposed to explain the survival of affected male patients. Cytogenetic studies in several sporadic cases with signs similar to IP exhibited an X/autosomal translocation involving a breakpoint at Xp11, suggesting a gene locus on Xp11 (IP1). Linkage analysis of familial IP, on the other hand, has identified a second locus, in the Xq28 region (IP2). Molecular genetic analysis of two candidate genes located at Xp11 and Xq28, as well as the human homologue of the murine Str gene, failed to reveal any disease-causing mutations. Although heterozygous female mice deficient for the IKKgamma/NEMO gene exhibited dermatopathy similar to that in human IP, studies of the gene in human IP have not yet been available. In an effort to isolate the genes causing IP, cosmid clones containing the translocation breakpoint located at Xp11 and the transcriptional map of the Xq28 region were constructed. These maps could be invaluable tools in the identification of genes in the near future.
Animals↗
Linkage and candidate gene analysis of autosomal-dominant familial exudative vitreoretinopathy.
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Chromosomes↗
Hereditary degenerative retinopathies: optimism for somatic gene therapy.
Retinitis pigmentosa comprises a large and exceptionally heterogeneous group of hereditary disorders of the retina. As a result of an extensive investigation around the world, primary genetic lesions have been described in many genes. Some of these genes encode enzymes that are involved in the signal transduction pathway. On the basis of in vitro functional assays and standard transgenic and knock-out experiments, it has been proposed that normal cell functions are disrupted because of an abnormal protein-folding and metabolic errors or structural defects in the membrane. This ultimately leads to a gene-mediated cell death known as apoptosis. Various gene transfer approaches using mouse models further suggest that the degeneration can be rescued to some extent. Although many questions remain to be answered, investigations during the last 10 years have enormously increased our understanding of this exceptionally heterogeneous disorder and give hope for an effective gene therapy and a possible cure.
Animals↗
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.
3' Untranslated Regions↗