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W N Frankel

Publications and source records attributed to W N Frankel.

At least 19 recordsLinked to original sources
PubMed2001

A null mutation in inositol polyphosphate 4-phosphatase type I causes selective neuronal loss in weeble mutant mice.

Weeble mutant mice have severe locomotor instability and significant neuronal loss in the cerebellum and in the hippocampal CA1 field. Genetic mapping was used to localize the mutation to the gene encoding inositol polyphosphate 4-phosphatase type I (Inpp4a), where a single nucleotide deletion results in a likely null allele. The substrates of INPP4A are intermediates in a pathway affecting intracellular Ca(2+) release but are also involved in cell cycle regulation through binding the Akt protooncogene; dysfunction in either may account for the neuronal loss of weeble mice. Although other mutations in phosphoinositide enzymes are associated with synaptic defects without neuronal loss, weeble shows that Inpp4a is critical for the survival of a subset of neurons during postnatal development in mice.

Alleles↗
PubMed2001

Of mice and genome sequence.

Availability of the mouse genome sequence will have a major impact on the study of vertebrate evolution, mammalian biology, and animal models of human disease. Resources to explore genome biology in mice will maximize the effect of this watershed event.

Animals↗
PubMed2001

Ducky mouse phenotype of epilepsy and ataxia is associated with mutations in the Cacna2d2 gene and decreased calcium channel current in cerebellar Purkinje cells.

The mouse mutant ducky, a model for absence epilepsy, is characterized by spike-wave seizures and ataxia. The ducky gene was mapped previously to distal mouse chromosome 9. High-resolution genetic and physical mapping has resulted in the identification of the Cacna2d2 gene encoding the alpha2delta2 voltage-dependent calcium channel subunit. Mutations in Cacna2d2 were found to underlie the ducky phenotype in the original ducky (du) strain and in a newly identified strain (du(2J)). Both mutations are predicted to result in loss of the full-length alpha2delta2 protein. Functional analysis shows that the alpha2delta2 subunit increases the maximum conductance of the alpha1A/beta4 channel combination when coexpressed in vitro in Xenopus oocytes. The Ca(2+) channel current in acutely dissociated du/du cerebellar Purkinje cells was reduced, with no change in single-channel conductance. In contrast, no effect on Ca(2+) channel current was seen in cerebellar granule cells, results consistent with the high level of expression of the Cacna2d2 gene in Purkinje, but not granule, neurons. Our observations document the first mammalian alpha2delta mutation and complete the association of each of the major classes of voltage-dependent Ca(2+) channel subunits with a phenotype of ataxia and epilepsy in the mouse.

Animals↗
PubMed2001

Biochemical and biophysical evidence for gamma 2 subunit association with neuronal voltage-activated Ca2+ channels.

A novel gene (Cacng2; gamma(2)) encoding a protein similar to the voltage-activated Ca(2+) channel gamma(1) subunit was identified as the defective gene in the epileptic and ataxic mouse, stargazer. In this study, we analyzed the association of this novel neuronal gamma(2) subunit with Ca(2+) channels of rabbit brain, and the function of the gamma(2) subunit in recombinant neuronal Ca(2+) channels expressed in Xenopus oocytes. Our results showed that the gamma(2) subunit and a closely related protein (called gamma(3)) co-sedimented and co-immunoprecipitated with neuronal Ca(2+) channel subunits in vivo. Electrophysiological analyses showed that gamma(2) co-expression caused a significant decrease in the current amplitude of both alpha(1B)(alpha(1)2.2)-class (36.8%) and alpha(1A)(alpha(1)2.1)-class (39.7%) Ca(2+) channels (alpha(1)beta(3)alpha(2)delta). Interestingly, the inhibitory effects of the gamma(2) subunit on current amplitude were dependent on the co-expression of the alpha(2)delta subunit. In addition, co-expression of gamma(2) or gamma(1) also significantly decelerates the activation kinetics of alpha(1B)-class Ca(2+) channels. Taken together, these results suggest that the gamma(2) subunit is an important constituent of the neuronal Ca(2+) channel complex and that it down-regulates neuronal Ca(2+) channel activity. Furthermore, the gamma(2) subunit likely contributes to the fine-tuning of neuronal Ca(2+) channels by counterbalancing the effects of the alpha(2)delta subunit.

Animals↗
PubMed2001

Electroconvulsive thresholds of inbred mouse strains.

The electroconvulsive threshold (ECT) test is used commonly in the screening of anti-epileptic drugs in rodent models, but little is known about its genetic or mechanistic basis. Thresholds for minimal clonic, maximal tonic, or psychomotor (partial) seizures were determined in 16 different inbred mouse strains in two different laboratories. A wide range of thresholds was observed, suggesting that a variety of neuroexcitability alleles exist in inbred strains. Although there was generally good cross-strain correlation between the three seizure types, several outlier strains were detected, showing that genetically encoded differences can affect the ability of a particular seizure type to spread through the brain. Furthermore, the relative seizure susceptibility of a strain was comparable between the two laboratories, suggesting that despite different test sites, instrumentation, and personnel, the ECT assay is portable and that common inbred strains can often be relied upon as calibration standards. Last, the ECT paradigm was also sensitive enough to detect single locus differences, laying the groundwork for mutation screens for new neuroexcitability models.

Animals↗
PubMed2001

High-resolution genetic and physical mapping of modifier-of-deafwaddler (mdfw) and Waltzer (Cdh23v).

Modifier-of-deafwaddler (mdfw) and waltzer (Cdh23v) are loci on mouse chromosome 10 encoding factors that are essential for the function of auditory hair cells. The BALB/cByJ-specific mdfw allele encodes a necessary and sufficient modifier that induces progressive early onset hearing loss in CBy-dfw2J heterozygotes. Recessive mutations in the waltzer locus result in circling behavior and congenital deafness. In this report we present a high-resolution integrated genetic and physical map of mdfw and Cdh23(v). Our genetic analyses localize mdfw between markers D10Mit60 and 148M13T7 within a 1.01-cM region. The Cdh23v critical interval is fully contained within the mdfw region and localizes between markers 146O23T7 and 148M13T7 within a 0.35-cM interval that is represented in an approximately 500-kb BAC contig. Our data suggest that mdfw and Cdh23v are allelic.

Alleles↗
PubMed2001

Mouse models for the Wolf-Hirschhorn deletion syndrome.

Wolf-Hirschhorn syndrome (WHS) is a deletion syndrome caused by segmental haploidy of chromosome 4p16.3. Its hallmark features include a 'Greek warrior helmet' facial appearance, mental retardation, various midline defects and seizures. The WHS critical region (WHSCR) lies between the Huntington's disease gene, HD, and FGFR3. In mice, the homologs of these genes map to chromosome 5 in a region of conserved synteny with human 4p16.3. To derive mouse models of WHS and map genes responsible for subphenotypes of the syndrome, five mouse lines bearing radiation-induced deletions spanning the WHSCR syntenic region were generated and characterized. Similar to WHS patients, these animals were growth-retarded, were susceptible to seizures and showed midline (palate closure, tail kinks), craniofacial and ocular anomalies (colobomas, corneal opacities). Other phenotypes included cerebellar hypoplasia and a shortened cerebral cortex. Expression of WHS-like traits was variable and influenced by strain background and deletion size. These mice represent the first animal models for WHS. This collection of nested chromosomal deletions will be useful for mapping and identifying loci responsible for the various subphenotypes of WHS, and provides a paradigm for the dissection of other deletion syndromes using the mouse.

Abnormalities, Multiple↗
PubMed2000

Multiple seizure susceptibility genes on chromosome 7 in SWXL-4 congenic mouse strains.

The SWXL-4 recombinant inbred mouse strain is unusually sensitive to recurrent tonic-clonic seizures upon routine handling and to seizures induced by chemoconvulsants. In a conventional intercross with the ABP/Le strain, we previously mapped a SWXL-4-derived quantitative trait locus called Szf1 (seizure frequency 1) to Chromosome 7. In the present study, we confirm the existence of Szf1 in both an independent cross and a congenic strain. However, derivative congenic recombinant strains show that an interaction between at least two genes on Chromosome 7-each of which has a very small effect on its own-account for Szf1.

Animals↗
PubMed2000

A new spontaneous mouse mutation in the Kcne1 gene.

A new mouse mutant, punk rocker (allele symbol Kcne1(pkr)), arose spontaneously on a C57BL/10J inbred strain background and is characterized by a distinctive head-tossing, circling, and ataxic phenotype. It is also profoundly and bilaterally deaf. The mutation resides in the Kcne1 gene on Chromosome (Chr) 16 and has been identified as a single base change within the coding region of the third exon. The C to T nucleotide substitution causes an arginine to be altered to a termination codon at amino acid position 67, and predictably this will result in a significantly truncated protein product. The Kcne1(pkr) mutant represents the first spontaneous mouse model for the human disorder, Jervell and Lange-Nielsen syndrome, associated with mutations in the homologous KCNE1 gene on human Chr 21.

Amino Acid Sequence↗
PubMed2000

The roads from phenotypic variation to gene discovery: mutagenesis versus QTLs.

In model organisms, chemical mutagenesis provides a powerful alternative to natural, polygenic variation (for example, quantitative trait loci (QTLs)) for identifying functional pathways and complex disease genes. Despite recent progress in QTLs, we expect that mutagenesis is will ultimately prove more effective because the prospects of gene identification are high and every gene affecting a trait is potentially a target.

Animals↗
PubMed2000

The mouse fidgetin gene defines a new role for AAA family proteins in mammalian development.

The mouse mutation fidget arose spontaneously in a heterogeneous albino stock. This mutant mouse is characterized by a side-to-side head-shaking and circling behaviour, due to reduced or absent semicircular canals. Fidget mice also have small eyes, associated with cell-cycle delay and insufficient growth of the retinal neural epithelium, and lower penetrance skeletal abnormalities, including pelvic girdle dysgenesis, skull bone fusions and polydactyly. By positional cloning, we found the gene mutated in fidget mice, fidgetin (Fign), which encodes a new member of the 'meiotic' or subfamily-7 (SF7; ref. 7) group of ATPases associated with diverse cellular activities (AAA proteins). We also discovered two closely related mammalian genes. AAA proteins are molecular chaperones that facilitate a variety of functions, including membrane fusion, proteolysis, peroxisome biogenesis, endosome sorting and meiotic spindle formation, but functions for the SF7 AAA proteins are largely unknown. Fidgetin is the first mutant AAA protein found in a mammalian developmental mutant, thus defining a new role for these proteins in embryonic development.

Adenosine Triphosphatases↗
PubMed2000

A major effect QTL determined by multiple genes in epileptic EL mice.

The EL mouse strain provides a polygenic model for epilepsy. Previous mapping experiments between EL and nonepileptic ABP mice identified, and a congenic strain confirmed, a quantitative trait locus (QTL), El2, which lowered the threshold to seizures induced by gentle rhythmic tossing. To narrow the map interval further we used a nested strategy to analyze a series of recombinants derived from the congenic strain. The recombinant strains revealed a complex pattern of inheritance, with at least two independent regions of Chromosome 2 necessary for rhythmic tossing seizures and additional regions associated with unusual gender effects. Similar results obtained using a completely independent paradigm, pentylenetetrazole-induced tonic-clonic seizures, exclude the possibility that the genetic complexity was a unique property of the testing assay. Thus, although conventional QTL mapping efforts detected and appeared to confirm a trait locus with effects large enough for fine-structure mapping, subsequent dissection revealed multiple loci. Although at least one of these loci was mapped to a 1-cM interval, its individual effect is small, perhaps approaching the practical limits for further study. Our results in the EL mouse may be prophetic for similar assaults on other polygenic, composite neurological behaviors which vary among inbred strains, begging the consideration of alternative strategies toward gene identification in these models.

Alleles↗
PubMed1999

Genetic modifiers of polycystic kidney disease in intersubspecific KAT2J mutants.

Polycystic kidney disease (PKD) is a genetically heterogeneous disorder. In addition to the many PKD-causative loci mapped in mouse and human, a number of reports indicate that modifier loci greatly influence the course of disease progression. Recently we reported a new mouse mutation, kat2J, on chromosome (Chr) 8 that causes late-onset PKD and anemia. During the mapping studies it was noted that the severity of PKD in the mutant (C57BL/6J-kat2J/+ x CAST/Ei)F2 generation was more variable than that in the parental C57BL/6J strain. This suggested that genetic background or modifier genes alter the clinical manifestations and progression of PKD. Genome scans using molecular markers revealed three loci that affect the severity of PKD. The CAST-derived modifier on Chr 1 affects both kidney weight and hematocrit. The CAST-derived modifier on Chr 19 affects kidney weight, and the C57BL/6J-derived modifier on Chr 2 affects hematocrit. Additional modifier loci are noted that interact with and modulate the effects of these three loci. The mapping of these modifier genes and their eventual identification will help to uncover factors that can delay disease progression. These, in turn, could be used to design suitable modes of therapy for various forms of human PKD.

Animals↗
PubMed1999

Quantitative trait loci for bone density in C57BL/6J and CAST/EiJ inbred mice.

Genetic analyses for loci regulating bone mineral density have been conducted in a cohort of F(2) mice derived from intercross matings of (C57BL/6J x CAST/EiJ)F(1) parents. Femurs were isolated from 714 4-month-old females when peak adult bone density had been achieved. Bone mineral density (BMD) data were obtained by peripheral quantitative computed tomography (pQCT), and genotype data were obtained by Polymerase Chain Reaction (PCR) assays for polymorphic markers carried in genomic DNA of each mouse. Genome-wide scans for co-segregation of genetic marker data with high or low BMD revealed loci on eight different chromosomes, four of which (Chrs 1, 5, 13, and 15) achieved conservative statistical criteria for suggestive, significant, or highly significant linkage with BMD. These four quantitative trait loci (QTLs) were confirmed by a linear regression model developed to describe the main effects; none of the loci exhibited significant interaction effects by ANOVA. The four QTLs have been named Bmd1 (Chr 1), Bmd2 (Chr 5), Bmd3 (Chr 13), and Bmd4 (Chr 15). Additive effects were observed for Bmd1, recessive for Bmd3, and dominant effects for Bmd2 and Bmd4. The current large size of the QTL regions (6-->31 cM) renders premature any discussion of candidate genes at this time. Fine mapping of these QTLs is in progress to refine their genetic positions and to evaluate human homologies.

Age Factors↗
PubMed1999

Detecting genes in new and old mouse models for epilepsy: a prospectus through the magnifying glass.

Various spontaneous mutants and natural strain variants for either generalized tonic-clonic seizures, or non-convulsive absence seizures have been described in mice and rats over the years. Convulsive seizure models are usually ascertained by mere visual observation, while finding the less noticeable seizures of absence models often requires proactive screening of existing mutants with other phenotypes. To date, molecular cloning technologies has elucidated the primary basis of most of the known single locus epilepsy mutants. Together with the 20 or so mouse knockouts with seizure-related phenotypes described to date, the frequency at which the mutants appear and diversity of the proteins involved would suggest that 1000 or more genes can be mutated to give rise to influence epilepsy phenotypes. As many of these genes will cluster into molecular, cellular and developmental pathways, their identification may be very important for better understanding epileptic mechanisms. With this perspective, the approaches taken towards positional cloning of mouse epilepsy mutations is illustrated by comparing and contrasting the different stages of gene identification in three different models with which this author has been fortunate enough to be intimately involved: slow-wave epilepsy (common gene symbol: swe, Chr 4); tottering (tg, Chr 8); and stargazer (stg, Chr 15). The comparatively sobering outlook for positional cloning of the more common genetically 'complex' epilepsies will also be discussed, as will more efficient new strategies for model screening and identifying the remaining 985 (or so) genes.

Animals↗
PubMed1999

Ataxic mouse mutants and molecular mechanisms of absence epilepsy.

Mouse genetic models for common human diseases have been studied for most of the 20th century. Although many polygenic strain differences and spontaneous single gene mutants have been extensively characterized over the years, knowing their innermost secrets ultimately requires the identity of the mutated genes. One group of neurological mutants, detected initially due to cerebellar dysfunction, was identified as models for epilepsy when they were unexpectedly found to have spike-wave seizures associated with behavioral arrest, a central feature of absence or petit-mal epilepsy. A further surprise was that recently identified defective genes encode different subunits of voltage-gated Ca(2+)channels (VGCCs), implying common seizure mechanisms. In this review we first consider these spontaneous mutants with VGCC defects in the context of other mouse models for epilepsy. Then, from the new wave of genetic and functional studies of these mutants we discuss their prospects for yielding insight into the molecular mechanisms of epilepsy.

Animals↗