R M Gardiner

University College London, Londinium, England, United Kingdom

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Publications (58)255.33 Total impact

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    ABSTRACT: Primary ciliary dyskinesia is an autosomal recessive disorder characterised by recurrent sinopulmonary infections, bronchiectasis, and subfertility, due to dysfunction of the cilia. Fifty percent of patients with primary ciliary dyskinesia have defects of laterality (situs inversus) and this association is known as Kartagener syndrome. Primary ciliary dyskinesia has an estimated incidence of 1 in 20 000 live births. To identify loci for this genetically heterogeneous condition, genome wide linkage scans and subsequent fine mapping were performed in two different isolated populations with distinct ciliary ultrastructural defects, from the Faroe Islands and the Druze community in northern Israel. A locus was mapped in seven families from the Faroe Islands to a 2.8 cM interval on chromosome 16p12.1-12.2, with a maximum lod score of 3.15, obtained using GENEHUNTER. A locus was mapped in three out of four Druze families from the Golan region of Israel to a 17 cM region on chromosome 15q13.1-15.1, with a maximum hlod score of 3.2 at (proportion of linked families) = 0.7, using GENEHUNTER. This study provides further evidence of the genetic heterogeneity underlying primary ciliary dyskinesia and has established a framework to facilitate isolation of two genes for primary ciliary dyskinesia. Determining the molecular basis of primary ciliary dyskinesia will provide insight into the genetic control of cilia assembly and function and the pathway which determines the vertebrate left right axis.
    Full-text · Article · Apr 2004 · Journal of Medical Genetics
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    ABSTRACT: A recent genome-wide scan revealed suggestive evidence for two susceptibility loci for idiopathic generalized epilepsy (IGE) in the chromosomal regions 5p15 and 5q14-q22 in families with typical absence seizures. The present replication study tested the validity of the tentative IGE loci on chromosome 5. Our study included 99 multiplex families in which at least one family member had typical absence seizures. Parametric and non-parametric multipoint linkage analyses were carried out between the IGE trait and 23 microsatellite polymorphisms covering the entire region of chromosome 5. Multipoint parametric heterogeneity lod scores < -2 were obtained along chromosome 5 when a proportion of linked families greater than 50% was assumed under recessive inheritance and > 60% under dominant inheritance. Furthermore, non-parametric multipoint linkage analyses revealed no hint of linkage throughout the candidate region (P > 0.05). Accordingly, we failed to support previous evidence for common IGE loci on chromosome 5. If there is a susceptibility locus for IGE on chromosome 5 then the size of the effect or the proportion of linked families is too small to detect linkage in the investigated family sample.
    No preview · Article · Oct 2002 · Epilepsy Research
  • R. Chodhari · H.M. Mitchison · R.M. Gardiner · E.M.K. Chung

    No preview · Article · Jul 2002 · Clinical Science
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    ABSTRACT: 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.
    Full-text · Article · Sep 2001 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    ABSTRACT: Dyneins are multisubunit protein complexes that couple ATPase activity with conformational changes. They are involved in the cytoplasmatic movement of organelles (cytoplasmic dyneins) and the bending of cilia and flagella (axonemal dyneins). Here we present the first complete cDNA and genomic sequences of a human axonemal dynein beta heavy chain gene, DNAH9, which maps to 17p12. The 14-kb-long cDNA is divided into 69 exons spread over 390 kb. The cDNA sequence of DNAH9 was determined using a combination of methods including 5' rapid amplification of cDNA ends, RT-PCR, and cDNA library screening. RT-PCR using nasal epithelium and testis RNA revealed several alternatively spliced transcripts. The genomic structure was determined using three overlapping BACs sequenced by the Whitehead Institute/MIT Center for Genome Research. The predicted protein, of 4486 amino acids, is highly homologous to sea urchin axonemal beta heavy chain dyneins (67% identity). It consists of an N-terminal stem and a globular C-terminus containing the four P-loops that constitute the motor domain. Lack of proper ciliary and flagellar movement characterizes primary ciliary dyskinesia (PCD), a genetically heterogeneous autosomal recessive disorder with respiratory tract infections, bronchiectasis, male subfertility, and, in 50% of cases, situs inversus (Kartagener syndrome, KS). Dyneins are excellent candidate genes for PCD and KS because in over 50% of cases the ultrastructural defects of cilia are related to the dynein complex. Genotype analysis was performed in 31 PCD families with two or more affected siblings using a highly informative dinucleotide polymorphism located in intron 26 of DNAH9. Two families with concordant inheritance of DNAH9 alleles in affected individuals were observed. A mutation search was performed in these two "candidate families," but only polymorphic variants were found. In the absence of pathogenic mutations, the DNAH9 gene has been excluded as being responsible for autosomal recessive PCD in these families.
    No preview · Article · Mar 2001 · Genomics
  • C. R. Fertleman · R. M. Gardiner · K. Parker · M. Rees

    No preview · Article · Feb 2001 · Autonomic Neuroscience
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    ABSTRACT: Genetic factors play a major role in the aetiology of idiopathic generalised epilepsies (IGEs). The present genome scan was designed to identify susceptibility loci that predispose to a spectrum of common IGE syndromes. Our collaborative study included 130 IGE-multiplex families ascertained through a proband with either an idiopathic absence epilepsy or juvenile myoclonic epilepsy, and one or more siblings affected by an IGE trait. In total, 413 microsatellite polymorphisms were genotyped in 617 family members. Non-parametric multipoint linkage analysis, using the GeneHunter program, provided significant evidence for a novel IGE susceptibility locus on chromosome 3q26 (Z(NPL) = 4.19 at D3S3725; P = 0.000017) and suggestive evidence for two IGE loci on chromosome 14q23 (Z(NPL) = 3.28 at D14S63; P = 0.000566), and chromosome 2q36 (Z(NPL) = 2.98 at D2S1371; P = 0.000535). The present linkage findings provide suggestive evidence that at least three genetic factors confer susceptibility to generalised seizures in a broad spectrum of IGE syndromes. The chromosomal segments identified harbour several genes involved in the regulation of neuronal ion influx which are plausible candidates for mutation screening.
    Full-text · Article · Jul 2000 · Human Molecular Genetics
  • R M Gardiner
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    ABSTRACT: A genetic contribution to aetiology is estimated to be present in up to 40% of patients with epilepsy. It is useful to categorise genetic epilepsies according to the mechanisms of inheritance into Mendelian disorders, non-mendelian or 'complex' disorders, and chromosomal disorders. Over 200 Mendelian diseases include epilepsy as part of the phenotype, and the genes for a number of these have been identified recently. These include autosomal recessive progressive myoclonic epilepsies such as Unverricht-Lundborg disease, Lafora disease and the neuronal ceroid lipofuscinoses, and three autosomal dominant idiopathic epilepsies. The last named have been shown to arise from mutations in ion channel genes. Autosomal dominant nocturnal frontal lobe epilepsy is caused by mutations in CHRNA4, benign familial neonatal convulsions by mutations in KCNQ2 and KCNQ3, and generalised epilepsy with febrile seizures plus by mutations in SCN1B. 'Complex', familial epilepsies are more difficult to analyse, but evidence has been obtained for loci predisposing to juvenile myoclonic epilepsy on chromosome 6p and 15q. Lastly, the genes underlying several spike-wave epilepsies in mice have been cloned, and three of these encode sub-units of voltage-gated calcium channels.
    No preview · Article · Jun 2000 · Journal of Neurology
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    ABSTRACT: Primary ciliary dyskinesia is an autosomal recessive condition characterised by chronic sinusitis, bronchiectasis, and subfertility. Situs inversus occurs in 50% of cases (Kartagener syndrome). It has an estimated incidence of 1 in 20 000 live births. The clinical phenotype is caused by defective ciliary function associated with a range of ultrastructural abnormalities including absent dynein arms, absent radial spokes, and disturbed ciliary orientation. The molecular genetic basis is unknown. A genome scan was performed in five Arabic families. Using GENEHUNTER, a maximal multipoint lod score (HLOD) of 4.4 was obtained on chromosome 19q13.3-qter at alpha (proportion of linked families) = 0.7. A 15 cM critical region is defined by recombinations at D19S572 and D19S218. These data provide significant evidence for a PCD locus on chromosome 19q and confirm locus heterogeneity.
    Full-text · Article · May 2000 · Journal of Medical Genetics
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    ABSTRACT: Primary ciliary dyskinesia (PCD), or immotile cilia syndrome (ICS), is an autosomal recessive disorder affecting ciliary movement with an incidence of 1 in 20000-30000. Dysmotility to complete immotility of cilia results in a multisystem disease of variable severity with recurrent respiratory tract infections leading to bronchiectasis and male subfertility. Ultrastructural defects are present in ciliated mucosa and spermatozoa. Situs inversus (SI) is found in about half of the patients (Kartagener syndrome). We have collected samples from 61 European and North American families with PCD. A genome-wide linkage search was performed in 31 multiplex families (169 individuals including 70 affecteds) using 188 evenly spaced (19cM average interval) polymorphic markers. Both parametric (recessive model) and non-parametric (identity by descent allele sharing) linkage analyses were used. No major locus for the majority of the families was identified, although the sample was powerful enough to detect linkage if 40% of the families were linked to one locus. These results strongly suggest extensive locus heterogeneity. Potential genomic regions harbouring PCD loci were localised on chromosomes 3p, 4q, 5p, 7p, 8q, 10p, 11q, 13q, 15q, 16p, 17q and 19q. Linkage analysis using PCD families with a dynein arm deficiency provided 'suggestive' evidence for linkage to chromosomal regions 8q, 16pter, while analyses using only PCD families with situs inversus resulted in 'suggestive' scores for chromosomes 8q, and 19q.
    Full-text · Article · Mar 2000 · European Journal of HumanGenetics
  • R M Gardiner
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    ABSTRACT: The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders characterized by the presence of autofluorescent lipopigment in neurons and other cell types. The childhood onset types display autosomal recessive inheritance. Naturally occurring animal NCLs have been described in many species including mouse, sheep and dog. In the last decade major advances have occurred in the molecular genetic analysis of the NCLs. Six disease gene loci have been mapped, and five disease genes have been isolated. Two of these encode lysosomal enzymes: CLN1 encodes palmitoyl-protein thioesterase (PPT), and CLN2 encodes tripeptidyl peptidase 1 (TPP1). The remaining three, CLN3, CLN5 and CLN8 encode putative membrane proteins of unknown function. The murine orthologue of CLN8 causes motor neuron degeneration (mnd), a mouse model of NCL. These advances have revolutionized diagnosis and classification, but a unified theory of pathogenesis and effective treatment remain elusive.
    No preview · Article · Feb 2000 · Neurological Sciences
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    ABSTRACT: The transcription factor FOXJ1 (alias HFH-4 or FKHL13) of the winged-helix/forkhead family is expressed in cells with cilia or flagella, and seems to be involved in the regulation of axonemal structural proteins. The knockout mouse Foxj1(-/-) shows abnormalities of organ situs, consistent with random determination of left-right asymmetry, and a complete absence of cilia. The human FOXJ1 gene which maps to chromosome 17q, is thus an excellent candidate gene for Kartagener Syndrome (KS), a subphenotype of Primary Ciliary Dyskinesia (PCD), characterized by bronchiectasis, chronic sinusitis and situs inversus. We have collected samples from 61 PCD families, in 31 of which there are at least two affected individuals. Two families with complete aciliogenesis, and six families, in which the affected members have microsatellite alleles concordant for a locus on distal chromosome 17q, were screened for mutations in the two exons and intron-exon junctions of the FOXJ1 gene. No sequence abnormalities were observed in the DNAs of the affected individuals of the selected families. These results demonstrate that the FOXJ1 gene is not responsible for the PCD/KS phenotype in the families examined.
    Full-text · Article · Feb 2000 · Cytogenetics and cell genetics
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    ABSTRACT: Primary Ciliary Dyskinesia (PCD) is an autosomal recessive disorder in which dysmotility to immobility of cilia and flagella result in upper respiratory tract infections, bronchiectasis and male sub-fertility. About half of patients have situs inversus (Kartagener syndrome). Extensive genetic heterogeneity is expected given the complex ultrastructure of cilia and flagella. Recently, the first report of mutations in a specific gene (DNAI1) were reported in a single Kartagener patient (Pennarun et al., AM J HUM GENET 65 suppl, A35, 1999). In Switzerland and as part of a European consortium, we collected DNA samples from 61 families, 31 of which had two or more affected members. A genome-wide linkage search was performed using 188 evenly-spaced microsatellites. Linkage analysis was performed in all families with two affecteds, and in sub-sets of families with situs inversus and with dynein arm deficiency. Data was analyzed using both parametric and non-parametric methods. Although no marker showed statistically-significant values for linkage, several chromosomal regions (4q, 5p, 8p, 16p, and 19q) were identified with suggestive scores. These findings support the hypothesis that mutations in several distinct genes may produce the PCD/ Kartagener phenotypes. As dyneins are good candidates for this disorder, we are currently screening PCD patients for mutations in dynein-related genes mapping to the pinpointed chromosomal regions. Supported by the Swiss OFES (950458) and the Milena Carvajal Foundation, Geneva.
    Full-text · Article · Jan 2000 · Genetics in Medicine
  • Ruth E. Williams · R M Gardiner · H H Goebel
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    ABSTRACT: A European NCL Clinical Case Registry has been set up in London, as part of a European Union-funded Concerted Action project. Concerted Action participants provide written information about children which is then anonymized and entered on the Registry. Contributors are able to request information contained within the Registry for the purpose of epidemiological, molecular, diagnostic, or therapeutic research. Up to May 1998, 60 cases were entered on the Registry.
    No preview · Article · May 1999 · Molecular Genetics and Metabolism
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    ABSTRACT: JNCL is a neurodegenerative disease of childhood caused by mutations in the CLN3 gene. A mouse model for JNCL was created by disrupting exons 1-6 of Cln3, resulting in a null allele. Cln3 null mice appear clinically normal at 5 months of age; however, like JNCL patients, they exhibit intracellular accumulation of autofluorescent material. A second approach will generate mice in which exons 7 and 8 of Cln3 are deleted, mimicking the common mutation in JNCL patients.
    No preview · Article · May 1999 · Molecular Genetics and Metabolism
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    ABSTRACT: Two distinct clinical subtypes of neuronal ceroid lipofuscinosis caused by mutations in the PPT gene, INCL and vJNCL/GROD, occur at a high frequency in the central region of Scotland. In this paper we summarize the clinical details and the molecular basis underlying the disease in the Scottish patients. Comparison of the combination of mutations in the different clinical types reveals a clear genotype-phenotype correlation.
    No preview · Article · May 1999 · Molecular Genetics and Metabolism
  • J D Sharp · R B Wheeler · B D Lake · M Fox · R M Gardiner · R E Williams
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    ABSTRACT: CLN6, the gene for a variant late infantile neuronal ceroid lipofuscinosis, has been mapped to chromosome 15q21-23 by homozygosity mapping. At present the family resource consists of 31 families. By the analysis of additional polymorphic markers in this resource the critical region has been narrowed down from 12 cM to less than 4 cM. A physical map is being constructed using YAC and PAC clones as a prerequisite to transcript mapping.
    No preview · Article · May 1999 · Molecular Genetics and Metabolism
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    ABSTRACT: To date two genes are known to be involved in variant LINCL, CLN5 and CLN6, which map to chromosomes 13q21 and 15q21-23. A subset of Turkish families with a variant phenotype has been identified. Affected individuals have curvilinear bodies and fingerprint profiles on EM but are recombinant at CLN5 and CLN6. These families appear to represent a new locus. Homozygosity mapping is being used to map this locus, which has been designated CLN7.
    No preview · Article · May 1999 · Molecular Genetics and Metabolism
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    ABSTRACT: To understand the cellular and molecular mechanisms that underlie generalized absence seizures sufficiently well to design rational, efficacious new therapies for patients, it is necessary to turn to animal models to gain insights into these mechanisms. The lethargic (lh/lh) mutant mouse expresses spontaneous absence seizures that share behavioral, electrographic, and anticonvulsant profiles with absence seizures in patients. This validates its use to study the mechanisms that underlie absence seizures. This chapter discusses two scientific approaches that involve the use of lh/lh mice. The first part of the chapter discusses neurobiologic approaches used to investigate critical mechanisms that regulate the synchronized burst firing within the thalamocortical network that generates absence seizures. Two of these critical mechanisms have been studied in detail with lh/lh mice. The first critical mechanism involves the required activation of gamma-aminobutyric acid B (GABAB) receptors to generate absence seizures. Because the numbers of GABAB receptors are increased in thalamocortical populations among lh/lh mice compared with littermates without epilepsy, these receptors appear to play a pathophysiologic role in the expression of absence seizures among lh/lh mice. Moreover, there may be a role for GABAB receptors in the generation of absence seizures among humans, because administration of compounds that activate GABAB receptors can produce absence seizures among humans. These findings suggest that GABAB receptor antagonists may represent a new class of antiabsence compounds that will be efficacious against absence seizures among patients. A second critical mechanism that regulates generation of absence seizures involves GABAA receptors in the nucleus reticularis thalami (NRT), a nucleus that sends GABA-ergic afferents to thalamic relay nuclei. Activation of GABAA receptors in the NRT appears to suppress the generation of absence seizures among lh/lh mice and in other models. Moreover, clonazepam may exert its antiabsence actions through this mechanism. Together, these findings suggest that compounds that selectively activate GABAA receptor isoforms expressed in NRT may represent a class of antiabsence drugs that could have fewer side effects than compounds currently used to treat patients. The second part of the chapter discusses a molecular genetic approach to delineation of the mechanisms that underlie absence seizures. Absence seizures among lh/lh mice are caused by a single-gene defect on chromosome 2. If positional cloning and gene isolation techniques are successful, it will be possible to identify the lh disease gene. Subsequent studies of the lh gene product should greatly increase not only our understanding of the pathophysiologic basis for absence seizures among lh/lh mice but also our ability to seek similar mutations in homologous genes in human families that express absence seizures. Accordingly, strategies and progress in cloning and identifying the lh disease gene are presented.
    No preview · Article · Feb 1999 · Advances in neurology
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    ABSTRACT: Among the epilepsies, the progressive myoclonus epilepsies (PMEs) form a heterogeneous group of rare diseases characterized by myoclonus, epilepsy, and progressive neurologic deterioration, particularly dementia and ataxia. The success of the Human Genome Project and the fact that most PMEs are inherited through a mendelian or mitochondrial mode have resulted in important advances in the definition of the molecular basis of PME. The gene defects for the most common forms of PME (Unverricht-Lundborg disease, the neuronal ceroid lipofuscinoses, Lafora disease, type I sialidosis, and myoclonus epilepsy with ragged-red fibers) have been either identified or mapped to specific chromosome sites. Unverricht-Lundborg disease has been shown to be caused by mutations in the gene that codes for cystatin B, an inhibitor of cysteine protease. The most common mutation in Unverricht-Lundborg disease is an expansion of a dodecamer repeat located in a noncoding region upstream of the transcription start site of the cystatin B gene, making it the first human disease associated with instability of a dodecamer repeat. Juvenile neuronal ceroid lipofuscinosis is caused by mutations in the CLN3 gene, a gene of unknown function that encodes a 438-amino-acid protein of possible mitochondrial location. Other forms of neuronal ceroid lipofuscinosis that occur as PME and Lafora disease have been mapped by means of linkage analysis, but the corresponding gene defects remain unknown. Sialidosis has been shown to be caused by mutations in the sialidase gene, and myoclonus epilepsy with ragged-red fibers is well known to be caused by mutations in the mitochondrial gene that codes for tRNA(Lys). How the different PME gene defects described produce the various PME phenotypes, including epileptic seizures, remains unknown. The development of animal models that bear these mutations is needed to increase our knowledge of the basic mechanisms involved in the PMEs. This knowledge should lead to the development of new and effective forms of therapy, which are especially lacking for the PMEs.
    No preview · Article · Feb 1999 · Advances in neurology

Publication Stats

2k Citations
255.33 Total Impact Points

Institutions

  • 1996-2004
    • University College London
      • • Division of Medicine
      • • Department of Pharmacology
      Londinium, England, United Kingdom
  • 2001
    • Royal College Of Paediatrics and Child Health
      Londinium, England, United Kingdom
  • 1999
    • Fundación Jiménez Díaz
      Madrid, Madrid, Spain
    • Duke University
      Durham, North Carolina, United States
  • 1997
    • Leiden University
      Leyden, South Holland, Netherlands
  • 1994
    • University of Texas MD Anderson Cancer Center
      Houston, Texas, United States