R Hillermann

Publications (7)54.28 Total impact

• Article: Exon-intron structure of a 2.7-kb transcript of the STM7 gene with phosphatidylinositol-4-phosphate 5-kinase activity.

  M A Pook, J J Carvajal, K Doudney, R Hillermann, S Chamberlain
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  ABSTRACT: The STM7 gene encodes a novel phosphatidylinositol-4-phosphate 5-kinase (PtdInsP 5-kinase) that is subject to alternative splicing and developmental control. We have recently presented data indicating that several splice variants of STM7 incorporate elements of the X25 sequence, previously implicated in the pathogenesis of Friedreich's ataxia by the detection of an intronic GAA repeat expansion as the predominant mutation in affected individuals. We now report the exon-intron structure of STM7.I and primer sequences designed to facilitate full characterization, including details relating to a novel exon (STM7; exon 17) derived from the 3'-UTR of the PRKACG gene. The detection of a mutation(s) within these exons would provide additional support for the hypothesis that a defect in phosphoinositide metabolism gives rise to the disease phenotype.
  Genomics 06/1997; 42(1):170-2. · 3.02 Impact Factor
• Article: The Friedreich's ataxia gene encodes a novel phosphatidylinositol-4- phosphate 5-kinase.

  J J Carvajal, M A Pook, M dos Santos, K Doudney, R Hillermann, S Minogue, R Williamson, J J Hsuan, S Chamberlain
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  ABSTRACT: The STM7 gene on chromosome 9 was recently 'excluded' as a candidate for Friedreich's ataxia following the identification of an expanded intronic GAA triplet repeat in the adjacent gene, X25, in patients with the disease. Using RT-PCR, northern and sequence analyses, we now demonstrate that X25 comprises part of the STM7 gene, contributing to at least four splice variants, and report the identification of new coding sequences. Functional analysis of the STM7 recombinant protein corresponding to the reported 2.7-kilobase transcript has demonstrated PtdlnsP 5-kinase activity, supporting the idea that the disease is caused by a defect in the phosphoinositide pathway, possibly affecting vesicular trafficking or synaptic transmission.
  Nature Genetics 11/1996; 14(2):157-62. · 35.53 Impact Factor
• Article: Human glial cell line-derived neurotrophic factor (GDNF) maps to chromosome 5.

  N Bermingham, R Hillermann, F Gilmour, J E Martin, E M Fisher
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  ABSTRACT: Neurotrophic factors are essential neurone survival promoting molecules that are often secreted and that bind to neuronal cell surface receptors. Glial cell line-derived neurotrophic factor, GDNF, is a potent neurotrophic factor that promotes the survival of dopaminergic neurones in cultures including embryonic neuronal cultures. We have mapped the gene encoding GDNF by two independent methods: using a cell hybrid panel and by fluorescent in situ hybridisation. We find GDNF lies on the short arm of human chromosome 5, at 5p13.1-p13.3 ability to promote dopamine uptake in midbrain cultures. The protein was partially sequenced and a rat GDNF cDNA was isolated by screening a B49 cDNA library with an oligonucleotide probe designed from the amino-terminus of the rat protein. Human GDNF sequences were isolated by screening a human genomic library with a portion of the rat GDNF cDNA (Lin et al. 1993). We wished to localise the GDNF gene in the human genome and determine its proximity to possible sites of mutation, particularly phenotypes affecting neuronal function.
  Human Genetics 01/1996; 96(6):671-3. · 5.07 Impact Factor
• Article: Friedreich's ataxia: a defect in signal transduction?

  J J Carvajal, M A Pook, K Doudney, R Hillermann, D Wilkes, S al-Mahdawi, R Williamson, S Chamberlain
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  ABSTRACT: We have previously assigned the mutation causing Friedreich's ataxia (FRDA) to 9q13 by genetic linkage and fluorescent in situ hybridization analysis, and identified recombination events which position the gene centromeric to D9S5. We report here the extension of a yeast artificial chromosome contig to span the 860 kb interval immediately proximal to this marker, which includes the D9S886 and D9S887/888 loci reported to flank the FRDA locus, and the construction of a high resolution cosmid contig initiated from the D9S888 locus. Exon trapping and cDNA library screening strategies have resulted in the isolation of a candidate gene which traverses the centromeric boundary of the FRDA critical region. The gene spans a genomic interval greater than 220 kb with at least two of the coding exons located proximal to the D9S887/888 loci. Expression is complex, with multiple transcripts detected in a variety of tissues and evidence of alternative splicing and developmental control. The predicted amino acid sequence for the 2.7 kb transcript reported here shows a marked homology to the deduced amino acid sequence of the Saccharomyces cerevisiae MSS4 protein, proposed to function within the phosphoinositide cycle, suggesting a potential role for the human homologue in signal transduction. Whilst no evidence for mutation has been detected in this transcript, the sequence represents only one of the shorter alternatively spliced species identified by Northern analysis and direct sequencing. This gene remains a strong candidate for FRDA.
  Human Molecular Genetics 09/1995; 4(8):1411-9. · 7.64 Impact Factor
• Article: Physical evidence for the position of the Friedreich's ataxia locus FRDA proximal to D9S5.

  R Hillermann, C G See, M Pook, D Wilkes, J Carvajal, K Doudney, R Williamson, S Chamberlain
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  ABSTRACT: Orientation of the Friedreich's ataxia locus (FRDA) with respect to D9S15 and D9S5 has proved critical to the design of subsequent cloning strategies. The rarity of recombination events between FRDA and these markers, originally used to determine assignment to human chromosome region 9q13-->q21.1, has necessitated the instigation of physical mapping studies to determine order and, hence, the precise location of the disease gene. Simultaneous fluorescence in situ hybridisation using cosmid clones located in close proximity to the ends of a 1.2-Mb yeast artificial chromosome clone extending into the FRDA candidate region provides physical evidence for the order of the marker loci to be cen-D9S202-D9S5-D9S15-qter. The possibility that a pericentric inversion, occurring naturally in approximately 1% of the normal population, may affect the order of markers within this region has been eliminated. Considered in association with the interpretation of a recombination event detected in a single affected individual, these data indicate that the FRDA locus is located proximal to D9S5.
  Cytogenetics and cell genetics 02/1995; 71(3):214-6.
• Article: The SHB adaptor protein maps to human chromosome 9.

  I G Yulug, R Hillermann, E M Fisher
  Genomics 01/1995; 24(3):615-7. · 3.02 Impact Factor
• Article: Chromosomal assignment of the second locus for autosomal dominant cerebellar ataxia (SCA2) to chromosome 12q23–24.1

  S Gispert, R Twells, G Orozco, A Brice, J Weber, L Heredero, K. Scheufler, B Riley, R Allotey, C Nothers, [......], J Enczmann, M Farrall, J Beckmann, M Mullan, P Wernet, Y Agid, H.-J. Freund, R Williamson, G Auburger, S Chamberlain