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"ALS5 has been linked to a 6 cM region of chromosome 15q15.1-q21.1, but the causative gene mutation for ALS5 has yet to be identified." Are these worth checking out? Variants of Elp3, a subunit of the elongator complex are associated with ALS. The elongator complex interacts with RNA polymerase II Mary http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=610507*610507 LEO1 RNA POLYMERASE II ASSOCIATED FACTOR, S. CEREVISIAE, HOMOLOG OF; LEO1 Alternative titles; symbols REPLICATIVE SENESCENCE DOWNREGULATED LEO1-LIKE; RDL Gene map locus 15q15.3 *609885 ELONGATION FACTOR, RNA POLYMERASE II, 3; ELL3 Gene map locus 15q15.3 Handb Clin Neurol. 2007;82:301-12. Chapter 15 Juvenile amyotrophic lateral sclerosis. Orban P, Devon RS, Hayden MR, Leavitt BR. Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics and British Columbia Research Institute for Women and Children's Health, University of British Columbia, Vancouver, BC, Canada. Several forms of genetically defined juvenile amy-otrophic lateral sclerosis (ALS) have now been charac-terized and discussion of these conditions will form the basis for this chapter. ALS2 is an autosomal recessive form of ALS with a juvenile onset and very slow progression that mapped to chromosome 2q33. Nine different mutations have been identified in the ALS2 gene that result in premature stop codons, suggesting a loss of function in the gene product, alsin. The alsin protein is thought to function as a guanine-nucleotide exchange factor for GTPases and may play a role in vesicle transport or membrane trafficking processes. ALS4 is an autosomal dominant form of juvenile onset ALS associated with slow progression, severe muscle weakness and pyramidal signs, in the absence of bulbar and sensory abnormalities. Mutations in the SETX gene cause ALS4, and the SETX gene product senataxin may have DNA and RNA helicase activity and play a role in the regulation of RNA and/or DNA in the cell. A third form of juvenile-onset ALS (ALS5) is associated with slowly progressing lower motor neuron signs (weak-ness and atrophy) initially of the hands and feet, with eventual bulbar involvement. Progressive upper motor neuron disease becomes more obvious with time. ALS5 has been linked to a 6 cM region of chromosome 15q15.1-q21.1, but the causative gene mutation for ALS5 has yet to be identified. The high degree of clin-ical and genetic heterogeneity in the various forms of juvenile ALS can make differential diagnosis difficult, other genetic disorders that must be considered include: spinal muscular atrophy, hereditary spastic paraplegia, SBMA, GM2 gangliosidosis and the hereditary motor neuronopathies/motor forms of Charcot-Marie-Tooth disease. Acquired disorders that must also be consid-ered include heavy metal intoxications (especially lead), multifocal motor neuropathy, paraneoplastic syndromes, vitamin deficiencies (B12) and infections (HTLV-II, HIV and poliomyelitis). PMID: 18808900 [PubMed - in process]
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I’m given to understand that any day now we can expect a pair of reports identifying the gene behind, I believe, ALS6. It’s supposed to be interesting.
John McCarty, PhD
Treatment Investigator,
ALS Therapy Development Institute
John McCarty, PhD
Director of Therapeutic Investigation
ALS Therapy Development Institute
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Hi Dr McCarty,
By interesting, would you suggest that the mutation is amenable to treatment?
I'll be very interested to see if they report mutations in RPGRIP1L -12q12.2. Mutations in that gene have been reported in Joubert syndrome. p150glued mutations have been reported in ALS.
Mary
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May be way out of line... has anyone checked out www.23andme.com web site - where they give you a report on your genome (sp) with a report on your ancestory, disease probability, etc. It is only $399 for the report and has been named Time Invention of the Year. I sent an e-mail asking what they report on ALS. It is listed as reportable on their site. If there are genes that are identifiable then they should be able to report if a person has that gene. And at $399 it seems the less expensive alternative for finding out about SOD1 probability. Sharonca
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I'm looking forward to see the gene affected in ALS6. Should it be RPGRIP1L which might indicate that ALS is result of a ciliogenesis defect, then these studies are of interest. Sonic hedgehog requires cholesterol. Mary Primary cilia regulate hippocampal neurogenesis by mediating sonic hedgehog signaling Authors: Joshua J. Breunig, Matthew R. Sarkisian, Jon I. Arellano, Yury M. Morozov, Albert E. Ayoub, Sonal Sojitra, Baolin Wang, Richard A. Flavell, Pasko Rakic, and Terrence Town Summary: Primary cilia are present on mammalian neurons and glia, but their function is largely unknown. We generated conditional homozygous mutant mice for a gene we termed Stumpy. Mutants lack cilia and have conspicuous abnormalities in postnatally developing brain regions, including a hypoplasic hippocampus characterized by a primary deficiency in neural stem cells known as astrocyte-like neural precursors (ALNPs). Previous studies suggested that primary cilia mediate sonic hedgehog (Shh) signaling. Here, we find that loss of ALNP cilia leads to abrogated Shh activity, increased cell cycle exit, and morphological abnormalities in ALNPs. Processing of Gli3, a mediator of Shh signaling, is also altered in the absence of cilia. Further, key mediators of the Shh pathway localize to ALNP cilia. Thus, selective targeting of Shh machinery to primary cilia confers to ALNPs the ability to differentially respond to Shh mitogenic signals compared to neighboring cells. Our data suggest these organelles are cellular “antennae” critically required to modulate ALNP behavior. Source: Proceedings of the National Academy of Sciences of the United States of America; (08/26/08) Stem Cells. 2008 Oct;26(10):2564-75. Epub 2008 Jul 17. Directed evolution of motor neurons from genetically engineered neural precursors. Bohl D, Liu S, Blanchard S, Hocquemiller M, Haase G, Heard JM. Département Neuroscience, Institut Pasteur, Institut National de la Santé et de la Recherche Médicale U622, Unité Rétrovirus et Transfert Génétique, Paris, France. dbohl@pasteur.frStem cell-based therapies hold therapeutic promise for degenerative motor neuron diseases, such as amyotrophic lateral sclerosis, and for spinal cord injury. Fetal neural progenitors present less risk of tumor formation than embryonic stem cells but inefficiently differentiate into motor neurons, in line with their low expression of motor neuron-specific transcription factors and poor response to soluble external factors. To overcome this limitation, we genetically engineered fetal rat spinal cord neurospheres to express the transcription factors HB9, Nkx6.1, and Neurogenin2. Enforced expression of the three factors rendered neural precursors responsive to Sonic hedgehog and retinoic acid and directed their differentiation into cholinergic motor neurons that projected axons and formed contacts with cocultured myotubes. When transplanted in the injured adult rat spinal cord, a model of acute motor neuron degeneration, the engineered precursors transiently proliferated, colonized the ventral horn, expressed motor neuron-specific differentiation markers, and projected cholinergic axons in the ventral root. We conclude that genetic engineering can drive the differentiation of fetal neural precursors into motor neurons that efficiently engraft in the spinal cord. The strategy thus holds promise for cell replacement in motor neuron and related diseases. Disclosure of potential conflicts of interest is found at the end of this article. PMID: 18635866 [PubMed - in process]
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Quote:quote: Originally posted by Mary Reid"ALS5 has been linked to a 6 cM region of chromosome 15q15.1-q21.1, but the causative gene mutation for ALS5 has yet to be identified." Are these worth checking out? Variants of Elp3, a subunit of the elongator complex are associated with ALS. The elongator complex interacts with RNA polymerase II Mary http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=610507*610507 LEO1 RNA POLYMERASE II ASSOCIATED FACTOR, S. CEREVISIAE, HOMOLOG OF; LEO1 Alternative titles; symbols REPLICATIVE SENESCENCE DOWNREGULATED LEO1-LIKE; RDL Gene map locus 15q15.3 *609885 ELONGATION FACTOR, RNA POLYMERASE II, 3; ELL3 Gene map locus 15q15.3 I'm putting together the info which would implicate Leo1, a component of the PAF1 complex, in the formation of snoRNAs. Senataxin, which is mutated in a dominant form of ALS may also be implicated in this process. As an introduction to this, I'd like to propose that there is reason to suspect increased HBII-52 - human - in ALS. They find below that "MBII-52 forms a bona fide small nucleolar ribonucleoprotein particle that specifically decreases the efficiency of RNA editing by ADAR2". Deficient editing by ADAR2 is reported in ALS. HBII-52 is at 15q11.2. Mary J Cell Biol. 2005 Jun 6;169(5):745-53. ADAR2-mediated editing of RNA substrates in the nucleolus is inhibited by C/D small nucleolar RNAs. Vitali P, Basyuk E, Le Meur E, Bertrand E, Muscatelli F, Cavaillé J, Huttenhofer A. Laboratoire de Biologie Moléculaire des Eucaryotes, Centre National de la Recherche Scientifique, UMR 5095, Institut Fédératif de Recherche 109, 31062 Cedex Toulouse, France. Posttranscriptional, site-specific adenosine to inosine (A-to-I) base conversions, designated as RNA editing, play significant roles in generating diversity of gene expression. However, little is known about how and in which cellular compartments RNA editing is controlled. Interestingly, the two enzymes that catalyze RNA editing, adenosine deaminases that act on RNA (ADAR) 1 and 2, have recently been demonstrated to dynamically associate with the nucleolus. Moreover, we have identified a brain-specific small RNA, termed MBII-52, which was predicted to function as a nucleolar C/D RNA, thereby targeting an A-to-I editing site (C-site) within the 5-HT2C serotonin receptor pre-mRNA for 2'-O-methylation. Through the subcellular targeting of minigenes that contain natural editing sites, we show that ADAR2- but not ADAR1-mediated RNA editing occurs in the nucleolus. We also demonstrate that MBII-52 forms a bona fide small nucleolar ribonucleoprotein particle that specifically decreases the efficiency of RNA editing by ADAR2 at the targeted C-site. Our data are consistent with a model in which C/D small nucleolar RNA might play a role in the regulation of RNA editing. PMID: 15939761 [PubMed - indexed for MEDLINE] J Mol Med. 2005 Feb;83(2):110-20. Epub 2004 Dec 29. Deficient RNA editing of GluR2 and neuronal death in amyotropic lateral sclerosis. Kwak S, Kawahara Y. Department of Neurology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-8655 Tokyo, Japan. kwak-tky@umin.ac.jpOne plausible hypothesis for selective neuronal death in sporadic amyotropic lateral sclerosis (ALS) is excitotoxicity mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors, which are a subtype of ionotropic glutamate receptors. The Ca2+ conductance of AMPA receptors differs markedly depending on whether the GluR2 (or GluR-B) subunit is a component of the receptor. The properties of GluR2 are generated posttranscriptionally by RNA editing at the Q/R site in the putative second membrane domain (M2), during which the glutamine (Q) codon is substituted by an arginine (R) codon. AMPA receptors containing the unedited form of GluR2Q have high Ca2+ permeability in contrast to the low Ca2+ conductance of those containing the edited form of GluR2R. The role of Ca(2+)-permeable AMPA receptors, particularly GluR2 Q/R site RNA editing status, in neuronal death has been clearly demonstrated both in mice deficient in editing at the GluR2 Q/R site and in mice transgenic for an artificial Ca(2+)-permeable GluR2 subunit. We analyzed the expression level of mRNA of each AMPA receptor subunit in individual motor neurons, as well as the editing efficiency of GluR2 mRNA at the Q/R site in the single neuron level in control subjects and ALS cases. There was no significant difference as to the expression profile of AMPA receptor subunits or the proportion of GluR2 mRNA to total GluRs mRNA between normal subjects and ALS cases. By contrast, the editing efficiency varied greatly, from 0% to 100%, among the motor neurons of each individual with ALS, and was not complete in 44 of them (56%), whereas it remained 100% in normal controls. In addition, GluR2 editing efficiency was more than 99% in the cerebellar Purkinje cells of ALS, spinocerebellar degeneration and normal control groups. Thus, GluR2 underediting occurs in a disease specific and region selective manner. GluR2 modification by RNA editing is a biologically crucial event for neuronal survival, and its deficiency is a direct cause of neuronal death. Therefore, marked reduction of RNA editing in ALS motor neurons may be a direct cause of the selective motor neuron death seen in ALS. It is likely that the molecular mechanism underlying the deficiency in RNA editing is a reduction in the activity of ADAR2, a double- strand RNA specific deaminase. The restoration of this enzyme activity in ALS motor neurons may open the novel strategy for specific ALS therapy. PMID: 15624111 [PubMed - indexed for MEDLINE]
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Has anyone tried IP6 or calcium myo-inositol hexakisphosphate (calcium phytate) supplements? Mary http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=601218Macbeth et al. (2005) reported the crystal structure of human ADAR2 at 1.7-angstrom resolution. The structure revealed a zinc ion in the active site and suggested how the substrate adenosine is recognized. Unexpectedly, inositol hexakisphosphate (IP6) is buried within the enzyme core, contributing to the protein fold. Although there are no reports that adenosine deaminases that act on RNA (ADARs) require a cofactor, Macbeth et al. (2005) showed that IP6 is required for activity. Amino acids that coordinate IP6 in the crystal structure are conserved in some adenosine deaminases that act on transfer RNA, (ADATs), related enzymes that edit tRNA. Macbeth et al. (2005) showed that IP6 is also essential for in vivo and in vitro deamination of adenosine-37 of tRNA(alanine) (601431) by ADAT1 (604230). http://chemgroups.ucdavis.edu/~beal/pub%20pdf/Maydanovych-ChemRev-%2006.pdf It is possible that ADAR2’s structure (and its editing activity) fluctuates with IP6 levels in human cells, linking RNA editing by adenosine deamination to inositol signaling pathways.
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Mary, I don't know how you do what you do, but please keep it up as long as you have the energy to do it, knowing of course that 98% of it goes over most of our heads. It's that 2% that we would never have gotten otherwise that makes it worth our while to plow through your posts. With lots of practice we may be able to up our profit to 3%.
Thank you.
--Dave J.
PS: In the USA we have a national holiday, "Thanksgiving Day" 27 November this year, usually celebrated by gathering with family and by eating turkey, which is in effect our "national bird", all memorializing a highly mythologized harvest-fest of English colonists and American Indians together about 400 years ago. ......the funny part of all this is that the holiday is in the process of being adopted by Mexicans, whose national bird is arguably the....... "gaujalote", Aztec for the sound we call in English "gobble-gobble", turkey-talk. Today a binational manufacturer's rep visited my company and told me that her brother had made chile rellenos (stuffed large chile peppers, strictly a Mexican tradition) with turkey instead of the traditional Mexican asadero cheese, and topped 'em off with cranberry sauce (a USA thanksgiving traditional food originating in the northeastern colonies) and maize pudding (strictly Mexican). And, that the combo was fantastic!
It's all a metaphor for this forum.
Thank you all, from all over the world who join here both to prepare the food and to partake at the table.
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Thankyou so much Dave. My dearest wish is that one day Dr McCarty and his colleagues or other researchers on the list may find some benefit in my posts and that it may lead to a treatment.
Mary
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Quote:quote: Originally posted by Mary Reid"ALS5 has been linked to a 6 cM region of chromosome 15q15.1-q21.1, but the causative gene mutation for ALS5 has yet to be identified." Are these worth checking out? Variants of Elp3, a subunit of the elongator complex are associated with ALS. The elongator complex interacts with RNA polymerase II Mary http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=610507*610507 LEO1 RNA POLYMERASE II ASSOCIATED FACTOR, S. CEREVISIAE, HOMOLOG OF; LEO1 Alternative titles; symbols REPLICATIVE SENESCENCE DOWNREGULATED LEO1-LIKE; RDL Gene map locus 15q15.3 *609885 ELONGATION FACTOR, RNA POLYMERASE II, 3; ELL3 Gene map locus 15q15.3 I've looked at ELP3 in previous posts. Links here: http://www.als.net/forum/topic.asp?TOPIC_ID=3600&SearchTerms=elp3http://www.als.net/forum/topic.asp?TOPIC_ID=3562&whichpage=2&SearchTerms=elp3The epub version of this study came out last November. Mary Full text :http://hmg.oxfordjournals.org/cgi/content/full/18/3/472 Hum Mol Genet. 2009 Feb 1;18(3):472-81. Epub 2008 Nov 7. Links Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration. Simpson CL, Lemmens R, Miskiewicz K, Broom WJ, Hansen VK, van Vught PW, Landers JE, Sapp P, Van Den Bosch L, Knight J, Neale BM, Turner MR, Veldink JH, Ophoff RA, Tripathi VB, Beleza A, Shah MN, Proitsi P, Van Hoecke A, Carmeliet P, Horvitz HR, Leigh PN, Shaw CE, van den Berg LH, Sham PC, Powell JF, Verstreken P, Brown RH Jr, Robberecht W, Al-Chalabi A. The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors. Amyotrophic lateral sclerosis (ALS) is a spontaneous, relentlessly progressive motor neuron disease, usually resulting in death from respiratory failure within 3 years. Variation in the genes SOD1 and TARDBP accounts for a small percentage of cases, and other genes have shown association in both candidate gene and genome-wide studies, but the genetic causes remain largely unknown. We have performed two independent parallel studies, both implicating the RNA polymerase II component, ELP3, in axonal biology and neuronal degeneration. In the first, an association study of 1884 microsatellite markers, allelic variants of ELP3 were associated with ALS in three human populations comprising 1483 people (P = 1.96 x 10(-9)). In the second, an independent mutagenesis screen in Drosophila for genes important in neuronal communication and survival identified two different loss of function mutations, both in ELP3 (R475K and R456K). Furthermore, knock down of ELP3 protein levels using antisense morpholinos in zebrafish embryos resulted in dose-dependent motor axonal abnormalities [Pearson correlation: -0.49, P = 1.83 x 10(-12) (start codon morpholino) and -0.46, P = 4.05 x 10(-9) (splice-site morpholino), and in humans, risk-associated ELP3 genotypes correlated with reduced brain ELP3 expression (P = 0.01). These findings add to the growing body of evidence implicating the RNA processing pathway in neurodegeneration and suggest a critical role for ELP3 in neuron biology and of ELP3 variants in ALS. PMID: 18996918 [PubMed - in process]
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<font face="Tahoma">
<font color="navy">Gene . . . ALS6 . . .
"Agglutinin-like protein 6 serine rich"</font id="navy">
<font color="maroon">Really helpful to know that it's 'agglutinin-like' and 'serine rich'?</font id="maroon"></font id="Tahoma">
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Hi paqtec, Do you have the study for this please? I thought that it was the C.albicans gene. Dr McCarty, can you confirm ALS6 please? This is also of interest. Lysophosphatidylcholine acyltransferase 2 in the same ALS6 region. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=612040What's happening with platelet-activating factor in ALS? Would you expect increased activity of this enzyme with deficient neuropathy target esterase expression? Would the increased lysophosphatidylcholine as a result stimulate Lysophosphatidylcholine acyltransferase 2? Mary
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<font face="Tahoma"><font color="maroon">Came from Protein database.
"Gene name ALS6" --</font id="maroon"></font id="Tahoma"><font face="Tahoma">
<font color="navy">
FT /gene="ALS6"
FT /locus_tag="PICST_31759"
FT /product="agglutinin-like protein 6 serine rich"
FT /protein_id="ABN66587.2"
FT /translation="MCILVFVLITSVLGAQLTDVFQSLEIINNSGSNRAQDIRTAKLTW
FT KIEAGDAVEGDEFSLEMPNVFRTKFPGDQLYLVADYSIYASCVAVDGSYLAQNSYLNCT
FT TTSSVVESDFKATGTLSFDFVFNAGGSGSEIDTTAASILVPGENKINWSGLQTTVNIDA
FT GPFFAPVSNDKELVYFSRSTPQMYEQIFMLAGECNGGIVSGSIGMTTNDSLDCTQFALK
FT ATNNLNSFLLPETAINVQNTITCKEQSITFKFNSVANNYRVFLQGLEKFPTNSDAIRHI
FT FAYSIQCGDGTKITKSSGQDFVVIDGYEDSSGSVEYSTVYTTTTWTETYLTTVTIPCTD
FT ESATATVIVKVPTSCSSDLESSTHCPGCESESSSSVSCDEPEISSDTSSSLSTIYCDES
FT SSSSDTSSLIESSSDIYSSSLADTSVYTSSESSTTEECPETSSLSSTESSSSEVSSTTE
FT ECTETSSSSIADSSIYTSSESSILSSHDESSSTIETTDSISSVESSSSIQETSELTSSK
FT ESSSSVESTSSVELSSSVQATSSKELSSSVETTSSVFTSTESLSSDDTSSSIETTSTVS
FT SSSSEITSPCLQCTSSISSSSSVDVPSPWTSSSETESSSSSTTTSYTTIPSSSIEGASS
FT SPFVSSGLTSSESTSVSSNTPPEYTITITNRGTTIITIATCPGGCTRTTTVFPSETTTT
FT SIATSTETYCPDSSTEIDKSSSVLNTSITSTTAETTEETSKESTSETSTNDSTITSKTT
FT TTLINTSTETYCPESSTETDKSSNVLDTSITSTTSTSSSTKETTDSTKDSTKATTTTST
FT ISLSTSESTSSSNTGTLSTFSISTSTGNISSSISYTEIVSSPTEITSVTTDCTTNYIST
FT TITCSSCESNIESTSDKVSKPPGGTNYDTTNFAPTAPAPRSSETGQFPSSSDKASQEEP
FT IPSSSGTAVCEGDCDLTSRVEYDKLTPTQSTTQTTTHTTTQTTTQSTTQSTQSTSGTIP
FT VSASAQSSSAQSSKVADSSTFHFSSFSTSSVLPSGLPIPVAFDSAAARPVISLVALMMS
FT LLFL"
SQ Sequence 3159 BP;
atgtgcattc tcgtcttcgt ccttattact tctgtacttg gtgcacagtt gacggatgtc 60
tttcaatctc tagaaatcat caacaattca gggctgaatc gtgctcagga tattcgtact 120
gccaaactta catggaaaat cgaagctggt gatgcagttg aaggtgacga attcagcttg 180
gagatgccaa atgtgttcag aacaaagttt ccaggagacc agttgtatct tgttgctgac 240
tattcaatct atgctctgtg tgttgctgtt gatggttctt atcttgcaca aaattcttac 300
ttgaattgca cgaccactag ttctgttgtc gagtctgatt tcaaggctac gggaactctc 360
tcgtttgatt ttgtgtttaa tgctggaggc tctggaagtg agatagatac cactgctgct 420
agcatattgg tccctggaga aaataaaata aattggagtg gtttgcaaac tactgttaat 480
atcgatgctg gtcccttttt tgctcctgtt agcaatgata aagaacttgt gtatttctct 540
cgttcgactc ctcagatgta cgaacagata ttcatgcttg ccggagaatg taatggtggt 600
attgtctctg ggagtattgg tatgaccacc aacgatagtc tagattgtac tcagtttgcg 660
ttgaaagcaa caaacaactt aaattccttc cttttgccgg aaactgccat caatgtccaa 720
aacaccataa cttgcaaaga acaaagtatc accttcaaat ttaattcggt tgccaataac 780
taccgagtct ttctccaagg tcttgagaag tttccaacta actctgatgc tattagacat 840
atatttgcct acagtattca atgtggagac ggtacaaaaa ttacaaagct gagtggccag 900
gatttcgtag ttattgacgg ctatgaagac agttctggat cggtagaata ttcaacagtt 960
tacactacta ctacctggac agagacatat ttaacaacgg ttaccatccc ttgtactgat 1020
gaactggcta ctgccaccgt gattgtcaag gttccgacat cttgctcttc agatttagag 1080
ctgtctactc actgtccagg ttgtgagtct gaatcatcaa gttctgtaag ttgtgatgaa 1140
cctgaaattt catcagatac ttccagtctg ttatctacta tttattgcga tgaatcctct 1200
tctagctcag atacatcctc tcttattgaa agcagctccg atatatactc ttccagtttg 1260
gctgatacct ctgtttacac aagttctgaa tcctcaacta ctgaagaatg ccccgagacc 1320
tcctctcttt cttctactga atcttcttcg tctgaagtat cttcaacaac tgaggaatgt 1380
actgaaacac tgtcttcgag tattgctgat tcatcaatct atacgagctc agaatcttca 1440
attctttctt cgcatgatga actgtcctct acaattgaga ctactgattc tatttcttca 1500
gttgaatcat cttcctctat tcaggaaact tcggaattga catcttcaaa ggaatcttct 1560
tcatctgttg aatcgacatc ttcagtcgaa ttgtcctcct ccgttcaggc cacatcttcg 1620
aaggaattat cttcttcagt tgaaacgaca tcttcagtat ttacttctac cgagtcattg 1680
tcttctgatg atacgtcatc ttctatcgaa acaacttcaa ctgtgagttc atcctcctca 1740
gaaattacta gcccctgtct tcaatgcacc agttctattt ccagttctag ttccgttgat 1800
gttcctagtc cgtggacaag tagtctggaa actgagtctt cttcctcatc aaccactacc 1860
agttacacca caatcccttc ctctagcatt gaaggtgcgc tgtcctctcc ttttgtttct 1920
agtggattga cgagctctga atctacgctg gttctgtcca acactcctcc cgaatacact 1980
atcacaatta ccaaccgtgg aactacaatt ataaccattg caacttgtcc tggggggtgt 2040
acaaggacaa cgacggtatt ccccagtgag accactacta ctctgattgc aactagtaca 2100
gaaacatatt gcccggatag tctgacagaa attgacaaga gttcaagtgt tttgaataca 2160
tctataactt ctacgacagc tgaaactacc gaagaaacca gcaaagagtc tacttcagag 2220
acatccacca acgacagtac catcaccagc aagactacaa ccacattgat caacaccagt 2280
acagaaacat actgtccaga aagtctgacg gaaactgaca agagttcaaa tgttctcgac 2340
acatctataa cttccactac ttctactagt agcagtacga aggaaaccac agactctacc 2400
aaagatagta caaaggcaac tacgacaact tccactatca gtctatctac gtctgaaagc 2460
acctcctcca gcaatactgg cactttgagc actttttcaa tcagtacttc tactggaaat 2520
atctcatcct ctattagcta tacggagatt gttagtagtc ctacggaaat aacttctgtc 2580
actactgatt gtactactaa ttacatttcc acgactatta cttgctcctc gtgtgaatct 2640
aatattgagt caacctcaga taaggtttcc aagcctccag ggggaacaaa ttacgatacg 2700
actaattttg cacccactgc gcccgcgcca agatccagtg aaactggcca atttcccctg 2760
ctgtctgata aggccagcca agaagagcca attccactgt cgtccggaac ggctgtctgt 2820
gaaggtgatt gcgatttgac tagccgtgtg gaatatgaca aattgacccc gactcaatcc 2880
acgactcaga ccacgactca cacaaccacc cagacaacca ctcagtctac cactcaatcc 2940
actcaatcta cgtccgggac cattcctgtg tctgcgtctg cgcaaagtct gtctgcgcag 3000
tcttcaaaag ttgctgactc ttcgactttc cactttagtc tgttctccac cctgtctgtg 3060
ctaccttcag gattacccat tcccgtcgcg ttcgactcgg ctgctgctcg tcccgtgatc 3120
agccttgttg ctctcatgat gtcgcttctc ttcttgtaa 3159</font id="navy"></font id="Tahoma">
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Hi paqtec, Thanks for this. It seems that this ALS stands for agglutinin-like sequence. Mary http://www.kegg.com/dbget-bin/www_bget?refseq+XP_001384616 region_name="Candida_ALS" /note="Candida agglutinin-like protein (ALS). This family consists of several agglutinin-like proteins from different Candida species. ALS genes of Candida albicans encode a family of cell-surface glycoproteins with a three-domain structure. Each Als protein...; pfam05792" ALS6 agglutinin-like protein 6 serine rich [ Pichia stipitis CBS 6054 ] GeneID: 4838784 updated 21-Dec-2008 Summary Gene name ALS6 Locus tag PICST_31759 Gene type protein coding RNA name agglutinin-like protein 6 serine rich RefSeq status PROVISIONAL Organism Pichia stipitis CBS 6054 (strain: CBS 6054) Lineage Eukaryota; Fungi; Dikarya; Ascomycota; Saccharomycotina; Saccharomycetes; Saccharomycetales; Saccharomycetaceae; Pichia Also known as ALS6
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There’s probably a little nomenclature confusion – I was referring to the eventual identification of the gene linked or associated with the ALS6 genetic locus in humans.
John McCarty, PhD
Treatment Investigator,
ALS Therapy Development Institute
John McCarty, PhD
Director of Therapeutic Investigation
ALS Therapy Development Institute
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Quote:quote:Originally posted by Mary Reid
"ALS5 has been linked to a 6 cM region of chromosome 15q15.1-q21.1, but the causative gene mutation for ALS5 has yet to be identified."
*609885
ELONGATION FACTOR, RNA POLYMERASE II, 3; ELL3
Gene map locus 15q15.3
I've asked whether it may be possible that the gene that they are looking for called ALS5 is ELL3. Interesting that it binds ferritin. http://www.genecards.org/cgi-bin/carddisp.pl?gene=ELL3Mary
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http://string.embl.de/interactions/9606.ENSP00000368459I've just been looking at the above link and see that both ELP3 and ELL3 are interacting partners of Nuclear fragile X mental retardation-interacting protein 1. ALS has been reported in a patient with fragile X syndrome. Mary Neurology. 1990 Feb;40(2):378-80. Links Amyotrophic lateral sclerosis in a patient with fragile X syndrome. Desai HB, Donat J, Shokeir MH, Munoz DG. Department of Neurology, University Hospital, Saskatoon, Saskatchewan, Canada. Fragile X syndrome is a common cause of mental retardation. We report the clinical and pathologic features of a patient with fragile X syndrome who developed amyotrophic lateral sclerosis (ALS) at a relatively young age. Although the occurrence of these 2 diseases could be a mere coincidence, the development of ALS in this patient might be related to the chromosomal aberration of fragile X syndrome. PMID: 2300265 [PubMed - indexed for MEDLINE
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Am J Med Genet B Neuropsychiatr Genet. 2008 Dec 22. [Epub ahead of print] Links
The FMR1 gene and fragile X-associated tremor/ataxia syndrome.
Brouwer JR, Willemsen R, Oostra BA.
Department of Clinical Genetics, ErasmusMC, Rotterdam, The Netherlands.
The CGG-repeat present in the 5'UTR of the FMR1 gene is unstable upon transmission to the next generation. The repeat is up to 55 CGGs long in the normal population. In fragile X patients, a repeat length exceeding 200 CGGs (full mutation: FM) generally leads to methylation of the repeat and the promoter region, which is accompanied by silencing of the FMR1 gene. The gene product FMRP is involved in regulation of transport and translation of certain mRNA in the dendrite, thereby affecting synaptic plasticity. This is central to learning and memory processes. The absence of FMRP seen in FM is the cause of the mental retardation seen in fragile X patients. The premutation (PM) is defined as 55-200 CGGs. Female PM carriers are at risk of developing primary ovarian insufficiency. Recently it was discovered that elderly PM carriers might develop a progressive neurodegenerative disorder called fragile X-associated tremor/ataxia syndrome. Although arising from the mutations in the same gene, distinct mechanisms lead to fragile X syndrome (absence of FMRP) and FXTAS (toxic RNA gain of function). The pathogenic mechanisms thought to underlie these disorders are discussed, with a specific emphasis on FXTAS. This review gives insight on the implications of all possible repeat length categories seen in fragile X families. (c) 2008 Wiley-Liss, Inc.
PMID: 19105204 [PubMed - as supplied by publisher]
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Mutant SOD1 binds lysyl-tRNA synthetase.
FMRP regulates translation of elongation factor 1A.
Elongation factor 1A associates with the multi-aminoacyl-tRNA synthetase complex.
Mary
J Biol Chem. 2003 May 2;278(18):15669-78. Epub 2003 Feb 19. Links
The fragile X mental retardation protein FMRP binds elongation factor 1A mRNA and negatively regulates its translation in vivo.
Sung YJ, Dolzhanskaya N, Nolin SL, Brown T, Currie JR, Denman RB.
Department of Anatomy and Cell Biology, Columbia University, New York, NY 10032, USA.
Loss of the RNA-binding protein FMRP (fragile X mental retardation protein) leads to fragile X syndrome, the most common form of inherited mental retardation. Although some of the messenger RNA targets of this protein, including FMR1, have been ascertained, many have yet to be identified. We have found that Xenopus elongation factor 1A (EF-1A) mRNA binds tightly to recombinant human FMRP in vitro. Binding depended on protein determinants located primarily in the C-terminal end of hFMRP, but the hnRNP K homology domain influenced binding as well. When hFMRP was expressed in cultured cells, it dramatically reduced endogenous EF-1A protein expression but had no effect on EF-1A mRNA levels. In contrast, the translation of several other mRNAs, including those coding for dynamin and constitutive heat shock 70 protein, was not affected by the hFMRP expression. Most importantly, EF-1A mRNA and hFMR1 mRNA were coimmunoprecipitated with hFMRP. Finally, in fragile X lymphoblastoid cells in which hFMRP is absent, human EF-1A protein but not its corresponding mRNA is elevated compared with normal lymphoblastoid cells. These data suggest that hFMRP binds to EF-1A mRNA and also strongly argue that FMRP negatively regulates EF-1A expression in vivo.
FEBS Lett. 2008 Jun 25;582(15):2178-82. Epub 2008 Jun 5. Links
Structural and functional mapping of the archaeal multi-aminoacyl-tRNA synthetase complex.
Hausmann CD, Ibba M.
Department of Microbiology, The Ohio State University, 484 West 12th Avenue, Columbus, OH 43210-1292, USA.
Methanothermobacter thermautotrophicus contains a multi-aminoacyl-tRNA synthetase complex (MSC) of LysRS, LeuRS and ProRS. Elongation factor (EF) 1A also associates to the MSC, with LeuRS possibly acting as a core protein. Analysis of the MSC revealed that LysRS and ProRS specifically interact with the idiosyncratic N- and C- termini of LeuRS, respectively. EF-1A instead interacts with the inserted CP1 proofreading domain, consistent with models for post-transfer editing by class I synthetases such as LeuRS. Together with previous genetic data, these findings show that LeuRS plays a central role in mediating interactions within the archaeal MSC by acting as a core scaffolding protein.
PMID: 18538672 [PubMed - indexed for MEDLINE]
PMCID: PMC2486338 [Available on 2009/06/25]
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"triple CGG repeats on FMR1 correlate with anti-Müllerian hormone."
"Mullerian Inhibiting Substance (MIS) is a motor neuron survival factor"
Anti-Mullerian hormone is found at 19p13.3, a region implicated in ALS with FTD.
Mary
Reprod Sci. 2008 Dec 30. [Epub ahead of print] Links
Can the FMR1 (Fragile X) Gene Serve As Predictor of Response to Ovarian Stimulation?
Gleicher N, Weghofer A, Oktay K, Barad D.
Because triple CGG repeats on FMR1 correlate with anti-Müllerian hormone, repeats may also correlate with clinical outcomes. In 55 in vitro fertilization patients, repeats, corrected for gonadotropin dosage, were, therefore, correlated to oocytes. Patients were stratified by <35 and >/=35 repeats, and by age to <38 or >/=38 years. Less than 35 (but not >/=35) repeats demonstrated significantly lower anti-Müllerian hormone at ages >/=38 than at <38 years (P < .05). In >38 years, anti-Müllerian hormone was not affected by repeats. In <38 years, with <35 repeats (though not with >/=35), required significantly less gonadotropins than >/=38 (P < .05). In <38 years (though not >/=38), those with <35 repeats produced significantly more oocytes than women with >/=35 repeats (P = .006). In <38 years, retrieved oocytes were inversely related to repeats, adjusted for gonadotropin dosage (P = .03). This supports FMR1 testing as useful in fertility practice and suggests why response rates to increasing stimulation with gonadotropins may vary.
PMID: 19116286 [PubMed - as supplied by publisher]
Proc Natl Acad Sci U S A. 2005 Nov 8;102(45):16421-5. Epub 2005 Oct 31. Links
Mullerian inhibiting substance acts as a motor neuron survival factor in vitro.
Wang PY, Koishi K, McGeachie AB, Kimber M, Maclaughlin DT, Donahoe PK, McLennan IS.
Neuromuscular Research Group, Department of Anatomy and Structural Biology, University of Otago, Dunedin, New Zealand.
The survival of motor neurons is controlled by multiple factors that regulate different aspects of their physiology. The identification of these factors is important because of their relationship to motor neuron disease. We investigate here whether Mullerian Inhibiting Substance (MIS) is a motor neuron survival factor. We find that motor neurons from adult mice synthesize MIS and express its receptors, suggesting that mature motor neurons use MIS in an autocrine fashion or as a way to communicate with each other. MIS was observed to support the survival and differentiation of embryonic motor neurons in vitro. During development, male-specific MIS may have a hormone effect because the blood-brain barrier has yet to form, raising the possibility that MIS participates in generating sex-specific differences in motor neurons.
PMID: 16260730 [PubMed - indexed for MEDLINE
Fertil Steril. 2008 Apr 1. [Epub ahead of print] Links
A pilot study of premature ovarian senescence: I. Correlation of triple CGG repeats on the FMR1 gene to ovarian reserve parameters FSH and anti-Müllerian hormone.
Gleicher N, Weghofer A, Barad DH.
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut.
OBJECTIVE: To assess whether the number of triple CGG expansion of the FMR1 (fragile X) gene, known to correlate at premutation (55-200 repeats) and full mutation (>200 repeats) ranges with risk toward premature ovarian failure (POF), also correlates with milder forms of premature ovarian senescence. DESIGN: Retrospective, controlled cohort study. SETTING: Academically affiliated, private fertility center. PATIENT(S): Forty consecutive, new infertility patients, of which 11 presented with a primary diagnosis of repeated pregnancy loss (controls), 23 with prematurely elevated, age-specific baseline follicle stimulating hormone (FSH) levels (i.e., premature ovarian aging, POA) and 6 with POF. INTERVENTION(S): Determination of number of triple CGG repeats on both alleles of FMR1 gene and of FSH and anti-Müllerian hormone (AMH) levels as a reflection of ovarian reserve. MAIN OUTCOME MEASURE(S): Statistical correlation of higher (allele-2) triple repeat counts with patients' clinical diagnoses and with FSH and AMH levels. RESULT(S): Mean triple CGG counts increased in parallel to increasing severity of premature ovarian senescence. Repeat expansion numbers at all levels correlated statistically to FSH. An AMH level of <1.0 ng/mL statistically correlated to >32 triple repeats. CONCLUSION(S): Over 30 triple CGG repeats denote increased risk (and severity) toward premature ovarian senescence in parallel to increasing expansions. Numbers, considered well within the normal range, therefore already denote risk, suggesting that CGG repeats may represent a new test to predict ovarian function and assess female infertility.
PMID: 18384775 [PubMed - as supplied by publisher]
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