Distribution and threshold expression of the tRNA(Lys) mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF)
We investigated the distribution and expression of mutant mtDNAs carrying the A-to-G mutation at position 8344 in the tRNA(Lys) gene in the skeletal muscle of four patients with myoclonus epilepsy and ragged-red fibers (MERRF). The proportion of mutant genomes was greater than 80% of total mtDNAs in...
Gespeichert in:
Veröffentlicht in: | American journal of human genetics 1992-12, Vol.51 (6), p.1187-1200 |
---|---|
Hauptverfasser: | , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 1200 |
---|---|
container_issue | 6 |
container_start_page | 1187 |
container_title | American journal of human genetics |
container_volume | 51 |
creator | Boulet, L Karpati, G Shoubridge, E A |
description | We investigated the distribution and expression of mutant mtDNAs carrying the A-to-G mutation at position 8344 in the tRNA(Lys) gene in the skeletal muscle of four patients with myoclonus epilepsy and ragged-red fibers (MERRF). The proportion of mutant genomes was greater than 80% of total mtDNAs in muscle samples of all patients and was associated with a decrease in the activity of cytochrome c oxidase (COX). The vast majority of myoblasts, cloned from the satellite-cell population in the same muscles, were homoplasmic for the mutation. The overall proportion of mutant mtDNAs in this population was similar to that in differentiated muscle, suggesting that the ratio of mutant to wild-type mtDNAs in skeletal muscle is determined either in the ovum or during early development and changes little with age. Translation of all mtDNA-encoded genes was severely depressed in homoplasmic mutant myoblast clones but not in heteroplasmic or wild-type clones. The threshold for biochemical expression of the mutation was determined in heteroplasmic myotubes formed by fusion of different proportions of mutant and wild-type myoblasts. The magnitude of the decrease in translation in myotubes containing mutant mtDNAs was protein specific. Complex I and IV subunits were more affected than complex V subunits, and there was a rough correlation with both protein size and number of lysine residues. Approximately 15% wild-type mtDNAs restored translation and COX activity to near normal levels. These results show that the A-to-G substitution in tRNA(Lys) is a functionally recessive mutation that can be rescued by intraorganellar complementation with a small proportion of wild-type mtDNAs and explain the steep threshold for expression of the MERRF clinical phenotype. |
format | Article |
fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_1682926</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>73378814</sourcerecordid><originalsourceid>FETCH-LOGICAL-o203t-f0a9f031297c79dabd1ac75dd5188195463070eac5e54a04cc976423e5ca4cae3</originalsourceid><addsrcrecordid>eNpVUV2LFDEQHEQ5905_ghB8kLuHgWQyk-y8CMd9KawKiz6HbNKzE80kYzqj7v_wB5u7W0Sfuumqrqqmn1Qr1nFZC0G7p9WKUtrUfdPL59Up4ldKGVtTflKdMM5bLvpV9fvaYU5ut2QXA9HBkjwmwDF6S-DXXFq8B-JQ5kDy9uPl-eaAF2Rasn5YcYHgN_CQtS9DNB7uyXMBIWQkP10eyXSIxsfgDIHZeZjx8OCU9H4Ptk5gyeB2kJCcf7jZbm8vXlTPBu0RXh7rWfXl9ubz1bt68-nu_dXlpo4N5bkeqO4Hylm5z8je6p1l2sjO2o6t16zvWsGppKBNB12raWtML0XbcOiMbo0Gfla9fdSdl90E1pTESXs1JzfpdFBRO_U_Etyo9vGHYmLd9I0oAq8fBSJmp9C4DGY0MQQwWQnJpOBNIb05uqT4fQHManJowHsdIC6oJOey5G0L8dW_cf7mOD6L_wGElZSo</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>73378814</pqid></control><display><type>article</type><title>Distribution and threshold expression of the tRNA(Lys) mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF)</title><source>MEDLINE</source><source>Access via ScienceDirect (Elsevier)</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>Boulet, L ; Karpati, G ; Shoubridge, E A</creator><creatorcontrib>Boulet, L ; Karpati, G ; Shoubridge, E A</creatorcontrib><description>We investigated the distribution and expression of mutant mtDNAs carrying the A-to-G mutation at position 8344 in the tRNA(Lys) gene in the skeletal muscle of four patients with myoclonus epilepsy and ragged-red fibers (MERRF). The proportion of mutant genomes was greater than 80% of total mtDNAs in muscle samples of all patients and was associated with a decrease in the activity of cytochrome c oxidase (COX). The vast majority of myoblasts, cloned from the satellite-cell population in the same muscles, were homoplasmic for the mutation. The overall proportion of mutant mtDNAs in this population was similar to that in differentiated muscle, suggesting that the ratio of mutant to wild-type mtDNAs in skeletal muscle is determined either in the ovum or during early development and changes little with age. Translation of all mtDNA-encoded genes was severely depressed in homoplasmic mutant myoblast clones but not in heteroplasmic or wild-type clones. The threshold for biochemical expression of the mutation was determined in heteroplasmic myotubes formed by fusion of different proportions of mutant and wild-type myoblasts. The magnitude of the decrease in translation in myotubes containing mutant mtDNAs was protein specific. Complex I and IV subunits were more affected than complex V subunits, and there was a rough correlation with both protein size and number of lysine residues. Approximately 15% wild-type mtDNAs restored translation and COX activity to near normal levels. These results show that the A-to-G substitution in tRNA(Lys) is a functionally recessive mutation that can be rescued by intraorganellar complementation with a small proportion of wild-type mtDNAs and explain the steep threshold for expression of the MERRF clinical phenotype.</description><identifier>ISSN: 0002-9297</identifier><identifier>EISSN: 1537-6605</identifier><identifier>PMID: 1334369</identifier><language>eng</language><publisher>United States</publisher><subject>Adult ; AMINO ACIDS ; BASIC BIOLOGICAL SCIENCES ; CARBOXYLIC ACIDS ; CELL CONSTITUENTS ; Cells, Cultured ; CYTOCHROME OXIDASE ; DISEASES ; DISTRIBUTION ; DNA, Mitochondrial - genetics ; Electron Transport Complex IV - metabolism ; Electrophoresis, Polyacrylamide Gel ; ENZYME ACTIVITY ; ENZYMES ; Epilepsies, Myoclonic - genetics ; Epilepsies, Myoclonic - metabolism ; EPILEPSY ; Female ; FIBERS ; Flow Cytometry ; Gene Expression ; GENES ; HAEM DEHYDROGENASES ; Humans ; LEVELS ; LYSINE ; Male ; METABOLIC DISEASES ; MITOCHONDRIA ; Mitochondrial Encephalomyopathies - genetics ; Mitochondrial Encephalomyopathies - metabolism ; Mitochondrial Encephalomyopathies - physiopathology ; MUSCLES ; Muscles - enzymology ; Muscles - metabolism ; Muscles - pathology ; Mutation ; MUTATIONS ; MYOBLASTS ; NERVOUS SYSTEM DISEASES ; NUCLEIC ACIDS ; ORGANIC ACIDS ; ORGANIC COMPOUNDS ; OXIDOREDUCTASES ; PATIENTS ; PHENOTYPE ; Protein Biosynthesis ; PROTEINS ; RECESSIVE MUTATIONS ; RESIDUES ; RNA 550400 -- Genetics ; RNA, Transfer, Lys - genetics ; RNA, Transfer, Lys - metabolism ; SIZE ; TRANSFER RNA</subject><ispartof>American journal of human genetics, 1992-12, Vol.51 (6), p.1187-1200</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1682926/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC1682926/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1334369$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/6717632$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Boulet, L</creatorcontrib><creatorcontrib>Karpati, G</creatorcontrib><creatorcontrib>Shoubridge, E A</creatorcontrib><title>Distribution and threshold expression of the tRNA(Lys) mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF)</title><title>American journal of human genetics</title><addtitle>Am J Hum Genet</addtitle><description>We investigated the distribution and expression of mutant mtDNAs carrying the A-to-G mutation at position 8344 in the tRNA(Lys) gene in the skeletal muscle of four patients with myoclonus epilepsy and ragged-red fibers (MERRF). The proportion of mutant genomes was greater than 80% of total mtDNAs in muscle samples of all patients and was associated with a decrease in the activity of cytochrome c oxidase (COX). The vast majority of myoblasts, cloned from the satellite-cell population in the same muscles, were homoplasmic for the mutation. The overall proportion of mutant mtDNAs in this population was similar to that in differentiated muscle, suggesting that the ratio of mutant to wild-type mtDNAs in skeletal muscle is determined either in the ovum or during early development and changes little with age. Translation of all mtDNA-encoded genes was severely depressed in homoplasmic mutant myoblast clones but not in heteroplasmic or wild-type clones. The threshold for biochemical expression of the mutation was determined in heteroplasmic myotubes formed by fusion of different proportions of mutant and wild-type myoblasts. The magnitude of the decrease in translation in myotubes containing mutant mtDNAs was protein specific. Complex I and IV subunits were more affected than complex V subunits, and there was a rough correlation with both protein size and number of lysine residues. Approximately 15% wild-type mtDNAs restored translation and COX activity to near normal levels. These results show that the A-to-G substitution in tRNA(Lys) is a functionally recessive mutation that can be rescued by intraorganellar complementation with a small proportion of wild-type mtDNAs and explain the steep threshold for expression of the MERRF clinical phenotype.</description><subject>Adult</subject><subject>AMINO ACIDS</subject><subject>BASIC BIOLOGICAL SCIENCES</subject><subject>CARBOXYLIC ACIDS</subject><subject>CELL CONSTITUENTS</subject><subject>Cells, Cultured</subject><subject>CYTOCHROME OXIDASE</subject><subject>DISEASES</subject><subject>DISTRIBUTION</subject><subject>DNA, Mitochondrial - genetics</subject><subject>Electron Transport Complex IV - metabolism</subject><subject>Electrophoresis, Polyacrylamide Gel</subject><subject>ENZYME ACTIVITY</subject><subject>ENZYMES</subject><subject>Epilepsies, Myoclonic - genetics</subject><subject>Epilepsies, Myoclonic - metabolism</subject><subject>EPILEPSY</subject><subject>Female</subject><subject>FIBERS</subject><subject>Flow Cytometry</subject><subject>Gene Expression</subject><subject>GENES</subject><subject>HAEM DEHYDROGENASES</subject><subject>Humans</subject><subject>LEVELS</subject><subject>LYSINE</subject><subject>Male</subject><subject>METABOLIC DISEASES</subject><subject>MITOCHONDRIA</subject><subject>Mitochondrial Encephalomyopathies - genetics</subject><subject>Mitochondrial Encephalomyopathies - metabolism</subject><subject>Mitochondrial Encephalomyopathies - physiopathology</subject><subject>MUSCLES</subject><subject>Muscles - enzymology</subject><subject>Muscles - metabolism</subject><subject>Muscles - pathology</subject><subject>Mutation</subject><subject>MUTATIONS</subject><subject>MYOBLASTS</subject><subject>NERVOUS SYSTEM DISEASES</subject><subject>NUCLEIC ACIDS</subject><subject>ORGANIC ACIDS</subject><subject>ORGANIC COMPOUNDS</subject><subject>OXIDOREDUCTASES</subject><subject>PATIENTS</subject><subject>PHENOTYPE</subject><subject>Protein Biosynthesis</subject><subject>PROTEINS</subject><subject>RECESSIVE MUTATIONS</subject><subject>RESIDUES</subject><subject>RNA 550400 -- Genetics</subject><subject>RNA, Transfer, Lys - genetics</subject><subject>RNA, Transfer, Lys - metabolism</subject><subject>SIZE</subject><subject>TRANSFER RNA</subject><issn>0002-9297</issn><issn>1537-6605</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1992</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUV2LFDEQHEQ5905_ghB8kLuHgWQyk-y8CMd9KawKiz6HbNKzE80kYzqj7v_wB5u7W0Sfuumqrqqmn1Qr1nFZC0G7p9WKUtrUfdPL59Up4ldKGVtTflKdMM5bLvpV9fvaYU5ut2QXA9HBkjwmwDF6S-DXXFq8B-JQ5kDy9uPl-eaAF2Rasn5YcYHgN_CQtS9DNB7uyXMBIWQkP10eyXSIxsfgDIHZeZjx8OCU9H4Ptk5gyeB2kJCcf7jZbm8vXlTPBu0RXh7rWfXl9ubz1bt68-nu_dXlpo4N5bkeqO4Hylm5z8je6p1l2sjO2o6t16zvWsGppKBNB12raWtML0XbcOiMbo0Gfla9fdSdl90E1pTESXs1JzfpdFBRO_U_Etyo9vGHYmLd9I0oAq8fBSJmp9C4DGY0MQQwWQnJpOBNIb05uqT4fQHManJowHsdIC6oJOey5G0L8dW_cf7mOD6L_wGElZSo</recordid><startdate>19921201</startdate><enddate>19921201</enddate><creator>Boulet, L</creator><creator>Karpati, G</creator><creator>Shoubridge, E A</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope><scope>OTOTI</scope><scope>5PM</scope></search><sort><creationdate>19921201</creationdate><title>Distribution and threshold expression of the tRNA(Lys) mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF)</title><author>Boulet, L ; Karpati, G ; Shoubridge, E A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-o203t-f0a9f031297c79dabd1ac75dd5188195463070eac5e54a04cc976423e5ca4cae3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1992</creationdate><topic>Adult</topic><topic>AMINO ACIDS</topic><topic>BASIC BIOLOGICAL SCIENCES</topic><topic>CARBOXYLIC ACIDS</topic><topic>CELL CONSTITUENTS</topic><topic>Cells, Cultured</topic><topic>CYTOCHROME OXIDASE</topic><topic>DISEASES</topic><topic>DISTRIBUTION</topic><topic>DNA, Mitochondrial - genetics</topic><topic>Electron Transport Complex IV - metabolism</topic><topic>Electrophoresis, Polyacrylamide Gel</topic><topic>ENZYME ACTIVITY</topic><topic>ENZYMES</topic><topic>Epilepsies, Myoclonic - genetics</topic><topic>Epilepsies, Myoclonic - metabolism</topic><topic>EPILEPSY</topic><topic>Female</topic><topic>FIBERS</topic><topic>Flow Cytometry</topic><topic>Gene Expression</topic><topic>GENES</topic><topic>HAEM DEHYDROGENASES</topic><topic>Humans</topic><topic>LEVELS</topic><topic>LYSINE</topic><topic>Male</topic><topic>METABOLIC DISEASES</topic><topic>MITOCHONDRIA</topic><topic>Mitochondrial Encephalomyopathies - genetics</topic><topic>Mitochondrial Encephalomyopathies - metabolism</topic><topic>Mitochondrial Encephalomyopathies - physiopathology</topic><topic>MUSCLES</topic><topic>Muscles - enzymology</topic><topic>Muscles - metabolism</topic><topic>Muscles - pathology</topic><topic>Mutation</topic><topic>MUTATIONS</topic><topic>MYOBLASTS</topic><topic>NERVOUS SYSTEM DISEASES</topic><topic>NUCLEIC ACIDS</topic><topic>ORGANIC ACIDS</topic><topic>ORGANIC COMPOUNDS</topic><topic>OXIDOREDUCTASES</topic><topic>PATIENTS</topic><topic>PHENOTYPE</topic><topic>Protein Biosynthesis</topic><topic>PROTEINS</topic><topic>RECESSIVE MUTATIONS</topic><topic>RESIDUES</topic><topic>RNA 550400 -- Genetics</topic><topic>RNA, Transfer, Lys - genetics</topic><topic>RNA, Transfer, Lys - metabolism</topic><topic>SIZE</topic><topic>TRANSFER RNA</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Boulet, L</creatorcontrib><creatorcontrib>Karpati, G</creatorcontrib><creatorcontrib>Shoubridge, E A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><collection>OSTI.GOV</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>American journal of human genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Boulet, L</au><au>Karpati, G</au><au>Shoubridge, E A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Distribution and threshold expression of the tRNA(Lys) mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF)</atitle><jtitle>American journal of human genetics</jtitle><addtitle>Am J Hum Genet</addtitle><date>1992-12-01</date><risdate>1992</risdate><volume>51</volume><issue>6</issue><spage>1187</spage><epage>1200</epage><pages>1187-1200</pages><issn>0002-9297</issn><eissn>1537-6605</eissn><abstract>We investigated the distribution and expression of mutant mtDNAs carrying the A-to-G mutation at position 8344 in the tRNA(Lys) gene in the skeletal muscle of four patients with myoclonus epilepsy and ragged-red fibers (MERRF). The proportion of mutant genomes was greater than 80% of total mtDNAs in muscle samples of all patients and was associated with a decrease in the activity of cytochrome c oxidase (COX). The vast majority of myoblasts, cloned from the satellite-cell population in the same muscles, were homoplasmic for the mutation. The overall proportion of mutant mtDNAs in this population was similar to that in differentiated muscle, suggesting that the ratio of mutant to wild-type mtDNAs in skeletal muscle is determined either in the ovum or during early development and changes little with age. Translation of all mtDNA-encoded genes was severely depressed in homoplasmic mutant myoblast clones but not in heteroplasmic or wild-type clones. The threshold for biochemical expression of the mutation was determined in heteroplasmic myotubes formed by fusion of different proportions of mutant and wild-type myoblasts. The magnitude of the decrease in translation in myotubes containing mutant mtDNAs was protein specific. Complex I and IV subunits were more affected than complex V subunits, and there was a rough correlation with both protein size and number of lysine residues. Approximately 15% wild-type mtDNAs restored translation and COX activity to near normal levels. These results show that the A-to-G substitution in tRNA(Lys) is a functionally recessive mutation that can be rescued by intraorganellar complementation with a small proportion of wild-type mtDNAs and explain the steep threshold for expression of the MERRF clinical phenotype.</abstract><cop>United States</cop><pmid>1334369</pmid><tpages>14</tpages></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0002-9297 |
ispartof | American journal of human genetics, 1992-12, Vol.51 (6), p.1187-1200 |
issn | 0002-9297 1537-6605 |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_1682926 |
source | MEDLINE; Access via ScienceDirect (Elsevier); EZB-FREE-00999 freely available EZB journals; PubMed Central |
subjects | Adult AMINO ACIDS BASIC BIOLOGICAL SCIENCES CARBOXYLIC ACIDS CELL CONSTITUENTS Cells, Cultured CYTOCHROME OXIDASE DISEASES DISTRIBUTION DNA, Mitochondrial - genetics Electron Transport Complex IV - metabolism Electrophoresis, Polyacrylamide Gel ENZYME ACTIVITY ENZYMES Epilepsies, Myoclonic - genetics Epilepsies, Myoclonic - metabolism EPILEPSY Female FIBERS Flow Cytometry Gene Expression GENES HAEM DEHYDROGENASES Humans LEVELS LYSINE Male METABOLIC DISEASES MITOCHONDRIA Mitochondrial Encephalomyopathies - genetics Mitochondrial Encephalomyopathies - metabolism Mitochondrial Encephalomyopathies - physiopathology MUSCLES Muscles - enzymology Muscles - metabolism Muscles - pathology Mutation MUTATIONS MYOBLASTS NERVOUS SYSTEM DISEASES NUCLEIC ACIDS ORGANIC ACIDS ORGANIC COMPOUNDS OXIDOREDUCTASES PATIENTS PHENOTYPE Protein Biosynthesis PROTEINS RECESSIVE MUTATIONS RESIDUES RNA 550400 -- Genetics RNA, Transfer, Lys - genetics RNA, Transfer, Lys - metabolism SIZE TRANSFER RNA |
title | Distribution and threshold expression of the tRNA(Lys) mutation in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF) |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-23T09%3A13%3A20IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Distribution%20and%20threshold%20expression%20of%20the%20tRNA(Lys)%20mutation%20in%20skeletal%20muscle%20of%20patients%20with%20myoclonic%20epilepsy%20and%20ragged-red%20fibers%20(MERRF)&rft.jtitle=American%20journal%20of%20human%20genetics&rft.au=Boulet,%20L&rft.date=1992-12-01&rft.volume=51&rft.issue=6&rft.spage=1187&rft.epage=1200&rft.pages=1187-1200&rft.issn=0002-9297&rft.eissn=1537-6605&rft_id=info:doi/&rft_dat=%3Cproquest_pubme%3E73378814%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=73378814&rft_id=info:pmid/1334369&rfr_iscdi=true |