DYT16 revisited: exome sequencing identifies PRKRA mutations in a European dystonia family.
Identifieur interne : 000611 ( Main/Exploration ); précédent : 000610; suivant : 000612DYT16 revisited: exome sequencing identifies PRKRA mutations in a European dystonia family.
Auteurs : Michael Zech [Allemagne] ; Florian Castrop ; Barbara Schormair ; Angela Jochim ; Thomas Wieland ; Nadine Gross ; Peter Lichtner ; Annette Peters ; Christian Gieger ; Thomas Meitinger ; Tim M. Strom ; Konrad Oexle ; Bernhard Haslinger ; Juliane WinkelmannSource :
- Movement disorders : official journal of the Movement Disorder Society [ 1531-8257 ] ; 2014.
English descriptors
- KwdEn :
- MESH :
- chemical , genetics : RNA-Binding Proteins.
- geographic : Europe.
- genetics : Chromosomes, Human, Pair 2, DNA Copy Number Variations, Dystonic Disorders, Exome.
- Adolescent, Adult, Child, Family Health, Female, Humans, Male, Middle Aged, Phenotype, Severity of Illness Index, Young Adult.
Abstract
Recessive DYT16 dystonia associated with mutations in PRKRA has until now been reported only in seven Brazilian patients. The aim of this study was to elucidate the genetic cause underlying disease in a Polish family with autosomal-recessive, early-onset generalized dystonia and slight parkinsonism, and to explore further the role of PRKRA in a dystonia series of European ancestry. We employed whole-exome sequencing in two affected siblings of the Polish family and filtered for rare homozygous and compound heterozygous variants shared by both exomes. Validation of the identified variants as well as homozygosity screening and copy number variation analysis was carried out in the two affected individuals and their healthy siblings. PRKRA was analyzed in 339 German patients with various forms of dystonia and 376 population-based controls by direct sequencing or high-resolution melting. The previously described homozygous p.Pro222Leu mutation in PRKRA was found to segregate with the disease in the studied family, contained in a 1.2 Mb homozygous region identical by state with all Brazilian patients in chromosome 2q31.2. The clinical presentation with young-onset, progressive generalized dystonia and mild parkinsonism resembled the phenotype of the original DYT16 cases. PRKRA mutational screening in additional dystonia samples revealed three novel heterozygous changes (p.Thr34Ser, p.Asn102Ser, c.-14A>G), each in a single subject with focal/segmental dystonia. Our study provides the first independent replication of the DYT16 locus at 2q31.2 and strongly confirms the causal contribution of the PRKRA gene to DYT16. Our data suggest worldwide involvement of PRKRA in dystonia.
DOI: 10.1002/mds.25981
PubMed: 25142429
Affiliations:
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Strom</name></author><author><name sortKey="Oexle, Konrad" sort="Oexle, Konrad" uniqKey="Oexle K" first="Konrad" last="Oexle">Konrad Oexle</name></author><author><name sortKey="Haslinger, Bernhard" sort="Haslinger, Bernhard" uniqKey="Haslinger B" first="Bernhard" last="Haslinger">Bernhard Haslinger</name></author><author><name sortKey="Winkelmann, Juliane" sort="Winkelmann, Juliane" uniqKey="Winkelmann J" first="Juliane" last="Winkelmann">Juliane Winkelmann</name></author></analytic><series><title level="j">Movement disorders : official journal of the Movement Disorder Society</title><idno type="eISSN">1531-8257</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adolescent</term><term>Adult</term><term>Child</term><term>Chromosomes, Human, Pair 2 (genetics)</term><term>DNA Copy Number Variations (genetics)</term><term>Dystonic Disorders (genetics)</term><term>Europe</term><term>Exome (genetics)</term><term>Family Health</term><term>Female</term><term>Humans</term><term>Male</term><term>Middle Aged</term><term>Phenotype</term><term>RNA-Binding Proteins (genetics)</term><term>Severity of Illness Index</term><term>Young Adult</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>RNA-Binding Proteins</term></keywords><keywords scheme="MESH" type="geographic" xml:lang="en"><term>Europe</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Chromosomes, Human, Pair 2</term><term>DNA Copy Number Variations</term><term>Dystonic Disorders</term><term>Exome</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adolescent</term><term>Adult</term><term>Child</term><term>Family Health</term><term>Female</term><term>Humans</term><term>Male</term><term>Middle Aged</term><term>Phenotype</term><term>Severity of Illness Index</term><term>Young Adult</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Recessive DYT16 dystonia associated with mutations in PRKRA has until now been reported only in seven Brazilian patients. The aim of this study was to elucidate the genetic cause underlying disease in a Polish family with autosomal-recessive, early-onset generalized dystonia and slight parkinsonism, and to explore further the role of PRKRA in a dystonia series of European ancestry. We employed whole-exome sequencing in two affected siblings of the Polish family and filtered for rare homozygous and compound heterozygous variants shared by both exomes. Validation of the identified variants as well as homozygosity screening and copy number variation analysis was carried out in the two affected individuals and their healthy siblings. PRKRA was analyzed in 339 German patients with various forms of dystonia and 376 population-based controls by direct sequencing or high-resolution melting. The previously described homozygous p.Pro222Leu mutation in PRKRA was found to segregate with the disease in the studied family, contained in a 1.2 Mb homozygous region identical by state with all Brazilian patients in chromosome 2q31.2. The clinical presentation with young-onset, progressive generalized dystonia and mild parkinsonism resembled the phenotype of the original DYT16 cases. PRKRA mutational screening in additional dystonia samples revealed three novel heterozygous changes (p.Thr34Ser, p.Asn102Ser, c.-14A>G), each in a single subject with focal/segmental dystonia. Our study provides the first independent replication of the DYT16 locus at 2q31.2 and strongly confirms the causal contribution of the PRKRA gene to DYT16. Our data suggest worldwide involvement of PRKRA in dystonia.</div></front></TEI><affiliations><list><country><li>Allemagne</li></country><region><li>Bavière</li><li>District de Haute-Bavière</li></region><settlement><li>Munich</li></settlement><orgName><li>Université technique de Munich</li></orgName></list><tree><noCountry><name sortKey="Castrop, Florian" sort="Castrop, Florian" uniqKey="Castrop F" first="Florian" last="Castrop">Florian Castrop</name><name sortKey="Gieger, Christian" sort="Gieger, Christian" uniqKey="Gieger C" first="Christian" last="Gieger">Christian Gieger</name><name sortKey="Gross, Nadine" sort="Gross, Nadine" uniqKey="Gross N" first="Nadine" last="Gross">Nadine Gross</name><name sortKey="Haslinger, Bernhard" sort="Haslinger, Bernhard" uniqKey="Haslinger B" first="Bernhard" last="Haslinger">Bernhard Haslinger</name><name sortKey="Jochim, Angela" sort="Jochim, Angela" uniqKey="Jochim A" first="Angela" last="Jochim">Angela Jochim</name><name sortKey="Lichtner, Peter" sort="Lichtner, Peter" uniqKey="Lichtner P" first="Peter" last="Lichtner">Peter Lichtner</name><name sortKey="Meitinger, Thomas" sort="Meitinger, Thomas" uniqKey="Meitinger T" first="Thomas" last="Meitinger">Thomas Meitinger</name><name sortKey="Oexle, Konrad" sort="Oexle, Konrad" uniqKey="Oexle K" first="Konrad" last="Oexle">Konrad Oexle</name><name sortKey="Peters, Annette" sort="Peters, Annette" uniqKey="Peters A" first="Annette" last="Peters">Annette Peters</name><name sortKey="Schormair, Barbara" sort="Schormair, Barbara" uniqKey="Schormair B" first="Barbara" last="Schormair">Barbara Schormair</name><name sortKey="Strom, Tim M" sort="Strom, Tim M" uniqKey="Strom T" first="Tim M" last="Strom">Tim M. Strom</name><name sortKey="Wieland, Thomas" sort="Wieland, Thomas" uniqKey="Wieland T" first="Thomas" last="Wieland">Thomas Wieland</name><name sortKey="Winkelmann, Juliane" sort="Winkelmann, Juliane" uniqKey="Winkelmann J" first="Juliane" last="Winkelmann">Juliane Winkelmann</name></noCountry><country name="Allemagne"><region name="Bavière"><name sortKey="Zech, Michael" sort="Zech, Michael" uniqKey="Zech M" first="Michael" last="Zech">Michael Zech</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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