The location of constitutional neurofibromatosis 2 (NF2) splice site mutations is associated with the severity of NF2
Identifieur interne : 001007 ( Istex/Corpus ); précédent : 001006; suivant : 001008The location of constitutional neurofibromatosis 2 (NF2) splice site mutations is associated with the severity of NF2
Auteurs : M E Baser ; L. Kuramoto ; R. Woods ; H. Joe ; J M Friedman ; A J Wallace ; R T Ramsden ; S. Olschwang ; E. Bijlsma ; M. Kalamarides ; L. Papi ; R. Kato ; J. Carroll ; C. Lázaro ; F. Joncourt ; D M Parry ; G A Rouleau ; D G R. EvansSource :
- Journal of Medical Genetics [ 0022-2593 ] ; 2005-07.
English descriptors
- KwdEn :
- Amino, Amino terminal domain, Baser, Carboxy, Carboxy terminal domain, Covariates, Database, Deletion, Different regions, Equal groups, Exon, Exon number, Fewer meningiomas, Frameshift, Frameshift mutations, Friedman, Functional domains, Genet, Helical domain, Intracranial, Intracranial meningiomas, Intrafamilial, Kluwe, Kuramoto, Large deletions, Mautner, Meningioma, Merlin, Missense, Missense mutations, Molecular level, Mosaicism, Mutation, NF2, Nearest exon, Neurofibromatosis, Neurofibromatosis type, Nonsense mutations, Other covariates, Phenotype, Polyposis, Present study, Pulst, Ramsden, Reference group, Rouleau, Schwannomas, Severe disease, Single class, Somatic, Somatic mosaicism, Somatic mosaics, Splice, Splice site, Splice site mutations, Suppressor, Symptom, Tumour, Vestibular, genotype-phenotype correlation, neurofibromatosis 2, splice site mutation.
- Teeft :
- Amino, Amino terminal domain, Baser, Carboxy, Carboxy terminal domain, Covariates, Database, Deletion, Different regions, Equal groups, Exon, Exon number, Fewer meningiomas, Frameshift, Frameshift mutations, Friedman, Functional domains, Genet, Helical domain, Intracranial, Intracranial meningiomas, Intrafamilial, Kluwe, Kuramoto, Large deletions, Mautner, Meningioma, Merlin, Missense, Missense mutations, Molecular level, Mosaicism, Mutation, Nearest exon, Neurofibromatosis, Neurofibromatosis type, Nonsense mutations, Other covariates, Phenotype, Polyposis, Present study, Pulst, Ramsden, Reference group, Rouleau, Schwannomas, Severe disease, Single class, Somatic, Somatic mosaicism, Somatic mosaics, Splice, Splice site, Splice site mutations, Suppressor, Symptom, Tumour, Vestibular.
Abstract
Neurofibromatosis 2 (NF2) patients with constitutional splice site NF2 mutations have greater variability in disease severity than NF2 patients with other types of mutations; the cause of this variability is unknown. We evaluated genotype-phenotype correlations, with particular focus on the location of splice site mutations, using mutation and clinical information on 831 patients from 528 NF2 families with identified constitutional NF2 mutations. The clinical characteristics examined were age at onset of symptoms of NF2 and number of intracranial meningiomas, which are the primary indices of the severity of NF2. Two regression models were used to analyse genotype-phenotype correlations. People with splice site mutations in exons 1–5 had more severe disease than those with splice site mutations in exons 11–15. This result is compatible with studies showing that exons 2 and 3 are required for self-association of the amino terminal of the NF2 protein in vitro, and that deletions of exons 2 and 3 in transgenic and knockout mouse models of NF2 cause a high prevalence of Schwann cell derived tumours.
Url:
DOI: 10.1136/jmg.2004.029504
Links to Exploration step
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<term>Covariates</term>
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<term>Deletion</term>
<term>Different regions</term>
<term>Equal groups</term>
<term>Exon</term>
<term>Exon number</term>
<term>Fewer meningiomas</term>
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<term>Functional domains</term>
<term>Genet</term>
<term>Helical domain</term>
<term>Intracranial</term>
<term>Intracranial meningiomas</term>
<term>Intrafamilial</term>
<term>Kluwe</term>
<term>Kuramoto</term>
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<term>Mautner</term>
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<term>Merlin</term>
<term>Missense</term>
<term>Missense mutations</term>
<term>Molecular level</term>
<term>Mosaicism</term>
<term>Mutation</term>
<term>NF2</term>
<term>Nearest exon</term>
<term>Neurofibromatosis</term>
<term>Neurofibromatosis type</term>
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<term>Present study</term>
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<front><div type="abstract" xml:lang="en">Neurofibromatosis 2 (NF2) patients with constitutional splice site NF2 mutations have greater variability in disease severity than NF2 patients with other types of mutations; the cause of this variability is unknown. We evaluated genotype-phenotype correlations, with particular focus on the location of splice site mutations, using mutation and clinical information on 831 patients from 528 NF2 families with identified constitutional NF2 mutations. The clinical characteristics examined were age at onset of symptoms of NF2 and number of intracranial meningiomas, which are the primary indices of the severity of NF2. Two regression models were used to analyse genotype-phenotype correlations. People with splice site mutations in exons 1–5 had more severe disease than those with splice site mutations in exons 11–15. This result is compatible with studies showing that exons 2 and 3 are required for self-association of the amino terminal of the NF2 protein in vitro, and that deletions of exons 2 and 3 in transgenic and knockout mouse models of NF2 cause a high prevalence of Schwann cell derived tumours.</div>
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<aff id="AFF1"><label>1</label>
10622 Kinnard Ave, #203, Los Angeles, CA, USA</aff>
<aff id="AFF2"><label>2</label>
Department of Statistics, University of British Columbia, Vancouver, BC, Canada</aff>
<aff id="AFF3"><label>3</label>
Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada</aff>
<aff id="AFF4"><label>4</label>
University Department of Medical Genetics, St Mary’s Hospital, Manchester, UK</aff>
<aff id="AFF5"><label>5</label>
Department of Otolaryngology, Manchester Royal Infirmary, Manchester, UK</aff>
<aff id="AFF6"><label>6</label>
INSERM U434, Fondation Jean-Dausset-CEPH, Paris, France</aff>
<aff id="AFF7"><label>7</label>
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands</aff>
<aff id="AFF8"><label>8</label>
Department of Neurosurgery, University Hospital Beaujon, Clichy, France</aff>
<aff id="AFF9"><label>9</label>
Department of Clinical Physiopathology, University of Florence, Florence, Italy</aff>
<aff id="AFF10"><label>10</label>
Department of Pediatrics, Higashisaitama National Hospital, Saitama, Japan</aff>
<aff id="AFF11"><label>11</label>
Division of Molecular Pathology, Institute of Medical and Veterinary Science, Adelaide, Australia</aff>
<aff id="AFF12"><label>12</label>
Centre de Genètica Mèdica i Molecular – I.R.O., L’Hospitalet de Llobregat, Barcelona, Spain</aff>
<aff id="AFF13"><label>13</label>
Division of Human Genetics, Children’s University Hospital, Berne, Switzerland</aff>
<aff id="AFF14"><label>14</label>
Genetic Epidemiology Branch, National Cancer Institute, Bethesda, MD, USA</aff>
<aff id="AFF15"><label>15</label>
Department of Neurology, McGill University, Montreal, QC, Canada</aff>
</contrib-group>
<author-notes><corresp>Correspondence to:
Dr Michael E Baser
10622 Kinnard Ave, #203, Los Angeles, CA 90024; <ext-link xlink:href="michael.baserverizon.net" ext-link-type="email" xlink:type="simple">michael.baser@verizon.net</ext-link>
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<issue>7</issue>
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<issue-id pub-id-type="other">7</issue-id>
<issue-id pub-id-type="other">42/7</issue-id>
<fpage>540</fpage>
<history><date date-type="accepted"><day>15</day>
<month>12</month>
<year>2004</year>
</date>
<date date-type="rev-recd"><day>14</day>
<month>12</month>
<year>2004</year>
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<copyright-year>2005</copyright-year>
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<abstract xml:lang="en"><p>Neurofibromatosis 2 (NF2) patients with constitutional splice site <italic>NF2</italic>
mutations have greater variability in disease severity than NF2 patients with other types of mutations; the cause of this variability is unknown. We evaluated genotype-phenotype correlations, with particular focus on the location of splice site mutations, using mutation and clinical information on 831 patients from 528 NF2 families with identified constitutional <italic>NF2</italic>
mutations. The clinical characteristics examined were age at onset of symptoms of NF2 and number of intracranial meningiomas, which are the primary indices of the severity of NF2. Two regression models were used to analyse genotype-phenotype correlations. People with splice site mutations in exons 1–5 had more severe disease than those with splice site mutations in exons 11–15. This result is compatible with studies showing that exons 2 and 3 are required for self-association of the amino terminal of the NF2 protein in vitro, and that deletions of exons 2 and 3 in transgenic and knockout mouse models of NF2 cause a high prevalence of Schwann cell derived tumours.</p>
</abstract>
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<kwd>neurofibromatosis 2</kwd>
<kwd>NF2</kwd>
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<name type="personal"><namePart type="given">M E</namePart>
<namePart type="family">Baser</namePart>
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<name type="personal"><namePart type="given">L</namePart>
<namePart type="family">Kuramoto</namePart>
<affiliation>Department of Statistics, University of British Columbia, Vancouver, BC, Canada</affiliation>
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<namePart type="family">Joe</namePart>
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<name type="personal"><namePart type="given">J M</namePart>
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<name type="personal"><namePart type="given">A J</namePart>
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<name type="personal"><namePart type="given">R T</namePart>
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<name type="personal"><namePart type="given">S</namePart>
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<name type="personal"><namePart type="given">M</namePart>
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<name type="personal"><namePart type="given">L</namePart>
<namePart type="family">Papi</namePart>
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<name type="personal"><namePart type="given">R</namePart>
<namePart type="family">Kato</namePart>
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<role><roleTerm type="text">author</roleTerm>
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<name type="personal"><namePart type="given">J</namePart>
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<name type="personal"><namePart type="given">C</namePart>
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<name type="personal"><namePart type="given">D M</namePart>
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</name>
<name type="personal"><namePart type="given">G A</namePart>
<namePart type="family">Rouleau</namePart>
<affiliation>Department of Neurology, McGill University, Montreal, QC, Canada</affiliation>
<role><roleTerm type="text">author</roleTerm>
</role>
</name>
<name type="personal"><namePart type="given">D G R</namePart>
<namePart type="family">Evans</namePart>
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<abstract lang="en">Neurofibromatosis 2 (NF2) patients with constitutional splice site NF2 mutations have greater variability in disease severity than NF2 patients with other types of mutations; the cause of this variability is unknown. We evaluated genotype-phenotype correlations, with particular focus on the location of splice site mutations, using mutation and clinical information on 831 patients from 528 NF2 families with identified constitutional NF2 mutations. The clinical characteristics examined were age at onset of symptoms of NF2 and number of intracranial meningiomas, which are the primary indices of the severity of NF2. Two regression models were used to analyse genotype-phenotype correlations. People with splice site mutations in exons 1–5 had more severe disease than those with splice site mutations in exons 11–15. This result is compatible with studies showing that exons 2 and 3 are required for self-association of the amino terminal of the NF2 protein in vitro, and that deletions of exons 2 and 3 in transgenic and knockout mouse models of NF2 cause a high prevalence of Schwann cell derived tumours.</abstract>
<note type="author-notes">Correspondence to:
Dr Michael E Baser
10622 Kinnard Ave, #203, Los Angeles, CA 90024; michael.baser@verizon.net</note>
<subject lang="en"><genre>KWD</genre>
<topic>genotype-phenotype correlation</topic>
<topic>neurofibromatosis 2</topic>
<topic>NF2</topic>
<topic>splice site mutation</topic>
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