Hypomorphic NEMO mutation database and reconstitution system identifies phenotypic and immunologic diversity
Identifieur interne : 002F78 ( Ncbi/Curation ); précédent : 002F77; suivant : 002F79Hypomorphic NEMO mutation database and reconstitution system identifies phenotypic and immunologic diversity
Auteurs : Eric P. Hanson ; Linda Monaco-Shawver ; Laura A. Solt [États-Unis] ; Lisa A. Madge [États-Unis] ; Pinaki P. Banerjee ; Michael J. May [États-Unis] ; Jordan S. OrangeSource :
- The Journal of allergy and clinical immunology [ 0091-6749 ] ; 2008.
Abstract
Human hypomorphic NEMO mutations cause diverse clinical immunologic phenotypes, but understanding their scope and mechanistic links immune function and genotype is incomplete.
We created and analyzed a database of hypomorphic NEMO mutations to determine the spectrum of phenotypes and their associated genotypes and sought to establish a standardized NEMO reconstitution system to obtain mechanistic insights.
Phenotypes of 72 individuals with NEMO mutations were compiled. NEMO L153R and C417R were investigated further in a reconstitution system. TNF-α or Toll-like receptor 5 signals were evaluated for NF-κB activation, programmed cell death, and
32 different mutations were identified; 53% affect the zinc finger domain. 81% were associated with Ectodermal dysplasia, 76% with serious pyogenic infection, 39% with mycobacterial infection, 19% with serious viral infection, 21% with inflammatory diseases. 36% died at a mean age of 6.4 years. CD40, IL-1, TNF-α, TLR, and TCR signals were impaired in 15/16 (94%), 6/7 (86%), 9/11 (77%), 9/14 (64%), and 7/18 (39%), respectively. Hypomorphism-reconstituted NEMO-deficient cells demonstrated partial restoration of NEMO functions. Although both L153R and C417R impaired TLR and TNF-α induced NF-κB activation, L153R also increased TNF-α-induced programmed cell death with decreased
Distinct NEMO hypomorphs define specific disease and genetic characteristics. A reconstitution system can identify attributes of hypomorphisms independent of an individual’s genetic background. Apoptosis susceptibility in L153R reconstituted cells defines a specific phenotype of this mutation that likely contributes to the excessive inflammation with which it is clinically associated.
Url:
DOI: 10.1016/j.jaci.2008.08.018
PubMed: 18851874
PubMed Central: 2710968
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Eric P. Hanson<affiliation><nlm:aff id="A1">Division of Rheumatology, The Joseph Stokes Jr., Research Institute, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine</nlm:aff>
<wicri:noCountry code="subfield">University of Pennsylvania School of Medicine</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A2">Division of Allergy and Immunology, The Joseph Stokes Jr., Research Institute, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine</nlm:aff>
<wicri:noCountry code="subfield">University of Pennsylvania School of Medicine</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A2">Division of Allergy and Immunology, The Joseph Stokes Jr., Research Institute, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine</nlm:aff>
<wicri:noCountry code="subfield">University of Pennsylvania School of Medicine</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="A2">Division of Allergy and Immunology, The Joseph Stokes Jr., Research Institute, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine</nlm:aff>
<wicri:noCountry code="subfield">University of Pennsylvania School of Medicine</wicri:noCountry>
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<front><div type="abstract" xml:lang="en"><sec id="S1"><title>Background</title>
<p id="P1">Human hypomorphic NEMO mutations cause diverse clinical immunologic phenotypes, but understanding their scope and mechanistic links immune function and genotype is incomplete.</p>
</sec>
<sec id="S2"><title>Objective</title>
<p id="P2">We created and analyzed a database of hypomorphic NEMO mutations to determine the spectrum of phenotypes and their associated genotypes and sought to establish a standardized NEMO reconstitution system to obtain mechanistic insights.</p>
</sec>
<sec sec-type="methods" id="S3"><title>Methods</title>
<p id="P3">Phenotypes of 72 individuals with NEMO mutations were compiled. NEMO L153R and C417R were investigated further in a reconstitution system. TNF-α or Toll-like receptor 5 signals were evaluated for NF-κB activation, programmed cell death, and <italic>A20</italic>
gene expression.</p>
</sec>
<sec id="S4"><title>Results</title>
<p id="P4">32 different mutations were identified; 53% affect the zinc finger domain. 81% were associated with Ectodermal dysplasia, 76% with serious pyogenic infection, 39% with mycobacterial infection, 19% with serious viral infection, 21% with inflammatory diseases. 36% died at a mean age of 6.4 years. CD40, IL-1, TNF-α, TLR, and TCR signals were impaired in 15/16 (94%), 6/7 (86%), 9/11 (77%), 9/14 (64%), and 7/18 (39%), respectively. Hypomorphism-reconstituted NEMO-deficient cells demonstrated partial restoration of NEMO functions. Although both L153R and C417R impaired TLR and TNF-α induced NF-κB activation, L153R also increased TNF-α-induced programmed cell death with decreased <italic>A20</italic>
expression.</p>
</sec>
<sec id="S5"><title>Conclusion</title>
<p id="P5">Distinct NEMO hypomorphs define specific disease and genetic characteristics. A reconstitution system can identify attributes of hypomorphisms independent of an individual’s genetic background. Apoptosis susceptibility in L153R reconstituted cells defines a specific phenotype of this mutation that likely contributes to the excessive inflammation with which it is clinically associated.</p>
</sec>
</div>
</front>
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