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Am J Hum Genet. 2006 Apr;78(4):691-701. Epub 2006 Feb 15.

The NEMO mutation creating the most-upstream premature stop codon is hypomorphic because of a reinitiation of translation.

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  • 1Laboratoire de Genetique Humaine des Maladies Infectieuses, Faculte de Medecine Necker-Enfants Malades, 75015 Paris, France.

Abstract

Amorphic mutations in the NF- kappa B essential modulator (NEMO) cause X-dominant incontinentia pigmenti, which is lethal in males in utero, whereas hypomorphic mutations cause X-recessive anhidrotic ectodermal dysplasia with immunodeficiency, a complex developmental disorder and life-threatening primary immunodeficiency. We characterized the NEMO mutation 110_111insC, which creates the most-upstream premature translation termination codon (at codon position 49) of any known NEMO mutation. Surprisingly, this mutation is associated with a pure immunodeficiency. We solve this paradox by showing that a Kozakian methionine codon located immediately downstream from the insertion allows the reinitiation of translation. The residual production of an NH(2)-truncated NEMO protein was sufficient for normal fetal development and for the subsequent normal development of skin appendages but was insufficient for the development of protective immune responses.

PMID:
16532398
[PubMed - indexed for MEDLINE]
PMCID:
PMC1424680
Free PMC Article
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