The NEMO mutation creating the most-upstream premature stop codon is hypomorphic because of a reinitiation of translation by Puel Anne, Reichenbach Janine, Bustamante Jacinta, Ku Cheng-Lung, Feinberg Jacqueline, Döffinger Rainer, Bonnet Marion, Filipe-Santos Orchidée, de Beaucoudrey Ludovic, Durandy Anne, Horneff Gerd, Novelli Francesco, Wahn Volker, Smahi Asma, Israel Alain, Niehues Tim, Casanova Jean-Laurent in American journal of human genetics (2006). PubMed

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.

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