The NEMO Mutation Creating the Most-upstream Premature Stop Codon is Hypomorphic Because of a Reinitiation of Translation

Overview

Journal Am J Hum Genet

Publisher Cell Press

Specialty Genetics

Date 2006 Mar 15

PMID 16532398

Citations 46

Authors

Anne Puel

Janine Reichenbach

Jacinta Bustamante

Cheng-Lung Ku

Jacqueline Feinberg

Rainer Doffinger

Marion Bonnet

Orchidee Filipe-Santos

Ludovic de Beaucoudrey

Anne Durandy

Gerd Horneff

Francesco Novelli

Volker Wahn

Asma Smahi

Alain Israel

Tim Niehues

Jean-Laurent Casanova

Affiliations

Soon will be listed here.

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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