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

Puel, Anne, Reichenbach, Janine, Bustamante, Jacinta, Ku, Cheng-Lung, Feinberg, Jacqueline, Döffinger, Rainer, Bonnet, Marion ORCID: https://orcid.org/0000-0002-7559-2413, Filipe-Santos, Orchidée, de Beaucoudrey, Ludovic, Durandy, Anne, Horneff, Gerd, Novelli, Francesco, Wahn, Volker, Smahi, Asma, Israel, Alain, Niehues, Tim and Casanova, Jean-Laurent 2006. The NEMO mutation creating the most-upstream premature stop codon is hypomorphic because of a reinitiation of translation. American Journal of Human Genetics 78 (4) , pp. 691-701. 10.1086/501532

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Abstract

Amorphic mutations in the NF-κB 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 NH2-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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Elsevier (Cell Press)
ISSN:	0002-9297
Date of First Compliant Deposit:	17 February 2021
Date of Acceptance:	13 January 2006
Last Modified:	09 Nov 2022 10:11
URI:	https://orca.cardiff.ac.uk/id/eprint/138623

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