The NEMO mutation creating the most-upstream premature stop codon is hypomorphic because of a reinitiation of translation.
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.
Puel
Anne
A
Laboratoire de Genetique Humaine des Maladies Infectieuses, Faculte de Medecine Necker-Enfants Malades, 75015 Paris, France.
Reichenbach
Janine
J
Bustamante
Jacinta
J
Ku
Cheng-Lung
CL
Feinberg
Jacqueline
J
Döffinger
Rainer
R
Bonnet
Marion
M
Filipe-Santos
Orchidée
O
de Beaucoudrey
Ludovic
L
Durandy
Anne
A
Horneff
Gerd
G
Novelli
Francesco
F
Wahn
Volker
V
Smahi
Asma
A
Israel
Alain
A
Niehues
Tim
T
Casanova
Jean-Laurent
JL
D000595:Amino Acid Sequence; D001483:Base Sequence; D041321:Chromosomes, Human, X; D018388:Codon, Terminator; D004247:DNA; D005804:Genes, Lethal; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics*; D007184:Incontinentia Pigmenti / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D014176:Protein Biosynthesis
D018388:Codon, Terminator; C491731:IKBKG protein, human; D004247:DNA; D051550:I-kappa B Kinase