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.
Laboratoire de Genetique Humaine des Maladies Infectieuses, Faculte de Medecine Necker-Enfants Malades, 75015 Paris, France.
Anne
A
Puel
Janine
J
Reichenbach
Jacinta
J
Bustamante
Cheng-Lung
CL
Ku
Jacqueline
J
Feinberg
Rainer
R
Döffinger
Marion
M
Bonnet
Orchidée
O
Filipe-Santos
Ludovic
L
de Beaucoudrey
Anne
A
Durandy
Gerd
G
Horneff
Francesco
F
Novelli
Volker
V
Wahn
Asma
A
Smahi
Alain
A
Israel
Tim
T
Niehues
Jean-Laurent
JL
Casanova
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