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.