Alterations of the IKBKG locus and diseases: An update and a report of 13 novel mutations

作者：Fusco Francesca; Pescatore Alessandra; Bal Elodie; Ghoul Aida; Paciolla Mariateresa; Lioi Maria Brigida; D'Urso Michele; Rabia Smail Hadj; Bodemer Christine; Bonnefont Jean Paul; Munnich Arnold; Miano Maria Giuseppina; Smahi Asma; Ursini Matilde Valeria^*

来源：Human Mutation, 2008, 29(5): 595-604.

DOI：10.1002/humu.20739

• incontinentia pigmenti
• anhidrotic ectodermal dysplasia with immunodeficiency
• IKBKG mutations
• hotspot mutation

Mutations in the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG), also called nuclear factor-kappaB (NF-kappa B) essential modulator (NEMO), gene are the most common single cause of incontinentia pigmenti (IP) in females and anhydrotic ectodermal dysplasia with immunodeficiency (EDA-ID) in males. The IKBKG gene, located in the Xq28 chromosomal region, encodes for the regulatory subunit of the inhibitor of kappaB (IkB) kinase (IKK) complex required for the activation of the NF-kappa B pathway. Therefore, the remarkably heterogeneous and often severe clinical presentation reported in IP is due to the pleiotropic role of this signaling transcription pathway. A recurrent exon 4_10 genomic rearrangement in the IKBKG gene accounts for 60 to 80% of IP-causing mutations. Besides the IKBKG rearrangement found in IP females (which is lethal in males), a total of 69 different small mutations (missense, frameshift, nonsense, and splice-site mutations) have been reported, including 13 novel ones in this work. The updated distribution of all the IR and EDA-ID-causing mutations along the IKBKG gene highlights a secondary hotspot mutation in exon 10, which contains only 11% of the protein. Furthermore, familial inheritance analysis revealed an unexpectedly high incidence of sporadic cases (>65%). The sum of the observations can aid both in determining the molecular basis of IP and EDA-ID allelic diseases, and in genetic counseling in affected families.

• 出版日期2008-5