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

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

Publisher
John Wiley and Sons
Year
2008
Tongue
English
Weight
372 KB
Volume
29
Category
Article
ISSN
1059-7794

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✦ Synopsis

Communicated by Andrew O.M. Wilkie

Mutations in the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG), also called nuclear factor-kappaB (NF-kB) 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-kB 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 IP-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 (465%). 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. Hum Mutat 29(5),

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