Two cases of misinterpretation of molecular results in incontinentia pigmenti, and a PCR-based method to discriminate NEMO/IKKgamma dene deletion.
Familial incontinentia pigmenti (IP) is a rare X-linked dominant disorder that affects ectodermal tissues. Over 90% of IP carrier females have a recurrent genomic deletion of exons 4-10 of the NEMO (IKBKG-IKKgamma) gene, which encodes a regulatory component of the IkB kinase complex, required to activate the NF-kB pathway. In IP, mutations in NEMOlead to the complete loss of NF-kB activation creating a susceptibility to cellular apoptosis in response to TNF-alpha. This condition is lethal for males during embryogenesis while females, who are mosaic as a result of X-inactivation, can survive. Recently, a second nonfunctional copy of the gene, DeltaNEMO, was identified, opposite in direction to NEMO in a 35.5-kb duplicated sequence tract. PCR-based detection of the NEMO deletion is diagnostic for IP disease. However, we present instances in which ex 4-10 DeltaNEMO pseudogene deletion occurs in unaffected parents of two females with clinically characteristic IP. These were missed by the currently standard PCR-based method, but can be easily discriminated by a new PCR-based test reported here that permits unambiguous molecular diagnosis and proper familial genetic counseling for IP.
Bardaro
Tiziana
T
Institute of Genetics and Biophysics, Adriano Buzzati Traverso-CNR, Naples, Italy.
Falco
Geppino
G
Sparago
Angela
A
Mercadante
Vincenzo
V
Gean Molins
Esther
E
Tarantino
Enrico
E
Ursini
Matilde Valeria
MV
D'Urso
Michele
M
D004252:DNA Mutational Analysis / Q000379:methods; D003951:Diagnostic Errors; D005260:Female; D017353:Gene Deletion; D006801:Humans; D051550:I-kappa B Kinase; D007184:Incontinentia Pigmenti / Q000175:diagnosis*; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D008969:Molecular Sequence Data; D010375:Pedigree; D016133:Polymerase Chain Reaction / Q000379:methods*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011544:Pseudogenes
D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human