Premium
Novel splicing mutation in the NEMO ( IKK‐gamma ) gene with severe immunodeficiency and heterogeneity of X‐chromosome inactivation
Author(s) -
Ørstavik Karen Helene,
Kristiansen Marianne,
Knudsen Gun Peggy,
Storhaug Kari,
Vege Åshild,
Eiklid Kristin,
Abrahamsen Tore G,
Smahi Asma,
SteenJohnsen Jon
Publication year - 2005
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.31026
Subject(s) - exon , rna splicing , biology , gene , microbiology and biotechnology , genetics , x inactivation , zinc finger , alternative splicing , x chromosome , rna , transcription factor
We report on a family with three stillborn males, three affected males who were small for gestational age and died within 8 months, and one male who died at age 5 years. This boy had cone‐shaped teeth and oligoodontia. He had serious bacterial infections and inflammatory bowel disease. Mutations in the NF‐κB essential modulator ( NEMO ) gene have recently been shown to be the cause of a group of ectodermal dysplasia and immunodeficiency disorders (EDA‐ID). Analysis of the NEMO gene revealed a nucleotide change in the consensus sequence of the splicing donor site of exon 6 IVS6 + 5G → A(1027 + 5G → A), which has not previously been described in EDA‐ID. RT‐PCR analysis of fibroblast RNA from an aborted affected male fetus demonstrated a skipping of exons 4, 5, and 6 which resulted in a truncated protein of about 35 kDa revealed by NEMO antibody. The skipping of exons 4, 5, and 6 did not affect the ORF of the C‐terminal of NEMO encoded by exons 7, 8, 9, and 10, which contains a coiled‐coil motif (CC2), a leucin‐zipper (LZ), and a zinc finger motif (ZF) sub‐domains of NEMO. IκBα degradation was strongly impaired in the fetal fibroblasts, suggesting an impaired NF‐κB signaling. One healthy carrier had a completely skewed X‐inactivation pattern with the normal X active, whereas the two other carriers had a random X‐inactivation pattern. This family may represent a new phenotype within the EDA‐ID disorders. From the heterogeneity in X‐inactivation phenotype, we conclude that this mutation is not deleterious enough to be lethal for peripheral blood cells. © 2005 Wiley‐Liss, Inc.