S. Aradhya et al., Multiple pathogenic and benign genomic rearrangements occur at a 35 kb duplication involving the NEMO and LAGE2 genes, HUM MOL GEN, 10(22), 2001, pp. 2557-2567
The X-linked dominant and male-lethal disorder incontinentia pigmenti (IP)
is caused by mutations in a gene called NEMO(IKK-gamma). We recently report
ed the structure of NEMO and demonstrated that most IP patients carry an id
entical deletion that arises due to misalignment between repeats. Affected
male abortuses with the IP deletion had provided clues that a second, incom
plete copy of NEMO was present in the genome. We have now identified clones
containing this truncated copy (Delta NEMO) and incorporated them into a p
reviously constructed physical contig in distal Xq28. Delta NEMO maps 22 kb
distal to NEMO and only contains exons 3-10, confirming our proposed model
. A sequence of 26 kb 3 of the NEMO coding sequence is also present in the
same position relative to the Delta NEMO locus, bringing the total length o
f the duplication to 35.5 kb. The LAGE2 gene is also located within this du
plicated region, and a similar but unique LAGE1 gene is located just distal
to the duplicated loci. Mapping and sequence information indicated that th
e duplicated regions are in opposite orientation. Analysis of the great ape
s suggested that the NEMO/LAGE2 duplication occurred after divergence of th
e lineage leading to present day humans, chimpanzees and gorillas, similar
to 10-15 million years ago. Intriguingly, despite this substantial evolutio
nary history, only 22 single nucleotide differences exist between the two c
opies over the entire 35.5 kb, making the duplications > 99% identical. Thi
s high sequence identity and the inverted orientations of the two copies, a
long with duplications of smaller internal sections within each copy, predi
spose this region to various genomic alterations. We detected four rearrang
ements that involved NEMO, Delta NEMO or LAGE1 and LAGE2. The high sequence
similarity between the two NEMO/LAGE2 copies may be due to frequent gene c
onversion, as we have detected evidence of sequence transfer between them.
Together, these data describe an unusual and complex genomic region that is
susceptible to various types of pathogenic and polymorphic rearrangements,
including the recurrent lethal deletion associated with IP.