Sa. Pitts et al., hMRE11: Genomic structure and a null mutation identified in a transcript protected from nonsense-mediated mRNA decay, HUM MOL GEN, 10(11), 2001, pp. 1155-1162
We showed recently that mutation of the hMRE11 gene identified a new ataxia
telangiectasia-like disorder (ATLD), In this report we describe the genomi
c organization of the hMRE11 gene and the analysis of a promoter region tha
t appears to direct the divergent transcription of hMRE11 and the adjacent
gene, The characterization of the genomic organization of the hMRE11 gene a
llowed us to determine the basis of an apparent null hMRE11 allele present
in the mother and two patients in one of our two ATLD families. Polymorphic
markers in the hMRE11 gene, including the promoter region, provided eviden
ce that the mutated maternal allele was not deleted. An exon by exon search
revealed the presence of a missense mutation in exon 15, the effect of whi
ch was to create a premature termination codon, Transcripts derived from th
e mutant allele were found to be subject to nonsense-mediated mRNA decay (N
MD), Therefore, this allele was effectively null, because little if any mRN
A from it was available for translation, The ATLD patients carrying this pr
otein-truncating hMRE11 mutation have survived because the null allele they
inherited from their mother is present with a missense mutation inherited
from their father, which is expressed as normal levels of partially functio
nal MRE11 protein. The mutation in the maternal hMRE11 allele of family 2 w
as also identified in a further unrelated Italian family with ATLD and also
found to be subject to NMD.