hMRE11:: Genomic structure and a null mutation identified in a transcript protected from nonsense-mediated mRNA decay

We showed recently that mutation of the hMRE11 gene identified a new ataxia telangiectasia-like disorder (ATLD), In this report we describe the genomic organization of the hMRE11 gene and the analysis of a promoter region that appears to direct the divergent transcription of hMRE11 and the adjacent gene, The characterization of the genomic organization of the hMRE11 gene allowed 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 evidence 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 which was to create a premature termination codon, Transcripts derived from the mutant allele were found to be subject to nonsense-mediated mRNA decay (NMD), Therefore, this allele was effectively null, because little if any mRNA from it was available for translation, The ATLD patients carrying this protein-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 functional MRE11 protein. The mutation in the maternal hMRE11 allele of family 2 was also identified in a further unrelated Italian family with ATLD and also found to be subject to NMD.