A REPEATED ELEMENT IN THE REGULATORY REGION OF THE MNK GENE AND ITS DELETION IN A PATIENT WITH OCCIPITAL HORN SYNDROME

Occipital horn syndrome (OHS), an X-linked connective tissue disorder, has recently been shown to result from mutations in the Menkes diseas e gene (MNK), which encodes a copper-transporting ATPase, By Southern analysis we detected a small deletion in a region 5' to the MNK gene i n one patient with OHS, Genomic clones from an unaffected individual w ere isolated and sequenced, revealing three tandem 98 bp repeats situa ted upstream of the reported transcription start site, and analysis of the patient's DNA showed a deletion of one of the repeats, The deleti on is likely to be responsible for the disease in this patient, as it was not observed in 110 unaffected individuals analyzed, and no other mutation in the patient was detected by RT-PCR and chemical cleavage m ismatch analysis or by cDNA sequence analysis, The deletion is associa ted with a dramatic decrease in expression of a chloramphenicol acetyl transferase reporter gene, implicating the repeat sequences in regulat ion of MNK expression, although a quantitative analysis of MNK mRNA fr om a cell line derived from the patient shows no detectable reduction. Other experiments revealed no effect on the site of transcription ini tiation, termination or on splicing.