Nature Genetics
8, 195 - 202 (1994)
doi:10.1038/ng1094-195
Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locusStephen G. Kaler1, 4, Linda K. Gallo1, Virginia K. Proud2, Alan K. Percy2, Yvonne Mark1, Neil A. Segal1, David S. Goldstein3, Courtney S. Holmes3
& William A. Gahl1
1Section on Human Biochemical Genetics, Human Genetics Branch, National Institute of Child Health and Human Development, Building 10, Room 9S-242, Bethesda, Maryland 20892, USA
2Department of Pediatrics, University of Alabama School of Medicine, Birmingham, Alabama 35233, USA
3Clinical Neurosdence Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA
4Correspondence should be addressed to S.G.K. We have found mutations in the Menkes disease gene (MNK) which impair, but do not abolish, correct mRNA splicing in patients with less severe clinical phenotypes. In one family, four males aged 2−36 years with a distinctive Menkes variant have a mutation at the +3 position of a splice donor site near the 3' end of the Menkes coding sequence that is associated with exon skipping and a stable mutant transcript. In an unrelated 15-year-old male with typical occipital horn syndrome, a point mutation at the -2 exonic position of a splice donor site in the middle of the gene causes exon-skipping and activation of a cryptic splice acceptor site. In both mutations, maintenance of some normal splicing is demonstrable by RT-PCR, cDNA sequencing and ribonuclease protection.
REFERENCES
- Danks, D.M. Disorders of copper transport: Menkes disease and the occipital horn syndrome. in Connective Tissue and its Heritable Disorders: Molecular, genetic and medical aspects (eds Royce, P. M. & Steinmann, B.U.) 487−505 (Wiley-Liss, New York, 1993).
- Vulpe, C., Levinson, B., Whitney, S., Packman, S. & Gitschier, J. Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase. Nature Genet. 3, 7−13 (1993). | Article | PubMed | ISI | ChemPort |
- Chelly, J. et al. Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein. Nature Genet. 3, 14−19 (1993). | Article | PubMed | ISI | ChemPort |
- Mercer, J.F.B. et al. Isolation of a partial candidate gene for Menkes disease by positional cloning. Nature Genet. 3, 20−25 (1993). | Article | PubMed | ISI | ChemPort |
- Odermatt, A., Suter, H., Krapf, R. & Solioz, M. Primary structure of two P-type ATPases involved in copper homeostasis in Enterococcus hirae. J. biol. Chem. 268, 12775−12779 (1993). | PubMed | ISI | ChemPort |
- Levinson, B. et al. The mottled gene is the mouse homologue of the Menkes disease gene. Nature Genet. 6, 369−373 (1994). | Article | PubMed | ISI | ChemPort |
- Mercer, J.F.B. et al. Mutations in the murine homologue of the Menkes gene in dappled and blotchy mice. Nature Genet. 6, 374−378 (1994). | Article | PubMed | ISI | ChemPort |
- Bull, P.C., Thomas, G.R., Rommens, J.M., Forbes, J.R. & Cox, D.W., Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nature Genet. 5, 327−337 (1993). | Article | PubMed | ISI | ChemPort |
- Lazoff, S.G., Rybak, J.J., Parker, B.R. & Luzzatti, L. Skeletal dysplasia, occipital horns, diarrhea and obstructive uropathy — a new hereditary syndrome. Birth Defects 11, 71−74 (1975). | PubMed | ChemPort |
- Byers, P.H. et al. X-linked cutis laxa. Defective cross-link formation in collagen due to decreased lysyl oxidase activity. New Engl. J. Med. 303, 61−65 (1980). | PubMed | ISI | ChemPort |
- Kuivaniemi, H., Peltonen, L., Palotie, A., Kaitila, I. & Kivirikko, K.I. Abnormal copper metabolism and deficient lysyl oxidase activity in a heritable connective tissue disorder. J. clin. Invest. 69, 730−733 (1982). | PubMed | ISI | ChemPort |
- Sartoris, D.J. et al. Type IX Ehlers-Danlos syndrome: A new variant with pathognomonic radiographic features. Radiology 152, 665−670 (1984). | PubMed | ISI | ChemPort |
- Danks, D.M. The mild form of Menkes' disease: progress report on the original case. Am. J. med. Genet. 30, 859−864 (1988). | PubMed | ISI | ChemPort |
- Levinson, B. et al. Are X-linked cutis laxa and Menkes disease allelic? Nature Genet. 3, 6 (1993). | Article | PubMed | ISI | ChemPort |
- Tsukahara, M., Imaizumi, K., Kawai, S. & Kajii, T. Occipital horn syndrome: report of a case and review of the literature. Clin. Genet. 45, 32−35 (1994). | PubMed | ISI | ChemPort |
- Kaler, S.G., Goldstein, D.S., Holmes, C., Salerno, J.A. & Gahl, W.A. Plasma and cerebrospinal fluid neurochemical pattern in Menkes disease. Ann. Neurol. 33, 171−175 (1993). | PubMed | ISI | ChemPort |
- Newton, C.R. et al. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucl. Acids Res. 17, 2503−2516 (1989). | PubMed | ISI | ChemPort |
- Urlaub, G., Mitchell, P.J., Ciudad, C.J. & Chasin, L.A. Nonsense mutations in the dihydrofolate reductase gene affect RNA processing. Molec. cell. Biol. 9, 2868−2880 (1989). | PubMed | ISI | ChemPort |
- Mclntosh, I., Hamosh, A. & Dietz, H.C. Nonsense mutations and diminished mRNA levels. Nature Genet. 4, 219 (1993). | Article | PubMed | ISI | ChemPort |
- Daar, I.O. & Maquat, L.E. Premature translation termination mediates triosephosphate isomerase mRNA degradation. Molec. cell. Biol. 8, 802−813 (1988). | PubMed | ISI | ChemPort |
- Cheng, J, Fogel-Petrovic, M. & Maquat, L.E. Translation to near the distal end of the penultimate exon is required for normal levels of spliced triosephosphate isomerase mRNA. Molec. cell. Biol. 10, 5215−5255 (1990). | PubMed | ChemPort |
- Horowitz, D.S. & Krainer, A.R. Mechanisms for selecting 5' splice sites in mammalian pre-mRNA splicing. Trends Genet. 10, 100−106 (1994). | Article | PubMed | ISI | ChemPort |
- Mount, S.M. A catalogue of splice junction sequences. Nucl. Acids Res. 10, 459−472 (1982). | PubMed | ISI | ChemPort |
- Krawczak, M., Reiss, J. & Cooper, D.N. The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum. Genet. 90, 41−54 (1992). | PubMed | ISI | ChemPort |
- Biaggioni, I., Goldstein, D.S., Atkinson, T. & Robertson, D. Dopamine-beta hydroxylase deficiency in humans. Neurology 40, 370−373 (1990). | PubMed | ISI | ChemPort |
- Goldstein, D.S. et al. Positron emission imaging of cardiac sympathetic innervation and function using 18F-6-fluorodopamine: effects of chemical sympathectomy by 6-hydroxydopamine. J. Hypertension 9, 417−423 (1991). | ISI | ChemPort |
- Tsusui, K. & Terada, Y. On the mechanism of diarrhea due to reserpine. Mie. Med. J. 17, 273−281 (1968). | PubMed |
- Westman, J.A., Richardson, D.C., Rennert, O.M. & Morrow, G. Atypical Menkes' steely hair disease. Am. J. med. Genet. 30, 853−858 (1988). | PubMed | ISI | ChemPort |
- Gerdes, A.-M. et al. Variability in clinical expression of Menkes syndrome. Eur. J. Pediatr. 148, 132−135 (1988). | PubMed | ISI | ChemPort |
|
