Occipital horn syndrome and a mild Menkes phenotype associated with splice site mutations at the MNK locus

• Published in: Nature genetics Vol. 8; no. 2; pp. 195 - 202
• Main Authors: Kaler, Stephen G, Gallo, Linda K, Proud, Virginia K, Percy, Alan K, Mark, Yvonne, Segal, Neil A, Goldstein, David S, Holmes, Courtney S, Gahl, William A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01-10-1994
• Subjects: Adenosine Triphosphatases - chemistry; Adenosine Triphosphatases - genetics; Adolescent; Animals; Base Sequence; Biological and medical sciences; Carrier Proteins - genetics; Cation Transport Proteins; Cells, Cultured; Ceruloplasmin - analysis; Copper - blood; Copper-transporting ATPases; Dihydroxyphenylalanine - blood; Dihydroxyphenylalanine - cerebrospinal fluid; DNA Mutational Analysis; Ehlers-Danlos Syndrome - blood; Ehlers-Danlos Syndrome - cerebrospinal fluid; Ehlers-Danlos Syndrome - classification; Ehlers-Danlos Syndrome - genetics; Exons; Female; Fibroblasts - metabolism; Humans; Male; man; Medical sciences; Menkes Kinky Hair Syndrome - blood; Menkes Kinky Hair Syndrome - cerebrospinal fluid; Menkes Kinky Hair Syndrome - genetics; Menkes syndrome; Metabolic diseases; Metals (hemochromatosis...); Methoxyhydroxyphenylglycol - analogs & derivatives; Methoxyhydroxyphenylglycol - blood; Methoxyhydroxyphenylglycol - cerebrospinal fluid; Mice; Mice, Neurologic Mutants; MNK gene; Molecular Sequence Data; Occipital Bone - abnormalities; occipital horn syndrome; Other metabolic disorders; Pedigree; Phenotype; Point Mutation; Polymerase Chain Reaction; Recombinant Fusion Proteins; RNA Splicing; Sequence Homology, Amino Acid; Species Specificity; splicing; Terminator Regions, Genetic; Human; Skin disease; Nervous system diseases; Splicing; Metabolic diseases; Inorganic element; Enzymopathy; Cerebral disorder; Genetic disease; Gene; Exon skipping; Genetics; Menkes syndrome; X-Chromosome; Mutation; Copper
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng1094-195

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.