RGD Reference Report - Similar splice-site mutations of the ATP7A gene lead to different phenotypes: classical Menkes disease or occipital horn syndrome. - Rat Genome Database

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Similar splice-site mutations of the ATP7A gene lead to different phenotypes: classical Menkes disease or occipital horn syndrome.

Authors: Moller, LB  Tumer, Z  Lund, C  Petersen, C  Cole, T  Hanusch, R  Seidel, J  Jensen, LR  Horn, N 
Citation: Moller LB, etal., Am J Hum Genet 2000 Apr;66(4):1211-20. Epub 2000 Mar 17.
RGD ID: 734621
Pubmed: PMID:10739752   (View Abstract at PubMed)
PMCID: PMC1288188   (View Article at PubMed Central)
DOI: DOI:10.1086/302857   (Journal Full-text)

More than 150 point mutations have now been identified in the ATP7A gene. Most of these mutations lead to the classic form of Menkes disease (MD), and a few lead to the milder occipital horn syndrome (OHS). To get a better understanding of molecular changes leading to classic MD and OHS, we took advantage of the unique finding of three patients with similar mutations but different phenotypes. Although all three patients had mutations located in the splice-donor site of intron 6, only two of the patients had the MD phenotype; the third had the OHS phenotype. Fibroblast cultures from the three patients were analyzed by reverse transcriptase (RT)-PCR to try to find an explanation of the different phenotypes. In all three patients, exon 6 was deleted in the majority of the ATP7A transcripts. However, by RT-PCR amplification with an exon 6-specific primer, we were able to amplify exon 6-containing mRNA products from all three patients, even though they were in low abundance. Sequencing of these products indicated that only the patient with OHS had correctly spliced exon 6-containing transcripts. We used two different methods of quantitative RT-PCR analysis and found that the level of correctly spliced mRNA in this patient was 2%-5% of the level found in unaffected individuals. These findings indicate that the presence of barely detectable amounts of correctly spliced ATP7A transcript is sufficient to permit the development of the milder OHS phenotype, as opposed to classic MD.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
ATP7AHumancutis laxa susceptibilityIAGP DNA:splice-site mutationRGD 
Atp7aRatcutis laxa susceptibilityISOATP7A (Homo sapiens) RGD 
Atp7aMousecutis laxa susceptibilityISOATP7A (Homo sapiens) RGD 
ATP7AHumanMenkes disease  IAGP  RGD 
Atp7aRatMenkes disease  ISOATP7A (Homo sapiens) RGD 
Atp7aMouseMenkes disease  ISOATP7A (Homo sapiens) RGD 

Objects Annotated

Genes (Rattus norvegicus)
Atp7a  (ATPase copper transporting alpha)

Genes (Mus musculus)
Atp7a  (ATPase, copper transporting, alpha polypeptide)

Genes (Homo sapiens)
ATP7A  (ATPase copper transporting alpha)


Additional Information