Occipital horn syndrome and classical Menkes Syndrome caused by deep intronic mutations, leading to the activation of ATP7A pseudo-exon.
Eur J Hum Genet
; 22(4): 517-21, 2014 Apr.
Article
in En
| MEDLINE
| ID: mdl-24002164
ABSTRACT
Menkes disease is an X-linked disorder of copper metabolism caused by mutations in the ATP7A gene. Whereas most of the patients exhibit a severe classical form, about 9% of the patients exhibit a milder form of Menkes disease. The mildest form is called occipital horn syndrome (OHS). Mutations in the ATP7A gene can be identified in 95-98% of the Menkes disease patients by standard screening techniques. Investigation of RNA isolated from the fibroblasts of eleven patients with no identified mutations was performed, and revealed inclusion of new pseudo-exons into the ATP7A mRNA from three unrelated patients two patients with OHS and one patient with classical Menkes disease. The pseudo-exons were inserted between exons 10 and 11, between exons 16 and 17 and between exons 14 and 15 in the three patients, as a result of deep intronic mutations. This is the first time the activation of pseudo-exons is demonstrated in the ATP7A gene, and it demonstrates the usefulness of RNA analysis, in terms of revealing disease-causing mutations in noncoding regions. The fact that three different mutations cause disease by the activation of pseudo-exon inclusion also indicates that in Menkes disease this is an important mechanism, which has hitherto been overlooked.
Full text:
1
Database:
MEDLINE
Main subject:
Adenosine Triphosphatases
/
Cutis Laxa
/
Cation Transport Proteins
/
Ehlers-Danlos Syndrome
/
Menkes Kinky Hair Syndrome
Type of study:
Diagnostic_studies
/
Prognostic_studies
Limits:
Adolescent
/
Child
/
Humans
/
Male
Language:
En
Journal:
Eur J Hum Genet
Journal subject:
GENETICA MEDICA
Year:
2014
Type:
Article
Affiliation country:
Denmark