| Pseudoxanthoma
elasticum (PXE) (Grönblad-Strandberg-Syndrom
or Elastorrhexis generalisata) is a rare hereditary disorder of
the connective tissue with an estimated population frequency of
1 in 70000-160000. Prominent symptoms are yellowish papules or
plaques on the neck, armpits and other folds of the skin.
Calcification of elastic fibers caused by PXE manifests itself
in the eyes (retinal angioid streaks and hemorrhagic maculopathy),
gastrointestinal tract (bleeding), kidneys (calcification) and
cardiovascular system (intermittent claudication, coronary
artery disease, hypertension, mitral stenosis and mitral valve
prolapse). Disease symptoms are often not detected until the
second decade of life and progress slowly.
Excluding isolated cases, the disorder is
inherited in both an autosomal recessive and autosomal dominant
way. Mutations in the transmembrane ATP-binding cassette
transporter gene ABCC6 have been recognized as the cause of
Pseudoxanthoma elasticum1-3). This gene, also known
as multidrug resistance- associated protein MRP6, encodes a 1503
amino acid protein and is divided over 31 exons on 76 kB of
chromosome 16p13.1. The gene is expressed primarily in the liver
and kidney. It's function remains to be elucidated. Most
pathogenic mutations have been detected in the C-terminal-coding
part of the gene (large cytoplasmatic loop and 2nd nucleotide
binding domain). The most frequent mutations in the European and
North American population are R1141X and the Alu-mediated
deletion del23-29.4)
The screening of the ABCC6 gene
for mutations supports the clinical diagnosis of PXE and enables
detection of presymptomatic carriers of mutant alleles among
family members of PXE patients. Mild PXE-related symptoms have
been observed in heterozygous carriers of ABCC6 mutations 5,
6).
When suspecting Pseudoxanthoma
elasticum, we routinely amplify and sequence the exons 24 and
28 from the genomic DNA of the patient and screen for the
possible deletion mutation del23-297).
Mutations in these three parts of the gene cover up to 55% of
the alleles affected in PXE-patients4). When these
exons are free of mutations, it is possible to screen the
remaining 29 protein-coding exons of the ABCC6 gene for
mutations in the order of the ethnic background-dependent
frequency of mutations (e.g. intron 21, Exon 27-30)4).
We usually provide results of the initial screening for
mutations in exon 24 and 28 as well as for the del23-29 deletion
within 3 days after receipt of the sample.
When mutations are found, we
recommend analyzing the corresponding ABCC6 alleles of the
patient's relatives to detect carrier of the gene defect.
1) Ringpfeil
et al. (2000) Proc. Natl. Acad. Sci USA 97:6001-6006.
2) Le
Saux et al. (2000) Nature Genet. 25:223-227.
3) Bergen
et al. (2000) Nature Genet. 25:228-231.
4) Le
Saux et al. (2001) Am. J. Hum. Genet. 69:749-764.
5) Rubegni et al. (2000) Am.J. Cardiol. 85:1268-1271.
6) Trip et al. (2002) Circulation 106:773-775.
7) Ringpfeil et al. (2001) Am. J. Hum. Genet. 68:642-652.
|
| The recommended source for
genomic DNA is EDTA-blood. A typical sample volume is 0.5
ml. Blood samples can be send to us at ambient temperature.
Other sources may also be considered for analysis (e.g. prenatal samples, tissue biopsies or
paraffin embedded material). |
| Please contact us for an estimate
for the analysis of the ABCC6 gene of your patient.
|
| The screening service for ABCC6
mutations is available 7 days
a week. |
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