Mutation detection in the ABCC6 gene and genotype-phenotype analysis in a large international case series affected by pseudoxanthoma elasticum.
BACKGROUND
Pseudoxanthoma elasticum (PXE), an autosomal recessive disorder with considerable phenotypic variability, mainly affects the eyes, skin and cardiovascular system, characterised by dystrophic mineralization of connective tissues. It is caused by mutations in the ABCC6 (ATP binding cassette family C member 6) gene, which encodes MRP6 (multidrug resistance-associated protein 6).


OBJECTIVE
To investigate the mutation spectrum of ABCC6 and possible genotype-phenotype correlations.


METHODS
Mutation data were collected on an international case series of 270 patients with PXE (239 probands, 31 affected family members). A denaturing high-performance liquid chromatography-based assay was developed to screen for mutations in all 31 exons, eliminating pseudogene coamplification. In 134 patients with a known phenotype and both mutations identified, genotype-phenotype correlations were assessed.


RESULTS
In total, 316 mutant alleles in ABCC6, including 39 novel mutations, were identified in 239 probands. Mutations were found to cluster in exons 24 and 28, corresponding to the second nucleotide-binding fold and the last intracellular domain of the protein. Together with the recurrent R1141X and del23-29 mutations, these mutations accounted for 71.5% of the total individual mutations identified. Genotype-phenotype analysis failed to reveal a significant correlation between the types of mutations identified or their predicted effect on the expression of the protein and the age of onset and severity of the disease.


CONCLUSIONS
This study emphasises the principal role of ABCC6 mutations in the pathogenesis of PXE, but the reasons for phenotypic variability remain to be explored.
Pfendner
Ellen G
EG
GeneDx Inc., 207 Perry Parkway, Gaithersburg, Maryland 20877, USA. ellen@genedx.com
Vanakker
Olivier M
OM
Terry
Sharon F
SF
Vourthis
Sophia
S
McAndrew
Patricia E
PE
McClain
Monica R
MR
Fratta
Sarah
S
Marais
Anna-Susan
AS
Hariri
Susan
S
Coucke
Paul J
PJ
Ramsay
Michele
M
Viljoen
Denis
D
Terry
Patrick F
PF
De Paepe
Anne
A
Uitto
Jouni
J
Bercovitch
Lionel G
LG
D000483:Alleles; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003062:Codon; D004252:DNA Mutational Analysis; D005808:Genes, Recessive; D005838:Genotype; D006801:Humans; D007391:International Cooperation; D008957:Models, Genetic; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D011561:Pseudoxanthoma Elasticum / Q000235:genetics* / Q000473:pathology*; D012871:Skin Diseases / Q000235:genetics / Q000473:pathology
D003062:Codon; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C102029:ABCC6 protein, human