TY - JOUR
T1 - A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum
AU - Saux, Olivier Le
AU - Beck, Konstanze
AU - Sachsinger, Christine
AU - Silvestri, Chiara
AU - Treiber, Carina
AU - Goöring, Harald H.H.
AU - Johnson, Eric W.
AU - De Paepe, Anne
AU - Pope, F. Michael
AU - Pasquali-Ronchetti, Ivonne
AU - Bercovitch, Lionel
AU - Terry, Sharon
AU - Boyd, Charles D.
N1 - Funding Information:
We are very grateful to all the patients and their relatives, whose cooperation made this study possible. We would like to thank Drs. András Váradi and Balázs Sarkadi for valuable comments regarding the role and functional consequences of mutations in ABCC6. We are also grateful for the various contributions of the members of the PXE International Research Consortium, particularly Patrick Terry. This work was supported by National Institutes of Health grant EY13019 (to C.B.), Research Centers in Minority Institutions grant RR03061 from National Center for Research Resources to the Pacific Biomedical Research Center of the University of Hawaii, and Telethon-Italy grant 696 (to I.P.R.).
PY - 2001
Y1 - 2001
N2 - To better understand the pathogenetics of pseudoxanthoma elasticum (PXE), we performed a mutational analysis of ATP-binding cassette subfamily C member 6 (ABCC6) in 122 unrelated patients with PXE, the largest cohort of patients yet studied. Thirty-six mutations were characterized, and, among these, 28 were novel variants (for a total of 43 PXE mutations known to date). Twenty-one alleles were missense variants, six were small insertions or deletions, five were nonsense, two were alleles likely to result in aberrant mRNA splicing, and two were large deletions involving ABCC6. Although most mutations appeared to be unique variants, two disease-causing alleles occurred frequently in apparently unrelated individuals. R1141X was found in our patient cohort at a frequency of 18.8% and was preponderant in European patients. ABCC6de123-29 occurred at a frequency of 12.9% and was prevalent in patients from the United States. These results suggested that R1141X and ABCC6del23-29 might have been derived regionally from founder alleles. Putative disease-causing mutations were identified in ∼64% of the 244 chromosomes studied, and 85.2% of the 122 patients were found to have at least one disease-causing allele. Our results suggest that a fraction of the undetected mutant alleles could be either genomic rearrangements or mutations occurring in noncoding regions of the ABCC6 gene. The distribution pattern of ABCC6 mutations revealed a cluster of disease-causing variants within exons encoding a large C-terminal cytoplasmic loop and in the C-terminal nucleotide-binding domain (NBD2). We discuss the potential structural and functional significance of this mutation pattern within the context of the complex relationship between the PXE phenotype and the function of ABCC6.
AB - To better understand the pathogenetics of pseudoxanthoma elasticum (PXE), we performed a mutational analysis of ATP-binding cassette subfamily C member 6 (ABCC6) in 122 unrelated patients with PXE, the largest cohort of patients yet studied. Thirty-six mutations were characterized, and, among these, 28 were novel variants (for a total of 43 PXE mutations known to date). Twenty-one alleles were missense variants, six were small insertions or deletions, five were nonsense, two were alleles likely to result in aberrant mRNA splicing, and two were large deletions involving ABCC6. Although most mutations appeared to be unique variants, two disease-causing alleles occurred frequently in apparently unrelated individuals. R1141X was found in our patient cohort at a frequency of 18.8% and was preponderant in European patients. ABCC6de123-29 occurred at a frequency of 12.9% and was prevalent in patients from the United States. These results suggested that R1141X and ABCC6del23-29 might have been derived regionally from founder alleles. Putative disease-causing mutations were identified in ∼64% of the 244 chromosomes studied, and 85.2% of the 122 patients were found to have at least one disease-causing allele. Our results suggest that a fraction of the undetected mutant alleles could be either genomic rearrangements or mutations occurring in noncoding regions of the ABCC6 gene. The distribution pattern of ABCC6 mutations revealed a cluster of disease-causing variants within exons encoding a large C-terminal cytoplasmic loop and in the C-terminal nucleotide-binding domain (NBD2). We discuss the potential structural and functional significance of this mutation pattern within the context of the complex relationship between the PXE phenotype and the function of ABCC6.
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U2 - 10.1086/323704
DO - 10.1086/323704
M3 - Article
C2 - 11536079
AN - SCOPUS:0034835028
VL - 69
SP - 749
EP - 764
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 4
ER -