Mutations in the GGCX and ABCC6 genes in a family with pseudoxanthoma elasticum-like phenotypes.
A characteristic feature of classic pseudoxanthoma elasticum (PXE), an autosomal recessive disorder caused by mutations in the ABCC6 gene, is aberrant mineralization of connective tissues, particularly the elastic fibers. Here, we report a family with PXE-like cutaneous features in association with multiple coagulation factor deficiency, an autosomal recessive disorder associated with GGCX mutations. The proband and her sister, both with severe skin findings with extensive mineralization, were compound heterozygotes for missense mutations in the GGCX gene, which were shown to result in reduced gamma-glutamyl carboxylase activity and in undercarboxylation of matrix gla protein. The proband's mother and aunt, also manifesting with PXE-like skin changes, were heterozygous carriers of a missense mutation (p.V255M) in GGCX and a null mutation (p.R1141X) in the ABCC6 gene, suggesting digenic nature of their skin findings. Thus, reduced gamma-glutamyl carboxylase activity in individuals either compound heterozygous for a missense mutation in GGCX or with haploinsufficiency in GGCX in combination with heterozygosity for ABCC6 gene expression results in aberrant mineralization of skin leading to PXE-like phenotype. These findings expand the molecular basis of PXE-like phenotypes, and suggest a role for multiple genetic factors in pathologic tissue mineralization in general.
Li
Qiaoli
Q
Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Grange
Dorothy K
DK
Armstrong
Nicole L
NL
Whelan
Alison J
AJ
Hurley
Maria Y
MY
Rishavy
Mark A
MA
Hallgren
Kevin W
KW
Berkner
Kathleen L
KL
Schurgers
Leon J
LJ
Jiang
Qiujie
Q
Uitto
Jouni
J
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019735:Carbon-Carbon Ligases / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D011561:Pseudoxanthoma Elasticum / Q000235:genetics*; D017386:Sequence Homology, Amino Acid
D019735:Carbon-Carbon Ligases; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C102029:ABCC6 protein, human; C020660:glutamyl carboxylase
J Biol Chem. 2000 Oct 20;275(42):32572-7
10934213
Thromb Haemost. 1992 Nov 10;68(5):521-5
1455398
Curr Opin Clin Nutr Metab Care. 2000 Nov;3(6):433-8
11085828
Thromb Haemost. 2000 Dec;84(6):937-41
11154138
Exp Dermatol. 2001 Aug;10(4):221-8
11493310
Am J Hum Genet. 2001 Oct;69(4):749-64
11536079
Lab Invest. 2002 Apr;82(4):515-8
11950908
J Biol Chem. 2002 Aug 9;277(32):28584-91
12034728
J Biol Chem. 2003 Nov 21;278(47):46488-93
12968027
Nature. 2004 Feb 5;427(6974):537-41
14765194
Nature. 2004 Feb 5;427(6974):541-4
14765195
Br J Haematol. 2004 Aug;126(4):546-9
15287948
J Thromb Haemost. 2004 Sep;2(9):1564-72
15333032
Proc Natl Acad Sci U S A. 2004 Sep 21;101(38):13732-7
15365175
Biochemistry. 1995 Jan 17;34(2):481-9
7819240
J Biol Chem. 1997 May 2;272(18):11718-22
9115224
Methods Enzymol. 1997;282:313-33
9330298
Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):466-71
9435215
Ann Dermatol Venereol. 1996;123(9):555-8
9615107
Arterioscler Thromb Vasc Biol. 1998 Sep;18(9):1400-7
9743228
Blood. 1998 Dec 15;92(12):4554-9
9845520
Br J Cancer. 1999 Jul;80(9):1342-9
10424734
Int J Cardiol. 2005 Apr 28;100(3):389-93
15837081
Annu Rev Nutr. 2005;25:127-49
16011462
Arterioscler Thromb Vasc Biol. 2005 Aug;25(8):1629-33
15961706
Hum Mutat. 2005 Sep;26(3):235-48
16086317
J Invest Dermatol. 2005 Nov;125(5):900-5
16297187
J Invest Dermatol. 2006 Apr;126(4):782-6
16410789
Blood Coagul Fibrinolysis. 2006 Sep;17(6):503-7
16905958
Blood. 2006 Sep 15;108(6):1925-31
16720838
Rheumatology (Oxford). 2006 Nov;45(11):1349-55
17050587
Proc Natl Acad Sci U S A. 2000 May 23;97(11):6001-6
10811882
Nat Genet. 2000 Jun;25(2):223-7
10835642
Nat Genet. 2000 Jun;25(2):228-31
10835643
J Invest Dermatol. 2007 Mar;127(3):581-7
17110937
Semin Pediatr Neurol. 2007 Mar;14(1):34-45
17331882
Mol Vis. 2007;13:287-92
17356515
Blood. 2007 Apr 1;109(7):2823-31
17138823
J Invest Dermatol. 2007 Jun;127(6):1392-402
17273159
Lab Invest. 2007 Oct;87(10):998-1008
17724449
J Med Genet. 2007 Oct;44(10):621-8
17617515
Biochem Biophys Res Commun. 2007 Dec 14;364(2):208-13
17942075
J Med Genet. 2008 Mar;45(3):182-6
18310267
Arch Dermatol. 2008 Mar;144(3):301-6
18347285
Cell Cycle. 2008 Jun 1;7(11):1575-9
18469514
J Med Genet. 2008 Jul;45(7):465-72
18310263
J Vasc Res. 2008;45(5):427-36
18401181
Exp Dermatol. 2009 Jan;18(1):1-11
19054062
J Biol Chem. 1987 Nov 15;262(32):15334-7
2890628
J Am Acad Dermatol. 1989 Nov;21(5 Pt 2):1150-2
2808851
Science. 1991 Dec 13;254(5038):1634-6
1749935
Blood. 2000 Nov 15;96(10):3650-2
11071668