title: Mutations in the GGCX and ABCC6 genes in a family with pseudoxanthoma elasticum-like phenotypes.
abstract: 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.
authors.affiliation: Department of Dermatology and Cutaneous Biology, Jefferson Medical College, Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Qiaoli
authors.initials: Q
authors.lastname: Li
authors.forename: Dorothy K
authors.initials: DK
authors.lastname: Grange
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Armstrong
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Whelan
authors.forename: Maria Y
authors.initials: MY
authors.lastname: Hurley
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rishavy
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Hallgren
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Berkner
authors.forename: Leon J
authors.initials: LJ
authors.lastname: Schurgers
authors.forename: Qiujie
authors.initials: Q
authors.lastname: Jiang
authors.forename: Jouni
authors.initials: J
authors.lastname: Uitto
mesh_terms: 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
chemical_list: D019735:Carbon-Carbon Ligases; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C102029:ABCC6 protein, human; C020660:glutamyl carboxylase
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