Mutations in the GGCX and ABCC6 Genes in a Family with Pseudoxanthoma Elasticum-Like Phenotypes
| Autor: | Alison J. Whelan, Qiaoli Li, Nicole L. Armstrong, Jouni Uitto, Kathleen L. Berkner, Kevin W. Hallgren, Leon J. Schurgers, Mark A. Rishavy, Qiujie Jiang, Maria Yadira Hurley, Dorothy K. Grange |
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| Rok vydání: | 2009 |
| Předmět: |
Adult
Male Proband Adolescent Molecular Sequence Data Mutation Missense ABCC6 Dermatology Compound heterozygosity Biochemistry Article 03 medical and health sciences 0302 clinical medicine Matrix gla protein medicine Animals Humans Missense mutation Amino Acid Sequence Pseudoxanthoma Elasticum Molecular Biology 030304 developmental biology Genetics 0303 health sciences Base Sequence Sequence Homology Amino Acid biology Cell Biology Pseudoxanthoma elasticum medicine.disease Null allele Carbon-Carbon Ligases 030220 oncology & carcinogenesis Mutation biology.protein Female Multidrug Resistance-Associated Proteins Haploinsufficiency |
| Zdroj: | Journal of Investigative Dermatology. 129:553-563 |
| ISSN: | 0022-202X |
| DOI: | 10.1038/jid.2008.271 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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