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Title: Spectrum of PORCN mutations in Focal Dermal Hypoplasia

Author
item SUTTON, V - BAYLOR COLLEGE MED
item WANG, X - BAYLOR COLLEGE MED
item PERAZA-LLANES, J - IMSS, MERIDA, MEXICO
item YU, Z - BAYLOR COLLEGE MED
item ROSETTA, R - BAYLOR COLLEGE MED
item KOU, Y - BAYLOR COLLEGE MED
item EBLE, T - BAYLOR COLLEGE MED
item PATEL, A - BAYLOR COLLEGE MED
item THALLER, C - BAYLOR COLLEGE MED
item FANG, P - BAYLOR COLLEGE MED
item FERNANDES, P - BAYLOR COLLEGE MED
item Van Den Veyver, Ignatia

Submitted to: American Society of Human Genetics
Publication Type: Abstract Only
Publication Acceptance Date: 10/23/2007
Publication Date: 10/23/2007
Citation: Sutton, V.R., Wang, X., Peraza-Llanes, J.O., Yu, Z., Rosetta, R., Kou, Y.C., Eble, T.N., Patel, A., Thaller, C., Fang, P., Fernandes, P.H., Van Den Veyver, I.B. 2007. Spectrum of PORCN mutations in Focal Dermal Hypoplasia [abstract]. In: 57th Annual Meeting of The American Society of Human Genetics, October 23-27, 2007, San Diego, California. p. 90.

Interpretive Summary:

Technical Abstract: Focal Dermal Hypoplasia (FDH), also known as Goltz syndrome (OMIM 305600), is a genetic disorder that affects multiple organ systems early in development. Features of FDH include skin abnormalities, (hypoplasia, atrophy, linear pigmentation, and herniation of fat through dermal defects); papillomas of the mucous membranes; patterning defects of the hands and feet, including syndactyly, polydactyly, camptodactyly, and oligodactyly; osteopathia striata; colobomas and other ocular abnormalities; and hypodontia/oligodontia. FDH displays X-linked dominant inheritance; 95% of cases are sporadic and only 10% of cases are males. Using array-based comparative genomic hybridization, we identified a 219-kb heterozygous deletion in Xp11.23 in two girls with FDH. The deleted region contained seven known genes: SLC38A5, FTSJ1, EBP, PORCN, OATL1, RBM3, and WDR13. Sequencing of genes in the deleted region revealed heterozygous mutations in PORCN in eleven additional females and mosaic mutations in all four males analyzed. Seven of thirteen mutations result in stop codons, all of which suggests that FDH is due to loss of function of PORCN. The two females with deletions were found to have 100% skewing of X-inactivation (XCI) while 3 of 7 with point mutations had skewed XCI. We have also screened individuals with Aicardi syndrome and have found no mutations in PORCN. This proves that FDH, Aicardi syndrome, and Microphthalmia with linear skin defects are not allelic. PORCN encodes the human homolog of Drosophila porcupine. Drosophila and murine Pourcupine are transmembrane endoplasmic reticulum proteins required for post-translational modification and secretion of Wnt proteins. In situ hybridization of E12.5 mouse embryos was performed and revealed expression in axial and appendicular cartilage, retina, tooth buds, and dorsal skin, which suggests that the pleiotropic features of FDH can be explained by defective Wnt signaling.