Role of PORCN in Focal Dermal Hypoplasia (Goltz Syndrome)
Focal dermal hypoplasia (FDH) or Goltz syndrome is an X-linked dominant developmental disorder with a variable presentation of streaks of hypoplastic skin with typical fat nodules in the dermis, limb deformities, eye abnormalities, dental defects, brittle hair, dystrophic nails and osteopathia striata (linear bone density abnormalities).
My laboratory discovered that heterozygous mutations in females and mosaic mutations in males in the PORCN gene cause FDH. PORCN encodes the human homolog of Drosophila porcupine, an endoplasmic reticulum protein that lipid-modifies Wnt proteins, facilitating their secretion from Wnt-producing cells. Porcupine is essential for canonical Wnt-signaling, a major developmental signaling pathway. Our discovery that FDH is caused by loss of function of PORCN adds FDH to a small but growing list of Mendelian disorders resulting from defective WNT signaling. It necessitates further investigation into the function of PORCN in development, into the biological and phenotypic consequences of its loss of function and into potential new treatments.
The overall goal of this project is to initiate these studies. Because FDH is a disorder with different types of birth defects, developmental disorders that have some, but not all, of the phenotypic features of FDH may also be caused by mutations in PORCN. For the first specific aim of this project, I propose to characterize such patients in detail and perform mutation analysis and X chromosome inactivation studies. All data will be analyzed for correlation of specific features or overall severity with types of mutations and status of XCI. For specific aim two, I propose to study by cell-based assays if mutations in human PORCN affect canonical WNT signaling. To study the role of Porcn in vivo in an animal model, I propose in specific aim 3 to generate and characterize a mutant mouse model with tissue-specific Porcn loss of function. Lastly, glycogen synthase kinase 3b (GSK3b?? inhibitors, such as lithium, may provide new treatments for some of the features of FDH. Lithium is well known to inhibit GSK3b, resulting in activation of b-catenin and increased canonical WNT signaling output. For specific aim 4, I propose to study lithium as a therapeutic agent for FDH in cultured cells and in the generated mouse model.
Relevance of the project to IDDRC mission:
This project is highly relevant to the mission of the BCM IDDRC. FDH is characterized by multiple birth defects of variable severity and caused by mutations in PORCN, a critical gene for regulation of WNT-signaling, which is very important in development. The studies proposed here will have implications far beyond the understanding of FDH itself and will increase overall insight into the role of PORCN and WNT-signaling in human development and birth defects. Affected individuals can have learning disability, blindness and deafness.
The disorder is X-linked dominant and sporadic, hence the identification and functional analysis of PORCN mutations, and generation of mouse models are highly challenging and require use of novel technologies (such as genome arrays), DNA sequencing methods, mouse embryonic stem cell manipulations, and detailed (neuro)pathological evaluation. All these will benefit significantly from availability of the BCM IDDRC cores