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Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome.

ABSTRACT: The Drosophila porcupine gene is required for secretion of wingless and other Wnt proteins, and sporadic mutations in its unique human ortholog, PORCN, cause a pleiotropic X-linked dominant disorder, focal dermal hypoplasia (FDH, also known as Goltz syndrome). We generated a conditional allele of the X-linked mouse Porcn gene and analyzed its requirement in Wnt signaling and embryonic development. We find that Porcn-deficient cells exhibit a cell-autonomous defect in Wnt ligand secretion but remain responsive to exogenous Wnts. Consistent with the female-specific inheritance pattern of FDH, Porcn hemizygous male embryos arrest during early embryogenesis and fail to generate mesoderm, a phenotype previously associated with loss of Wnt activity. Heterozygous Porcn mutant females exhibit a spectrum of limb, skin, and body patterning abnormalities resembling those observed in human patients with FDH. Many of these defects are recapitulated by ectoderm-specific deletion of Porcn, substantiating a long-standing hypothesis regarding the etiology of human FDH and extending previous studies that have focused on downstream elements of Wnt signaling, such as ?-catenin. Conditional deletion of Porcn thus provides an experimental model of FDH, as well as a valuable tool to probe Wnt ligand function in vivo.

SUBMITTER: Barrott JJ

PROVIDER: S-EPMC3150921 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome.

Barrott Jared J JJ Cash Gabriela M GM Smith Aaron P AP Barrow Jeffery R JR Murtaugh L Charles LC

Proceedings of the National Academy of Sciences of the United States of America 20110718 31

The Drosophila porcupine gene is required for secretion of wingless and other Wnt proteins, and sporadic mutations in its unique human ortholog, PORCN, cause a pleiotropic X-linked dominant disorder, focal dermal hypoplasia (FDH, also known as Goltz syndrome). We generated a conditional allele of the X-linked mouse Porcn gene and analyzed its requirement in Wnt signaling and embryonic development. We find that Porcn-deficient cells exhibit a cell-autonomous defect in Wnt ligand secretion but rem ...[more]

PMID: 21768372

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Project description:Focal dermal hypoplasia (Goltz syndrome), is an extremely rare genetic disorder characterized by distinct skin manifestations and a wide range of abnormalities involving the ocular, dental, skeletal, urinary, gastrointestinal, cardiovascular, and central nervous systems. The objective of the present series is to emphasize the different typical as well as unusual features of this rare syndrome.This cross-sectional observational study was performed over a period of 8 years in a tertiary care hospital of Eastern India. Consecutive patients with the clinical diagnosis of Goltz syndrome were studied.A total of 8 patients with Goltz syndrome were evaluated. Out of them, one patient was a boy and the rest were girl. The age ranged from 3 days to 9 years. There was no family history. A characteristic Blaschkoid hypo- and hyper-pigmented skin lesions, congenital nodular fat herniation, and skin atrophy were present in all patients. Congenital cutaneous aplasia was present in 50% of the patients. Facial asymmetry and ear deformity (megalopinna and low-set ears) were seen in 37.5% and 12.5% of patients, respectively. Cutaneous telangiectasia was noticed in 37.5% of patients. Freckle- and lentigines-like pigmentation within the hypopigmented macules was found in 25% of patients. Raspberry-like papillomas around mouth were documented in 6 (75%) patients. Dysplastic nail changes with ridging were seen in 7 (87.5%) patients. Genital abnormality in the form of bilateral undescended testes and microphthalmia with aniridia were found in one patient each. Limb defects were present in all patients. Left-sided renal agenesis was found in one patient. The patient also had multiple cortical cysts of the right kidney.Genetic testing could not be performed in the present series.Our case series showed a few unusual or extremely rare manifestations such as undescended testes, dermal sinus, kyphoscoliosis, aniridia, unilateral kidney agenesis, and renal cortical cysts among others.

Dataset Information

Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome.

Publications

Deletion of mouse Porcn blocks Wnt ligand secretion and reveals an ectodermal etiology of human focal dermal hypoplasia/Goltz syndrome.

Similar Datasets

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