PORCN mutations in focal dermal hypoplasia: coping with lethality

✍ Scribed by Dorothea Bornholdt; Frank Oeffner; Arne König; Rudolf Happle; Yasemin Alanay; Jeffrey Ascherman; Paul J. Benke; María del Carmen Boente; Ineke van der Burgt; Nicolas Chassaing; Ian Ellis; Christina Raissa I. Francisco; Patricia Della Giovanna; Ben Hamel; Cristina Has; Kaatje Heinelt; Andreas Janecke; Wolfgang Kastrup; Bart Loeys; Ingo Lohrisch; Carlo Marcelis; Yasmin Mehraein; Marie Eleanore O. Nicolas; Dana Pagliarini; Mauro Paradisi; Annalisa Patrizi; Maria Piccione; Hildegunde Piza-Katzer; Bettina Prager; Katrina Prescott; Juliane Strien; G. Eda Utine; Marc S. Zeller; Karl-Heinz Grzeschik

• Book ID: 102263913
• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 348 KB
• Volume: 30
• Category: Article
• ISSN: 1059-7794
• DOI: 10.1002/humu.20992

✦ Synopsis

The X-linked dominant trait focal dermal hypoplasia (FDH, Goltz syndrome) is a developmental defect with focal distribution of affected tissues due to a block of Wnt signal transmission from cells carrying a detrimental PORCN mutation on an active X-chromosome. Molecular characterization of 24 unrelated patients from different ethnic backgrounds revealed 23 different mutations of the PORCN gene in Xp11.23. Three were microdeletions eliminating PORCN and encompassing neighboring genes such as EBP, the gene associated with Conradi-Hünermann-Happle syndrome (CDPX2). 12/24 patients carried nonsense mutations resulting in loss of function. In one case a canonical splice acceptor site was mutated, and 8 missense mutations exchanged highly conserved amino acids. FDH patients overcome the consequences of potentially lethal X-chromosomal mutations by extreme skewing of X-chromosome inactivation in females, enabling transmission of the trait in families, or by postzygotic mosaicism both in male and female individuals. Molecular characterization of the PORCN mutations in cases diagnosed as Goltz syndrome is particularly relevant for genetic counseling of patients and their families since