title: PORCN mutations in focal dermal hypoplasia: coping with lethality.
abstract: 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 no functional diagnostic test is available and carriers of the mutation might otherwise be overlooked due to considerable phenotypic variability associated with the mosaic status.
authors.affiliation: Zentrum für Humangenetik, Philipps-Universität Marburg, Germany.
authors.forename: Dorothea
authors.initials: D
authors.lastname: Bornholdt
authors.forename: Frank
authors.initials: F
authors.lastname: Oeffner
authors.forename: Arne
authors.initials: A
authors.lastname: König
authors.forename: Rudolf
authors.initials: R
authors.lastname: Happle
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Alanay
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ascherman
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Benke
authors.forename: María del Carmen
authors.initials: Mdel C
authors.lastname: Boente
authors.forename: Ineke
authors.initials: I
authors.lastname: van der Burgt
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chassaing
authors.forename: Ian
authors.initials: I
authors.lastname: Ellis
authors.forename: Christina Raissa I
authors.initials: CR
authors.lastname: Francisco
authors.forename: Patricia
authors.initials: P
authors.lastname: Della Giovanna
authors.forename: Ben
authors.initials: B
authors.lastname: Hamel
authors.forename: Cristina
authors.initials: C
authors.lastname: Has
authors.forename: Kaatje
authors.initials: K
authors.lastname: Heinelt
authors.forename: Andreas
authors.initials: A
authors.lastname: Janecke
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kastrup
authors.forename: Bart
authors.initials: B
authors.lastname: Loeys
authors.forename: Ingo
authors.initials: I
authors.lastname: Lohrisch
authors.forename: Carlo
authors.initials: C
authors.lastname: Marcelis
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Mehraein
authors.forename: Marie Eleanore O
authors.initials: ME
authors.lastname: Nicolas
authors.forename: Dana
authors.initials: D
authors.lastname: Pagliarini
authors.forename: Mauro
authors.initials: M
authors.lastname: Paradisi
authors.forename: Annalisa
authors.initials: A
authors.lastname: Patrizi
authors.forename: Maria
authors.initials: M
authors.lastname: Piccione
authors.forename: Hildegunde
authors.initials: H
authors.lastname: Piza-Katzer
authors.forename: Bettina
authors.initials: B
authors.lastname: Prager
authors.forename: Katrina
authors.initials: K
authors.lastname: Prescott
authors.forename: Juliane
authors.initials: J
authors.lastname: Strien
authors.forename: G Eda
authors.initials: GE
authors.lastname: Utine
authors.forename: Marc S
authors.initials: MS
authors.lastname: Zeller
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Grzeschik
mesh_terms: D000217:Acyltransferases; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005489:Focal Dermal Hypoplasia / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D020033:Protein Isoforms; D000217:Acyltransferases; C491188:PORCN protein, human