PORCN mutations in focal dermal hypoplasia: coping with lethality.
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.
Bornholdt
Dorothea
D
Zentrum für Humangenetik, Philipps-Universität Marburg, Germany.
Oeffner
Frank
F
König
Arne
A
Happle
Rudolf
R
Alanay
Yasemin
Y
Ascherman
Jeffrey
J
Benke
Paul J
PJ
Boente
María del Carmen
Mdel C
van der Burgt
Ineke
I
Chassaing
Nicolas
N
Ellis
Ian
I
Francisco
Christina Raissa I
CR
Della Giovanna
Patricia
P
Hamel
Ben
B
Has
Cristina
C
Heinelt
Kaatje
K
Janecke
Andreas
A
Kastrup
Wolfgang
W
Loeys
Bart
B
Lohrisch
Ingo
I
Marcelis
Carlo
C
Mehraein
Yasmin
Y
Nicolas
Marie Eleanore O
ME
Pagliarini
Dana
D
Paradisi
Mauro
M
Patrizi
Annalisa
A
Piccione
Maria
M
Piza-Katzer
Hildegunde
H
Prager
Bettina
B
Prescott
Katrina
K
Strien
Juliane
J
Utine
G Eda
GE
Zeller
Marc S
MS
Grzeschik
Karl-Heinz
KH
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
D008565:Membrane Proteins; D020033:Protein Isoforms; D000217:Acyltransferases; C491188:PORCN protein, human