Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes.
Interferon regulatory factor 6 (IRF6) belongs to a family of nine transcription factors that share a highly conserved helix-turn-helix DNA-binding domain and a less conserved protein-binding domain. Most IRFs regulate the expression of interferon-alpha and -beta after viral infection, but the function of IRF6 is unknown. The gene encoding IRF6 is located in the critical region for the Van der Woude syndrome (VWS; OMIM 119300) locus at chromosome 1q32-q41 (refs 2,3). The disorder is an autosomal dominant form of cleft lip and palate with lip pits, and is the most common syndromic form of cleft lip or palate. Popliteal pterygium syndrome (PPS; OMIM 119500) is a disorder with a similar orofacial phenotype that also includes skin and genital anomalies. Phenotypic overlap and linkage data suggest that these two disorders are allelic. We found a nonsense mutation in IRF6 in the affected twin of a pair of monozygotic twins who were discordant for VWS. Subsequently, we identified mutations in IRF6 in 45 additional unrelated families affected with VWS and distinct mutations in 13 families affected with PPS. Expression analyses showed high levels of Irf6 mRNA along the medial edge of the fusing palate, tooth buds, hair follicles, genitalia and skin. Our observations demonstrate that haploinsufficiency of IRF6 disrupts orofacial development and are consistent with dominant-negative mutations disturbing development of the skin and genitalia.
Kondo
Shinji
S
Department of Pediatrics, The University of Iowa, Iowa City, Iowa 52242, USA.
Schutte
Brian C
BC
Richardson
Rebecca J
RJ
Bjork
Bryan C
BC
Knight
Alexandra S
AS
Watanabe
Yoriko
Y
Howard
Emma
E
de Lima
Renata L L Ferreira
RL
Daack-Hirsch
Sandra
S
Sander
Achim
A
McDonald-McGinn
Donna M
DM
Zackai
Elaine H
EH
Lammer
Edward J
EJ
Aylsworth
Arthur S
AS
Ardinger
Holly H
HH
Lidral
Andrew C
AC
Pober
Barbara R
BR
Moreno
Lina
L
Arcos-Burgos
Mauricio
M
Valencia
Consuelo
C
Houdayer
Claude
C
Bahuau
Michel
M
Moretti-Ferreira
Danilo
D
Richieri-Costa
Antonio
A
Dixon
Michael J
MJ
Murray
Jeffrey C
JC
D000818:Animals; D001665:Binding Sites / Q000235:genetics / Q000502:physiology; D015152:Blotting, Northern; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D004200:Diseases in Twins / Q000235:genetics; D005260:Female; D005835:Genitalia / Q000002:abnormalities*; D006801:Humans; D017403:In Situ Hybridization; D050835:Interferon Regulatory Factors; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D010375:Pedigree; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012868:Skin Abnormalities / Q000235:genetics*; D013329:Structure-Activity Relationship; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics*; D014430:Twins, Monozygotic / Q000235:genetics
D004268:DNA-Binding Proteins; C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors; D014157:Transcription Factors; D004247:DNA