Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes

被引:632
作者
Kondo, S
Schutte, BC
Richardson, RJ
Bjork, BC
Knight, AS
Watanabe, Y
Howard, E
de Lima, RLLF
Daack-Hirsch, S
Sander, A
McDonald-McGinn, DM
Zackai, EH
Lammer, EJ
Aylsworth, AS
Ardinger, HH
Lidral, AC
Pober, BR
Moreno, L
Arcos-Burgos, M
Valencia, C
Houdayer, C
Bahuau, M
Moretti-Ferreira, D
Richieri-Costa, A
Dixon, MJ
Murray, JC [1 ]
机构
[1] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA
[2] Univ Iowa, Interdisciplinary PhD Program Genet, Iowa City, IA 52242 USA
[3] Univ Manchester, Sch Biol Sci, Manchester, Lancs, England
[4] Univ Manchester, Dept Dent Med & Surg, Manchester, Lancs, England
[5] Harvard Univ, Brigham & Womens Hosp, Boston, MA 02115 USA
[6] Univ Estadual Paulista, Serv Aconselhamento Genet, Botucatu, SP, Brazil
[7] Univ Hamburg, Clin Oral Maxillofacial Surg, Hamburg, Germany
[8] Childrens Hosp Philadelphia, Div Human Genet & Mol Biol, Philadelphia, PA 19104 USA
[9] Childrens Hosp, Oakland, CA 94609 USA
[10] Univ N Carolina, Dept Pediat & Genet, Chapel Hill, NC USA
[11] Univ Kansas, Childrens Med Ctr, Dept Pediat, Kansas City, KS USA
[12] Univ Iowa, Dept Orthodont, Iowa City, IA USA
[13] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA
[14] Univ Iowa, PhD Program Oral Sci, Iowa City, IA USA
[15] Univ Antioquia, Medellin, Colombia
[16] Hop Enfants Armand Trousseau, Serv Biochim & Biol Mol, Paris, France
[17] Hop Enfants Armand Trousseau, Serv Chirurg Maxillofaciale & Plast Stomatol, Paris, France
[18] Univ Sao Paulo, Serv Chirurg Maxillofaciale & Lesoes Labio Palati, Dept Clin Genet, Bauru, Brazil
[19] Univ Iowa, Dept Biol, Iowa City, IA 52242 USA
关键词
D O I
10.1038/ng985
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
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(1), 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(4), 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(5). Phenotypic overlap(6) and linkage data(7) 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.
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收藏
页码:285 / 289
页数:5
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