Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes (2024)

Abstract

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-α and -β after viral infection1, 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 pits4, 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 anomalies5. Phenotypic overlap6 and linkage data7 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.

Original languageEnglish
Pages (from-to)285-289
Number of pages4
JournalNature Genetics
Volume32
Issue number2
DOIs
Publication statusPublished - 1 Oct 2002

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Kondo, S., Schutte, B. C., Richardson, R. J., Bjork, B. C., Knight, A. S., Watanabe, Y., Howard, E., de Lima, R. L. L. F., Daack-Hirsch, S., Sander, A., McDonald-McGinn, D. M., Zackai, E. H., Lammer, E. J., Aylsworth, A. S., Ardinger, H. H., Lidral, A. C., Pober, B. R., Moreno, L., Arcos-Burgos, M., ... Murray, J. C. (2002). Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nature Genetics, 32(2), 285-289. https://doi.org/10.1038/ng985

Kondo, Shinji ; Schutte, Brian C. ; Richardson, Rebecca J. et al. / Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. In: Nature Genetics. 2002 ; Vol. 32, No. 2. pp. 285-289.

@article{cb7395899b804f3a8bb7dd96e369f11e,

title = "Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes",

abstract = "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-α and -β after viral infection1, 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 pits4, 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 anomalies5. Phenotypic overlap6 and linkage data7 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.",

author = "Shinji Kondo and Schutte, {Brian C.} and Richardson, {Rebecca J.} and Bjork, {Bryan C.} and Knight, {Alexandra S.} and Yoriko Watanabe and Emma Howard and {de Lima}, {Renata L L Ferreira} and Sandra Daack-Hirsch and Achim Sander and McDonald-McGinn, {Donna M.} and Zackai, {Elaine H.} and Lammer, {Edward J.} and Aylsworth, {Arthur S.} and Ardinger, {Holly H.} and Lidral, {Andrew C.} and Pober, {Barbara R.} and Lina Moreno and Mauricio Arcos-Burgos and Consuelo Valencia and Claude Houdayer and Michel Bahuau and Danilo Moretti-Ferreira and Antonio Richieri-Costa and Dixon, {Michael J.} and Murray, {Jeffrey C.}",

year = "2002",

month = oct,

day = "1",

doi = "10.1038/ng985",

language = "English",

volume = "32",

pages = "285--289",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Springer Nature",

number = "2",

}

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 2002, 'Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes', Nature Genetics, vol. 32, no. 2, pp. 285-289. https://doi.org/10.1038/ng985

Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. / Kondo, Shinji; Schutte, Brian C.; Richardson, Rebecca J. et al.
In: Nature Genetics, Vol. 32, No. 2, 01.10.2002, p. 285-289.

Research output: Contribution to journalArticlepeer-review

TY - JOUR

T1 - Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes

AU - Kondo, Shinji

AU - Schutte, Brian C.

AU - Richardson, Rebecca J.

AU - Bjork, Bryan C.

AU - Knight, Alexandra S.

AU - Watanabe, Yoriko

AU - Howard, Emma

AU - de Lima, Renata L L Ferreira

AU - Daack-Hirsch, Sandra

AU - Sander, Achim

AU - McDonald-McGinn, Donna M.

AU - Zackai, Elaine H.

AU - Lammer, Edward J.

AU - Aylsworth, Arthur S.

AU - Ardinger, Holly H.

AU - Lidral, Andrew C.

AU - Pober, Barbara R.

AU - Moreno, Lina

AU - Arcos-Burgos, Mauricio

AU - Valencia, Consuelo

AU - Houdayer, Claude

AU - Bahuau, Michel

AU - Moretti-Ferreira, Danilo

AU - Richieri-Costa, Antonio

AU - Dixon, Michael J.

AU - Murray, Jeffrey C.

PY - 2002/10/1

Y1 - 2002/10/1

N2 - 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-α and -β after viral infection1, 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 pits4, 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 anomalies5. Phenotypic overlap6 and linkage data7 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.

AB - 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-α and -β after viral infection1, 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 pits4, 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 anomalies5. Phenotypic overlap6 and linkage data7 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.

U2 - 10.1038/ng985

DO - 10.1038/ng985

M3 - Article

C2 - 12219090

SN - 1061-4036

VL - 32

SP - 285

EP - 289

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

Kondo S, Schutte BC, Richardson RJ, Bjork BC, Knight AS, Watanabe Y et al. Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nature Genetics. 2002 Oct 1;32(2):285-289. doi: 10.1038/ng985

Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes (2024)
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