Mutations in the interleukin receptor IL11RA cause autosomal recessive Crouzon-like craniosynostosis.
We have characterized a novel autosomal recessive Crouzon-like craniosynostosis syndrome in a 12-affected member family from Antakya, Turkey, the presenting features of which include: multiple suture synostosis, midface hypoplasia, variable degree of exophthalmos, relative prognathism, a beaked nose, and conductive hearing loss. Homozygosity mapping followed by targeted next-generation sequencing identified a c.479+6T>G mutation in the interleukin 11 receptor alpha gene (IL11RA) on chromosome 9p21. This donor splice-site mutation leads to a high percentage of aberrant IL11RA mRNA transcripts in an affected individual and altered mRNA splicing determined by in vitro exon trapping. An extended IL11RA mutation screen was performed in a cohort of 79 patients with an initial clinical diagnosis of Crouzon syndrome, pansynostosis, or unclassified syndromic craniosynostosis. We identified mutations segregating with the disease in five families: a German patient of Turkish origin and a Turkish family with three affected sibs all of whom were homozygous for the previously identified IL11RA c.479+6T>G mutation; a family with pansynostosis with compound heterozygous missense mutations, p.Pro200Thr and p.Arg237Pro; and two further Turkish families with Crouzon-like syndrome carrying the homozygous nonsense mutations p.Tyr232* and p.Arg292*. Using transient coexpression in HEK293T and COS7 cells, we demonstrated dramatically reduced IL11-mediated STAT3 phosphorylation for all mutations. Immunofluorescence analysis of mouse Il11ra demonstrated specific protein expression in cranial mesenchyme which was localized around the coronal suture tips and in the lambdoidal suture. In situ hybridization analysis of adult zebrafish also detected zfil11ra expression in the coronal suture between the overlapping frontal and parietal plates. This study demonstrates that mutations in the IL11RA gene cause an autosomal recessive Crouzon-like craniosynostosis.
Center for Molecular Medicine Cologne (CMMC), University of Cologne 50931, Cologne, Germany ; Institute of Human Genetics, University of Cologne 50931, Cologne, Germany ; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne 50931, Cologne, Germany.
Katharina
K
Keupp
Center for Molecular Medicine Cologne (CMMC), University of Cologne 50931, Cologne, Germany ; Institute of Human Genetics, University of Cologne 50931, Cologne, Germany ; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne 50931, Cologne, Germany.
Yun
Y
Li
Department of Plastic and Reconstructive Surgery, Hacettepe University Medical Faculty 06100, Ankara, Turkey ; Department of Plastic and Reconstructive Surgery, Medical Faculty, Kirikkale University 71100, Kirikkale, Turkey.
Ibrahim
I
Vargel
Department of Human Genetics, Radboud University Nijmegen Medical Centre 6500HB, Nijmegen, The Netherlands.
Alexander
A
Hoischen
Department of Physiology and Pharmacology, University of Bristol BS8 1TD Bristol, U.K.
Rebecca
R
Richardson
Department of Human Genetics, Radboud University Nijmegen Medical Centre 6500HB, Nijmegen, The Netherlands.
Kornelia
K
Neveling
Department of Pediatrics, Pediatric Genetics Unit, Hacettepe University Medical Faculty 06100, Ankara, Turkey ; Department of Pediatrics, Pediatric Genetics Unit, Acibadem University 34457, İstanbul, Turkey.
Yasemin
Y
Alanay
Department of Medical Genetics, Gene Mapping Laboratory, Hacettepe University Medical Faculty 06100, Ankara, Turkey ; Department of Biology, Duzce University 81620, Duzce, Turkey.
Elif
E
Uz
Department of Pediatric Genetics, Marmara University Medical Faculty 34668, Istanbul, Turkey.
Nursel
N
Elcioğlu
Center for Molecular Medicine Cologne (CMMC), University of Cologne 50931, Cologne, Germany ; Institute of Human Genetics, University of Cologne 50931, Cologne, Germany.
Martin
M
Rachwalski
Department of Orthodontics, Hacettepe University Faculty of Dentistry 06100, Ankara, Turkey.
Soner
S
Kamaci
Department of Plastic and Reconstructive Surgery, Hacettepe University Medical Faculty 06100, Ankara, Turkey.
Gökhan
G
Tunçbilek
Department of Medical Genetics, Gene Mapping Laboratory, Hacettepe University Medical Faculty 06100, Ankara, Turkey.
Burcu
B
Akin
Medical Faculty, Institute of Biochemistry, University of Kiel 24118, Kiel, Germany.
Joachim
J
Grötzinger
Department of Plastic and Reconstructive Surgery, Hacettepe University Medical Faculty 06100, Ankara, Turkey.
Ersoy
E
Konas
Department of Plastic and Reconstructive Surgery, Hacettepe University Medical Faculty 06100, Ankara, Turkey.
Emin
E
Mavili
Medical Faculty, Institute of Biochemistry and Molecular Biology, RWTH Aachen University 52074, Aachen, Germany.
Gerhard
G
Müller-Newen
Department for Neurosurgery, Medical Faculty, University of Würzburg 97070, Würzburg, Germany.
Hartmut
H
Collmann
Department of Human Genetics, Radboud University Nijmegen Medical Centre 6500HB, Nijmegen, The Netherlands ; Department of Haematology and Genetics, South Eastern Area Laboratory Services 2031, Sydney, Australia.
Tony
T
Roscioli
Department of Human Genetics, Radboud University Nijmegen Medical Centre 6500HB, Nijmegen, The Netherlands ; Department of Haematology and Genetics, South Eastern Area Laboratory Services 2031, Sydney, Australia.
Michael F
MF
Buckley
Center for Molecular Medicine Cologne (CMMC), University of Cologne 50931, Cologne, Germany ; Institute of Human Genetics, University of Cologne 50931, Cologne, Germany ; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne 50931, Cologne, Germany.
Gökhan
G
Yigit
Department of Human Genetics, Radboud University Nijmegen Medical Centre 6500HB, Nijmegen, The Netherlands.
Christian
C
Gilissen
Medical Faculty, Institute of Human Genetics, University of Würzburg 97047, Würzburg, Germany.
Wolfram
W
Kress
Department of Human Genetics, Radboud University Nijmegen Medical Centre 6500HB, Nijmegen, The Netherlands.
Joris
J
Veltman
Center for Molecular Medicine Cologne (CMMC), University of Cologne 50931, Cologne, Germany ; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne 50931, Cologne, Germany ; Institute of Developmental Biology, University of Cologne 50674, Cologne, Germany.
Matthias
M
Hammerschmidt
Department of Medical Genetics, Gene Mapping Laboratory, Hacettepe University Medical Faculty 06100, Ankara, Turkey.
Nurten A
NA
Akarsu
Center for Molecular Medicine Cologne (CMMC), University of Cologne 50931, Cologne, Germany ; Institute of Human Genetics, University of Cologne 50931, Cologne, Germany ; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne 50931, Cologne, Germany.
Bernd
B
Wollnik
Autosomal recessive craniosynostosis; Crouzon; FGFR2; IL11RA; supernumerary teeth; tooth erruption