Inactivation of IL11 signaling causes craniosynostosis, delayed tooth eruption, and supernumerary teeth

Pekka Nieminen; Neil V Morgan; Aimée L Fenwick; Satu Parmanen; Lotta Veistinen; Marja L Mikkola; Peter J van der Spek; Andrew Giraud; Louise Judd; Sirpa Arte; Louise A Brueton; Steven A Wall; Irene M J Mathijssen; Eamonn R Maher; Andrew O M Wilkie; Sven Kreiborg; Irma Thesleff

doi:10.1016/j.ajhg.2011.05.024

Inactivation of IL11 signaling causes craniosynostosis, delayed tooth eruption, and supernumerary teeth

Pekka Nieminen, Neil V Morgan, Aimée L Fenwick, Satu Parmanen, Lotta Veistinen, Marja L Mikkola, Peter J van der Spek, Andrew Giraud, Louise Judd, Sirpa Arte, Louise A Brueton, Steven A Wall, Irene M J Mathijssen, Eamonn R Maher, Andrew O M Wilkie, Sven Kreiborg, Irma Thesleff

101 Citations (Scopus)

Abstract

Craniosynostosis and supernumerary teeth most often occur as isolated developmental anomalies, but they are also separately manifested in several malformation syndromes. Here, we describe a human syndrome featuring craniosynostosis, maxillary hypoplasia, delayed tooth eruption, and supernumerary teeth. We performed homozygosity mapping in three unrelated consanguineous Pakistani families and localized the syndrome to a region in chromosome 9. Mutational analysis of candidate genes in the region revealed that all affected children harbored homozygous missense mutations (c.662C>G [p.Pro221Arg], c.734C>G [p.Ser245Cys], or c.886C>T [p.Arg296Trp]) in IL11RA (encoding interleukin 11 receptor, alpha) on chromosome 9p13.3. In addition, a homozygous nonsense mutation, c.475C>T (p.Gln159X), and a homozygous duplication, c.916_924dup (p.Thr306_Ser308dup), were observed in two north European families. In cell-transfection experiments, the p.Arg296Trp mutation rendered the receptor unable to mediate the IL11 signal, indicating that the mutation causes loss of IL11RA function. We also observed disturbed cranial growth and suture activity in the Il11ra null mutant mice, in which reduced size and remodeling of limb bones has been previously described. We conclude that IL11 signaling is essential for the normal development of craniofacial bones and teeth and that its function is to restrict suture fusion and tooth number. The results open up the possibility of modulation of IL11 signaling for the treatment of craniosynostosis.

Original language	English
Journal	American Journal of Human Genetics
Volume	89
Issue number	1
Pages (from-to)	67-81
Number of pages	15
ISSN	0002-9297
DOIs	https://doi.org/10.1016/j.ajhg.2011.05.024
Publication status	Published - 15 Jul 2011

Keywords

Animals
Cell Line
Child
Child, Preschool
Chromosome Mapping
Codon, Nonsense
Computational Biology
Craniosynostoses
DNA Mutational Analysis
Down-Regulation
Female
Gene Expression Regulation, Developmental
Humans
Interleukin-11
Male
Mice
Mice, Inbred C57BL
Pedigree
Signal Transduction
Tooth Eruption
Tooth, Supernumerary
Transcription Factors

Access to Document

10.1016/j.ajhg.2011.05.024

Cite this

Nieminen, P., Morgan, N. V., Fenwick, A. L., Parmanen, S., Veistinen, L., Mikkola, M. L., van der Spek, P. J., Giraud, A., Judd, L., Arte, S., Brueton, L. A., Wall, S. A., Mathijssen, I. M. J., Maher, E. R., Wilkie, A. O. M., Kreiborg, S., & Thesleff, I. (2011). Inactivation of IL11 signaling causes craniosynostosis, delayed tooth eruption, and supernumerary teeth. American Journal of Human Genetics, 89(1), 67-81. https://doi.org/10.1016/j.ajhg.2011.05.024

Nieminen, P, Morgan, NV, Fenwick, AL, Parmanen, S, Veistinen, L, Mikkola, ML, van der Spek, PJ, Giraud, A, Judd, L, Arte, S, Brueton, LA, Wall, SA, Mathijssen, IMJ, Maher, ER, Wilkie, AOM, Kreiborg, S & Thesleff, I 2011, 'Inactivation of IL11 signaling causes craniosynostosis, delayed tooth eruption, and supernumerary teeth', American Journal of Human Genetics, vol. 89, no. 1, pp. 67-81. https://doi.org/10.1016/j.ajhg.2011.05.024

@article{3cb8c1a113ae457f80d47f169e20aada,

title = "Inactivation of IL11 signaling causes craniosynostosis, delayed tooth eruption, and supernumerary teeth",

abstract = "Craniosynostosis and supernumerary teeth most often occur as isolated developmental anomalies, but they are also separately manifested in several malformation syndromes. Here, we describe a human syndrome featuring craniosynostosis, maxillary hypoplasia, delayed tooth eruption, and supernumerary teeth. We performed homozygosity mapping in three unrelated consanguineous Pakistani families and localized the syndrome to a region in chromosome 9. Mutational analysis of candidate genes in the region revealed that all affected children harbored homozygous missense mutations (c.662C>G [p.Pro221Arg], c.734C>G [p.Ser245Cys], or c.886C>T [p.Arg296Trp]) in IL11RA (encoding interleukin 11 receptor, alpha) on chromosome 9p13.3. In addition, a homozygous nonsense mutation, c.475C>T (p.Gln159X), and a homozygous duplication, c.916_924dup (p.Thr306_Ser308dup), were observed in two north European families. In cell-transfection experiments, the p.Arg296Trp mutation rendered the receptor unable to mediate the IL11 signal, indicating that the mutation causes loss of IL11RA function. We also observed disturbed cranial growth and suture activity in the Il11ra null mutant mice, in which reduced size and remodeling of limb bones has been previously described. We conclude that IL11 signaling is essential for the normal development of craniofacial bones and teeth and that its function is to restrict suture fusion and tooth number. The results open up the possibility of modulation of IL11 signaling for the treatment of craniosynostosis.",

keywords = "Animals, Cell Line, Child, Child, Preschool, Chromosome Mapping, Codon, Nonsense, Computational Biology, Craniosynostoses, DNA Mutational Analysis, Down-Regulation, Female, Gene Expression Regulation, Developmental, Humans, Interleukin-11, Male, Mice, Mice, Inbred C57BL, Pedigree, Signal Transduction, Tooth Eruption, Tooth, Supernumerary, Transcription Factors",

author = "Pekka Nieminen and Morgan, {Neil V} and Fenwick, {Aim{\'e}e L} and Satu Parmanen and Lotta Veistinen and Mikkola, {Marja L} and {van der Spek}, {Peter J} and Andrew Giraud and Louise Judd and Sirpa Arte and Brueton, {Louise A} and Wall, {Steven A} and Mathijssen, {Irene M J} and Maher, {Eamonn R} and Wilkie, {Andrew O M} and Sven Kreiborg and Irma Thesleff",

year = "2011",

month = jul,

day = "15",

doi = "10.1016/j.ajhg.2011.05.024",

language = "English",

volume = "89",

pages = "67--81",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "1",

}

TY - JOUR

T1 - Inactivation of IL11 signaling causes craniosynostosis, delayed tooth eruption, and supernumerary teeth

AU - Nieminen, Pekka

AU - Morgan, Neil V

AU - Fenwick, Aimée L

AU - Parmanen, Satu

AU - Veistinen, Lotta

AU - Mikkola, Marja L

AU - van der Spek, Peter J

AU - Giraud, Andrew

AU - Judd, Louise

AU - Arte, Sirpa

AU - Brueton, Louise A

AU - Wall, Steven A

AU - Mathijssen, Irene M J

AU - Maher, Eamonn R

AU - Wilkie, Andrew O M

AU - Kreiborg, Sven

AU - Thesleff, Irma

PY - 2011/7/15

Y1 - 2011/7/15

N2 - Craniosynostosis and supernumerary teeth most often occur as isolated developmental anomalies, but they are also separately manifested in several malformation syndromes. Here, we describe a human syndrome featuring craniosynostosis, maxillary hypoplasia, delayed tooth eruption, and supernumerary teeth. We performed homozygosity mapping in three unrelated consanguineous Pakistani families and localized the syndrome to a region in chromosome 9. Mutational analysis of candidate genes in the region revealed that all affected children harbored homozygous missense mutations (c.662C>G [p.Pro221Arg], c.734C>G [p.Ser245Cys], or c.886C>T [p.Arg296Trp]) in IL11RA (encoding interleukin 11 receptor, alpha) on chromosome 9p13.3. In addition, a homozygous nonsense mutation, c.475C>T (p.Gln159X), and a homozygous duplication, c.916_924dup (p.Thr306_Ser308dup), were observed in two north European families. In cell-transfection experiments, the p.Arg296Trp mutation rendered the receptor unable to mediate the IL11 signal, indicating that the mutation causes loss of IL11RA function. We also observed disturbed cranial growth and suture activity in the Il11ra null mutant mice, in which reduced size and remodeling of limb bones has been previously described. We conclude that IL11 signaling is essential for the normal development of craniofacial bones and teeth and that its function is to restrict suture fusion and tooth number. The results open up the possibility of modulation of IL11 signaling for the treatment of craniosynostosis.

AB - Craniosynostosis and supernumerary teeth most often occur as isolated developmental anomalies, but they are also separately manifested in several malformation syndromes. Here, we describe a human syndrome featuring craniosynostosis, maxillary hypoplasia, delayed tooth eruption, and supernumerary teeth. We performed homozygosity mapping in three unrelated consanguineous Pakistani families and localized the syndrome to a region in chromosome 9. Mutational analysis of candidate genes in the region revealed that all affected children harbored homozygous missense mutations (c.662C>G [p.Pro221Arg], c.734C>G [p.Ser245Cys], or c.886C>T [p.Arg296Trp]) in IL11RA (encoding interleukin 11 receptor, alpha) on chromosome 9p13.3. In addition, a homozygous nonsense mutation, c.475C>T (p.Gln159X), and a homozygous duplication, c.916_924dup (p.Thr306_Ser308dup), were observed in two north European families. In cell-transfection experiments, the p.Arg296Trp mutation rendered the receptor unable to mediate the IL11 signal, indicating that the mutation causes loss of IL11RA function. We also observed disturbed cranial growth and suture activity in the Il11ra null mutant mice, in which reduced size and remodeling of limb bones has been previously described. We conclude that IL11 signaling is essential for the normal development of craniofacial bones and teeth and that its function is to restrict suture fusion and tooth number. The results open up the possibility of modulation of IL11 signaling for the treatment of craniosynostosis.

KW - Animals

KW - Cell Line

KW - Child

KW - Child, Preschool

KW - Chromosome Mapping

KW - Codon, Nonsense

KW - Computational Biology

KW - Craniosynostoses

KW - DNA Mutational Analysis

KW - Down-Regulation

KW - Female

KW - Gene Expression Regulation, Developmental

KW - Humans

KW - Interleukin-11

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Pedigree

KW - Signal Transduction

KW - Tooth Eruption

KW - Tooth, Supernumerary

KW - Transcription Factors

U2 - 10.1016/j.ajhg.2011.05.024

DO - 10.1016/j.ajhg.2011.05.024

M3 - Journal article

C2 - 21741611

SN - 0002-9297

VL - 89

SP - 67

EP - 81

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 1

ER -

Inactivation of IL11 signaling causes craniosynostosis, delayed tooth eruption, and supernumerary teeth

Abstract

Keywords

Access to Document

Fingerprint

Cite this