Cranioectodermal Dysplasia, Sensenbrenner Syndrome, Is a Ciliopathy Caused by Mutations in the IFT122 Gene

Joanna Walczak-Sztulpa, Jonathan Eggenschwiler, Daniel Osborn, Desmond A. Brown, Francesco Emma, Claus Klingenberg, Raoul C. Hennekam, Giuliano Torre, Masoud Garshasbi, Andreas Tzschach, Malgorzata Szczepanska, Marian Krawczynski, Jacek Zachwieja, Danuta Zwolinska, Philip L. Beales, Hans Hilger Ropers, Anna Latos-Bielenska, Andreas W. Kuss

Research output: Contribution to journalArticle

118 Citations (Scopus)

Abstract

Cranioectodermal dysplasia (CED) is a disorder characterized by craniofacial, skeletal, and ectodermal abnormalities. Most cases reported to date are sporadic, but a few familial cases support an autosomal-recessive inheritance pattern. Aiming at the elucidation of the genetic basis of CED, we collected 13 patients with CED symptoms from 12 independent families. In one family with consanguineous parents two siblings were affected, permitting linkage analysis and homozygosity mapping. This revealed a single region of homozygosity with a significant LOD score (3.57) on chromosome 3q21-3q24. By sequencing candidate genes from this interval we found a homozygous missense mutation in the IFT122 (WDR10) gene that cosegregated with the disease. Examination of IFT122 in our patient cohort revealed one additional homozygous missense change in the patient from a second consanguineous family. In addition, we found compound heterozygosity for a donor splice-site change and a missense change in one sporadic patient. All mutations were absent in 340 control chromosomes. Because IFT122 plays an important role in the assembly and maintenance of eukaryotic cilia, we investigated patient fibroblasts and found significantly reduced frequency and length of primary cilia as compared to controls. Furthermore, we transiently knocked down ift122 in zebrafish embryos and observed the typical phenotype found in other models of ciliopathies. Because not all of our patients harbored mutations in IFT122, CED seems to be genetically heterogeneous. Still, by identifying CED as a ciliary disorder, our study suggests that the causative mutations in the unresolved cases most likely affect primary cilia function too.

Original languageEnglish
Pages (from-to)949-956
Number of pages8
JournalAmerican Journal of Human Genetics
Volume86
Issue number6
DOIs
Publication statusPublished - Jul 11 2010

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Mutation
Cilia
Genes
Chromosomes
Inheritance Patterns
RNA Splice Sites
Zebrafish
Missense Mutation
Cranioectodermal Dysplasia
Ciliopathies
Siblings
Embryonic Structures
Fibroblasts
Parents
Maintenance
Phenotype

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Cranioectodermal Dysplasia, Sensenbrenner Syndrome, Is a Ciliopathy Caused by Mutations in the IFT122 Gene. / Walczak-Sztulpa, Joanna; Eggenschwiler, Jonathan; Osborn, Daniel; Brown, Desmond A.; Emma, Francesco; Klingenberg, Claus; Hennekam, Raoul C.; Torre, Giuliano; Garshasbi, Masoud; Tzschach, Andreas; Szczepanska, Malgorzata; Krawczynski, Marian; Zachwieja, Jacek; Zwolinska, Danuta; Beales, Philip L.; Ropers, Hans Hilger; Latos-Bielenska, Anna; Kuss, Andreas W.

In: American Journal of Human Genetics, Vol. 86, No. 6, 11.07.2010, p. 949-956.

Research output: Contribution to journalArticle

Walczak-Sztulpa, J, Eggenschwiler, J, Osborn, D, Brown, DA, Emma, F, Klingenberg, C, Hennekam, RC, Torre, G, Garshasbi, M, Tzschach, A, Szczepanska, M, Krawczynski, M, Zachwieja, J, Zwolinska, D, Beales, PL, Ropers, HH, Latos-Bielenska, A & Kuss, AW 2010, 'Cranioectodermal Dysplasia, Sensenbrenner Syndrome, Is a Ciliopathy Caused by Mutations in the IFT122 Gene', American Journal of Human Genetics, vol. 86, no. 6, pp. 949-956. https://doi.org/10.1016/j.ajhg.2010.04.012
Walczak-Sztulpa, Joanna ; Eggenschwiler, Jonathan ; Osborn, Daniel ; Brown, Desmond A. ; Emma, Francesco ; Klingenberg, Claus ; Hennekam, Raoul C. ; Torre, Giuliano ; Garshasbi, Masoud ; Tzschach, Andreas ; Szczepanska, Malgorzata ; Krawczynski, Marian ; Zachwieja, Jacek ; Zwolinska, Danuta ; Beales, Philip L. ; Ropers, Hans Hilger ; Latos-Bielenska, Anna ; Kuss, Andreas W. / Cranioectodermal Dysplasia, Sensenbrenner Syndrome, Is a Ciliopathy Caused by Mutations in the IFT122 Gene. In: American Journal of Human Genetics. 2010 ; Vol. 86, No. 6. pp. 949-956.
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AU - Osborn, Daniel

AU - Brown, Desmond A.

AU - Emma, Francesco

AU - Klingenberg, Claus

AU - Hennekam, Raoul C.

AU - Torre, Giuliano

AU - Garshasbi, Masoud

AU - Tzschach, Andreas

AU - Szczepanska, Malgorzata

AU - Krawczynski, Marian

AU - Zachwieja, Jacek

AU - Zwolinska, Danuta

AU - Beales, Philip L.

AU - Ropers, Hans Hilger

AU - Latos-Bielenska, Anna

AU - Kuss, Andreas W.

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