C14ORF179 encoding IFT43 is mutated in Sensenbrenner syndrome
| Autor: | Dorus A. Mans, Liesbeth Spruijt, Emine Bolat, Nicole de Leeuw, Janneke H M Schuurs-Hoeijmakers, Machteld M. Oud, Sylvia E. C. van Beersum, Han G. Brunner, Elisabeth A.M. Cornelissen, Valérie Cormier-Daire, Heleen H. Arts, Ronald Roepman, Ernie M.H.F. Bongers, Nine V A M Knoers |
|---|---|
| Přispěvatelé: | Department of human genetics, Radboud University Medical Center [Nijmegen] - Nijmegen Centre for Molecular Life Sciences - Institute for Genetic and Metabolic Disorders, CHU Necker - Enfants Malades [AP-HP], University Medical Center Utrecht, Radboud University Medical Center [Nijmegen]-Nijmegen Centre for Molecular Life Sciences-Institute for Genetic and Metabolic Disorders, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University Medical Center [Utrecht] |
| Rok vydání: | 2011 |
| Předmět: |
Male
Carrier Proteins/genetics Genetics and epigenetic pathways of disease [NCMLS 6] Calcium and bone medicine.disease_cause Craniofacial Abnormalities Ectodermal Dysplasia Fibroblasts/physiology Recombinant Proteins/genetics Molecular genetics Ciliary tip Child Genetics (clinical) Renal disorder [IGMD 9] Netherlands Oligonucleotide Array Sequence Analysis 0303 health sciences Mutation Renal Medicine Cilium 030305 genetics & heredity Single Nucleotide Syndrome Recombinant Proteins Transport protein Sensenbrenner syndrome Morocco Protein Transport Flagella Morocco/ethnology Cell biology Protein subunit Molecular Sequence Data Netherlands/epidemiology Biology Transfection Polymorphism Single Nucleotide 03 medical and health sciences Cilia/genetics Intraflagellar transport Genetics medicine Animals Humans Clinical genetics Cilia Polymorphism 030304 developmental biology Hereditary cancer and cancer-related syndromes [ONCOL 1] Base Sequence Siblings Craniofacial Abnormalities/ethnology Protein Transport/genetics Fibroblasts medicine.disease Ectodermal Dysplasia/ethnology Molecular biology Flagella/genetics Ciliopathy HEK293 Cells Genetics and epigenetic pathways of disease Renal disorder [NCMLS 6] sense organs Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6] Carrier Proteins |
| Zdroj: | Journal of Medical Genetics, 48, 6, pp. 390-5 Journal of Medical Genetics Journal of Medical Genetics, BMJ Publishing Group, 2011, 48 (6), pp.390. 〈10.1136/jmg.2011.088864〉 Journal of Medical Genetics, BMJ Publishing Group, 2011, 48 (6), pp.390. ⟨10.1136/jmg.2011.088864⟩ Journal of Medical Genetics; Vol 48 JOURNAL OF MEDICAL GENETICS, 48(6), 390-395. BMJ PUBLISHING GROUP Journal of Medical Genetics, 48, 390-5 |
| ISSN: | 1468-6244 0022-2593 |
| Popis: | Contains fulltext : 95685.pdf (Publisher’s version ) (Closed access) BACKGROUND: Sensenbrenner syndrome is a heterogeneous ciliopathy that is characterised by skeletal and ectodermal anomalies, accompanied by chronic renal failure, heart defects, liver fibrosis and other features. OBJECTIVE: To identify an additional causative gene in Sensenbrenner syndrome. METHODS: Single nucleotide polymorphism array analysis and standard sequencing techniques were applied to identify the causative gene. The effect of the identified mutation on protein translation was determined by western blot analysis. Antibodies against intraflagellar transport (IFT) proteins were used in ciliated fibroblast cell lines to investigate the molecular consequences of the mutation on ciliary transport. RESULTS: Homozygosity mapping and positional candidate gene sequence analysis were performed in two siblings with Sensenbrenner syndrome of a consanguineous Moroccan family. In both siblings, a homozygous mutation in the initiation codon of C14ORF179 was identified. C14ORF179 encodes IFT43, a subunit of the IFT complex A (IFT-A) machinery of primary cilia. Western blots showed that the mutation disturbs translation of IFT43, inducing the initiation of translation of a shorter protein product from a downstream ATG. The IFT-A protein complex is implicated in retrograde ciliary transport along axonemal microtubules. It was shown that in fibroblasts of one of the siblings affected by Sensenbrenner syndrome, disruption of IFT43 disturbs this transport from the ciliary tip to its base. As anterograde transport in the opposite direction apparently remains functional, the IFT complex B proteins accumulate in the ciliary tip. Interestingly, similar results were obtained using fibroblasts from a patient with Sensenbrenner syndrome with mutations in WDR35/IFT121, encoding another IFT-A subunit. CONCLUSIONS: The results indicate that Sensenbrenner syndrome is caused by disrupted IFT-A-mediated retrograde ciliary transport. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|