C14ORF179 encoding IFT43 is mutated in Sensenbrenner syndrome

Arts, Heleen H.; Bongers, Ernie M.H.F.; Mans, Dorus A.; Beersum, Sylvia E. C. van; Oud, Machteld M.; Bolat, Emine; Spruijt, Liesbeth; Cornelissen, Elisabeth A.M.; Schuurs-Hoeijmakers, Janneke; Leeuw, Nicole de; Cormier‐Daire, Valérie; Brunner, Han G.; Knoers, Nine V A M; Roepman, Ronald

doi:10.1136/jmg.2011.088864

Cited by 129 publications

(131 citation statements)

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“…Clinical manifestations of Sensenbrenner syndrome are highly variable and may differ between and within families [Gilissen et al, 2010;Walczak-Sztulpa et al, 2010;Arts et al, 2011;Bredrup et al, 2011;Bacino et al, 2012;Hoffer et al, 2013]. The phenotypes resulting from biallelic mutations in any one of the four known genes (i.e., IFT122, WDR35, IFT43, or WDR19) are not distinguishable [Walczak-Sztulpa et al, 2010;Arts et al, 2011;Bredrup et al, 2011;Bacino et al, 2012;Hoffer et al, 2013].…”

Section: Genotype-phenotype Analysismentioning

confidence: 99%

“…The phenotypes resulting from biallelic mutations in any one of the four known genes (i.e., IFT122, WDR35, IFT43, or WDR19) are not distinguishable [Walczak-Sztulpa et al, 2010;Arts et al, 2011;Bredrup et al, 2011;Bacino et al, 2012;Hoffer et al, 2013]. Reports published to date involve too few affected individuals to extract reliable insights into genotype-phenotype correlations.…”

Section: Genotype-phenotype Analysismentioning

confidence: 99%

“…Because of the skeletal and ectodermal anomalies, it has been referred to as cranioectodermal dysplasia (CED) [Gellis and Feingold, 1979;Savill et al, 1997;Tamai et al, 2002;Obikane et al, 2006;Fry et al, 2009;Konstantinidou et al, 2009], but for this study, we use the eponym Sensenbrenner syndrome. There is significant phenotypic variability and dramatic advances using microarray analysis and targeted-and whole-exome sequencing (WES) have demonstrated molecular heterogeneity [Gilissen et al, 2010;Walczak-Sztulpa et al, 2010;Arts et al, 2011;Bredrup et al, 2011;Hoffer et al, 2013], and showed that this syndrome is probably due to cilia dysfunction [Baker and Beales, 2009;Konstantinidou et al, 2009;Walczak-Sztulpa et al, 2010;Hildebrandt et al, 2011]. OMIM currently lists four molecular subtypes as CED1 (#218330, chr 3q221.3-q22.1, IFT122), CED2 (#613610, chr 2p24.1, WDR35), CED3 (#614099, chr 14q24.3, IFT43), and CED4 (#614378, chr 4p14, WDR19).…”

Section: Introductionmentioning

confidence: 99%

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Sensenbrenner syndrome (Cranioectodermal dysplasia): Clinical and molecular analyses of 39 patients including two new patients

Lin

Traum

Sahai

et al. 2013

American J of Med Genetics Pt A

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Sensenbrenner syndrome, also known as cranioectodermal dysplasia, is a rare multiple anomaly syndrome with distinctive craniofacial appearance, skeletal, ectodermal, connective tissue, renal, and liver anomalies. Dramatic advances with next‐generation sequencing have expanded its phenotypic variability and molecular heterogeneity. We review 39 patients including two new patients, one with compound heterozygous novel mutations in WDR35 and a previously unreported multisutural craniosynostosis that may be a part of Sensenbrenner syndrome. In 14 of 25 (56.0%) patients pathogenic mutations have been identified in 4 different genes that regulate (intraflagellar) cilia transport. We compared Sensenbrenner syndrome to asphyxiating thoracic dystrophy‐Jeune syndrome (ATD‐JS) and other ciliopathies. Our analyses showed that the high anterior hairline, forehead bossing and dolichocephaly (accompanied by sagittal craniosynostosis in more than half of the patients) occur in almost all patients with Sensenbrenner syndrome. Metaphyseal dysplasia with narrow thorax, proximal limb shortness, and short fingers are typical of Sensenbrenner syndrome and ATD‐JS. Respiratory complications have been reported in both syndromes, usually less severe with Sensenbrenner syndrome. Proposed diagnostic criteria for Sensenbrenner syndrome include the distinctive craniofacial appearance, ubiquitous brachydactyly and ectodermal anomalies, and sagittal craniosynostosis. Mild heart defects have been noted, but there have been no atrioventricular canal or heterotaxy defects that are common in Ellis‐Van Creveld syndrome. We anticipate that the steady identification of molecularly defined patients may allow correlation of phenotype and genotype. Additional natural history data will improve genetic counseling and current guidelines. © 2013 Wiley Periodicals, Inc.

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Section: Genotype-phenotype Analysismentioning

confidence: 99%

Section: Genotype-phenotype Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Sensenbrenner syndrome (Cranioectodermal dysplasia): Clinical and molecular analyses of 39 patients including two new patients

Lin

Traum

Sahai

et al. 2013

American J of Med Genetics Pt A

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“…Mutations in genes encoding IFT-A components cause ciliopathies characterized by skeletal abnormalities, renal malformations, and retinal degeneration. In humans, mutations in IFT122 (associated with Sensenbrenner syndrome) (9), WDR35/IFT121 (associated with Sensenbrenner and short-rib polydactyly syndromes) (10,11), TTC21B/IFT139 (associated with Jeune syndrome and nephronophthisis) (12), IFT43 (associated with Sensenbrenner syndrome) (13), and WDR19/IFT144 (associated with Sensenbrenner syndrome) (14) produce ciliopathies. Several studies have reported retinal abnormalities in these patients (12,14).…”

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confidence: 99%

Loss of ift122, a Retrograde Intraflagellar Transport (IFT) Complex Component, Leads to Slow, Progressive Photoreceptor Degeneration Due to Inefficient Opsin Transport

Boubakri

Chaya

Hirata

et al. 2016

Journal of Biological Chemistry

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Edited by Velia FowlerIn the retina, aberrant opsin transport from cell bodies to outer segments leads to retinal degenerative diseases such as retinitis pigmentosa. Opsin transport is facilitated by the intraflagellar transport (IFT) system that mediates the bidirectional movement of proteins within cilia. In contrast to functions of the anterograde transport executed by IFT complex B (IFT-B), the precise functions of the retrograde transport mediated by IFT complex A (IFT-A) have not been well studied in photoreceptor cilia. Here, we analyzed developing zebrafish larvae carrying a null mutation in ift122 encoding a component of IFT-A. ift122 mutant larvae show unexpectedly mild phenotypes, compared with those of mutants defective in IFT-B. ift122 mutants exhibit a slow onset of progressive photoreceptor degeneration mainly after 7 days post-fertilization. ift122 mutant larvae also develop cystic kidney but not curly body, both of which are typically observed in various ciliary mutants. ift122 mutants display a loss of cilia in the inner ear hair cells and nasal pit epithelia. Loss of ift122 causes disorganization of outer segment discs. Ectopic accumulation of an IFT-B component, ift88, is observed in the ift122 mutant photoreceptor cilia. In addition, pulsechase experiments using GFP-opsin fusion proteins revealed that ift122 is required for the efficient transport of opsin and the distal elongation of outer segments. These results show that IFT-A is essential for the efficient transport of outer segment proteins, including opsin, and for the survival of retinal photoreceptor cells, rendering the ift122 mutant a unique model for human retinal degenerative diseases.

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“…In Ift122 zebrafish morphants, pronephric cysts were observed 32 ; in contrast, Ift140 morphants showed no apparent ciliary or sensory neuron defects. 33 Missense mutations in IFT-A proteins have been described in patients with cranioectodermal dysplasia/Sensenbrenner's syndrome, 31,32,34,35 a ciliopathy associated with extensive craniofacial, skeletal, heart, liver, and ectodermal abnormalities. Some cranioectodermal dysplasia patients exhibit renal disease characterized by extensive glomerular sclerosis, renal cysts, interstitial fibrosis with focal inflammatory cell infiltration, scattered tubular atrophy, and chronic renal failure.…”

mentioning

confidence: 99%

Disruption of IFT Complex A Causes Cystic Kidneys without Mitotic Spindle Misorientation

Jonassen¹,

SanAgustin

Baker

et al. 2012

Journal of the American Society of Nephrology

106

110

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Intraflagellar transport (IFT) complexes A and B build and maintain primary cilia. In the mouse, kidneyspecific or hypomorphic mutant alleles of IFT complex B genes cause polycystic kidneys, but the influence of IFT complex A proteins on renal development is not well understood. In the present study, we found that HoxB7-Cre-driven deletion of the complex A gene Ift140 from collecting ducts disrupted, but did not completely prevent, cilia assembly. Mutant kidneys developed collecting duct cysts by postnatal day 5, with rapid cystic expansion and renal dysfunction by day 15 and little remaining parenchymal tissue by day 20. In contrast to many models of polycystic kidney disease, precystic Ift140-deleted collecting ducts showed normal centrosomal positioning and no misorientation of the mitotic spindle axis, suggesting that disruption of oriented cell division is not a prerequisite to cyst formation in these kidneys. Precystic collecting ducts had an increased mitotic index, suggesting that cell proliferation may drive cyst expansion even with normal orientation of the mitotic spindle. In addition, we observed significant increases in expression of canonical Wnt pathway genes and mediators of Hedgehog and tissue fibrosis in highly cystic, but not precystic, kidneys. Taken together, these studies indicate that loss of Ift140 causes pronounced renal cystic disease and suggest that abnormalities in several different pathways may influence cyst progression.

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C14ORF179 encoding IFT43 is mutated in Sensenbrenner syndrome

Abstract: Background

Cited by 129 publications

References 31 publications

Sensenbrenner syndrome (Cranioectodermal dysplasia): Clinical and molecular analyses of 39 patients including two new patients

Sensenbrenner syndrome (Cranioectodermal dysplasia): Clinical and molecular analyses of 39 patients including two new patients

Loss of ift122, a Retrograde Intraflagellar Transport (IFT) Complex Component, Leads to Slow, Progressive Photoreceptor Degeneration Due to Inefficient Opsin Transport

Disruption of IFT Complex A Causes Cystic Kidneys without Mitotic Spindle Misorientation

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