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Miriam Schmidts - One of the best experts on this subject based on the ideXlab platform.
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Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease
Orphanet Journal of Rare Diseases, 2020Co-Authors: Joanna Walczak-sztulpa, Miriam Schmidts, Heleen H. Arts, Machteld M. Oud, Renata Posmyk, Ewelina M. Bukowska-olech, Anna Wawrocka, Aleksander Jamsheer, Anna Latos-bielenska, Anna WasilewskaAbstract:Background Sensenbrenner syndrome, which is also known as cranioectodermal dysplasia (CED), is a rare, autosomal recessive ciliary chondrodysplasia characterized by a variety of clinical features including a distinctive craniofacial appearance as well as skeletal, ectodermal, liver and renal anomalies. Progressive renal disease can be life-threatening in this condition. CED is a genetically heterogeneous disorder. Currently, variants in any of six genes ( IFT122, WDR35, IFT140, IFT43, IFT52 and WDR19 ) have been associated with this syndrome. All of these genes encode proteins essential for intraflagellar transport (IFT) a process that is required for cilium assembly, maintenance and function. Intra- and interfamilial clinical variability has been reported in CED, which is consistent with CED’s genetic heterogeneity and is indicative of genetic background effects. Results Two male CED patients from two unrelated Polish families were included in this study. Clinical assessment revealed distinctive clinical features of Sensenbrenner syndrome, such as dolichocephaly, shortening of long bones and early onset renal failure. Ectodermal anomalies also included thin hair, short and thin nails, and small teeth in both patients. Next generation sequencing (NGS) techniques were performed in order to determine the underlying genetic cause of the disorder using whole exome sequencing (WES) for patient 1 and a custom NGS-based panel for patient 2. Subsequent qPCR and duplex PCR analysis were conducted for both patients. Genetic analyses identified compound heterozygous variants in the IFT140 gene in both affected individuals. Both patients harbored a tandem duplication variant p.Tyr1152_Thr1394dup on one allele. In addition, a novel missense variant, p.(Leu109Pro), and a previously described p.(Gly522Glu) variant were identified in the second allele in patients 1 and 2, respectively. Segregation analysis of the variants was consistent with the expected autosomal recessive disease inheritance pattern. Both patients had severe renal failure requiring kidney transplantation in early childhood. Conclusion The finding of compound heterozygous IFT140 mutations in two unrelated CED patients provide further evidence that IFT140 gene mutations are associated with this syndrome. Our studies confirm that IFT140 changes in patients with CED are associated with early onset end-stage renal disease. Moreover, this report expands our knowledge of the clinical- and molecular genetics of Sensenbrenner syndrome and it highlights the importance of multidisciplinary approaches in the care of CED patients.
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Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease
Orphanet Journal of Rare Diseases, 2020Co-Authors: Joanna Walczak-sztulpa, Miriam Schmidts, Heleen H. Arts, Machteld M. Oud, Renata Posmyk, Ewelina M. Bukowska-olech, Anna Wawrocka, Aleksander Jamsheer, Anna Latos-bielenska, Anna WasilewskaAbstract:Sensenbrenner syndrome, which is also known as cranioectodermal dysplasia (CED), is a rare, autosomal recessive ciliary chondrodysplasia characterized by a variety of clinical features including a distinctive craniofacial appearance as well as skeletal, ectodermal, liver and renal anomalies. Progressive renal disease can be life-threatening in this condition. CED is a genetically heterogeneous disorder. Currently, variants in any of six genes (IFT122, WDR35, IFT140, IFT43, IFT52 and WDR19) have been associated with this syndrome. All of these genes encode proteins essential for intraflagellar transport (IFT) a process that is required for cilium assembly, maintenance and function. Intra- and interfamilial clinical variability has been reported in CED, which is consistent with CED’s genetic heterogeneity and is indicative of genetic background effects. Two male CED patients from two unrelated Polish families were included in this study. Clinical assessment revealed distinctive clinical features of Sensenbrenner syndrome, such as dolichocephaly, shortening of long bones and early onset renal failure. Ectodermal anomalies also included thin hair, short and thin nails, and small teeth in both patients. Next generation sequencing (NGS) techniques were performed in order to determine the underlying genetic cause of the disorder using whole exome sequencing (WES) for patient 1 and a custom NGS-based panel for patient 2. Subsequent qPCR and duplex PCR analysis were conducted for both patients. Genetic analyses identified compound heterozygous variants in the IFT140 gene in both affected individuals. Both patients harbored a tandem duplication variant p.Tyr1152_Thr1394dup on one allele. In addition, a novel missense variant, p.(Leu109Pro), and a previously described p.(Gly522Glu) variant were identified in the second allele in patients 1 and 2, respectively. Segregation analysis of the variants was consistent with the expected autosomal recessive disease inheritance pattern. Both patients had severe renal failure requiring kidney transplantation in early childhood. The finding of compound heterozygous IFT140 mutations in two unrelated CED patients provide further evidence that IFT140 gene mutations are associated with this syndrome. Our studies confirm that IFT140 changes in patients with CED are associated with early onset end-stage renal disease. Moreover, this report expands our knowledge of the clinical- and molecular genetics of Sensenbrenner syndrome and it highlights the importance of multidisciplinary approaches in the care of CED patients.
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Cellular ciliary phenotyping indicates pathogenicity of novel variants in IFT140 and confirms a Mainzer–Saldino syndrome diagnosis
Cilia, 2018Co-Authors: Brooke L. Latour, Miriam Schmidts, Zeineb Bakey, Stef J. Letteboer, Dorien Lugtenberg, Ka Man Wu, Elisabeth A. M. Cornelissen, Helger G. Yntema, Ronald Roepman, Ernie M. H. F. BongersAbstract:Background Mainzer–Saldino syndrome (MZSDS) is a skeletal ciliopathy and part of the short-rib thoracic dysplasia (SRTD) group of ciliary disorders. The main characteristics of MZSDS are short limbs, mild narrow thorax, blindness, and renal failure. Thus far, variants in two genes are associated with MZSDS: IFT140, and IFT172 . In this study, we describe a 1-year-old girl presenting with mild skeletal abnormalities, Leber congenital amaurosis, and bilateral hearing difficulties. For establishing an accurate diagnosis, we combined clinical, molecular, and functional analyses. Methods We performed diagnostic whole-exome sequencing (WES) analysis to determine the genetic cause of the disease and analyzed two gene panels, containing all currently known genes in vision disorders, and in hearing impairment. Upon detection of the likely causative variants, ciliary phenotyping was performed in patient urine-derived renal epithelial cells (URECs) and rescue experiments were performed in CRISPR/Cas9-derived IFT140 knock out cells to determine the pathogenicity of the detected variants in vitro. Cilium morphology, cilium length, and intraflagellar transport (IFT) were evaluated by immunocytochemistry. Results Diagnostic WES revealed two novel compound heterozygous variants in IFT140 , encoding IFT140. Thorough investigation of WES data did not reveal any variants in candidate genes associated with hearing impairment. Patient-derived URECs revealed an accumulation of IFT-B protein IFT88 at the ciliary tip in 41% of the cells indicative of impaired retrograde IFT, while this was absent in cilia from control URECs. Furthermore, transfection of CRISPR/Cas9-derived IFT140 knock out cells with an IFT140 construct containing the patient mutation p.Tyr923Asp resulted in a significantly higher percentage of IFT88 tip accumulation than transfection with the wild-type IFT140 construct. Conclusions By combining the clinical, genetic, and functional data from this study, we could conclude that the patient has SRTD9, also called Mainzer–Saldino syndrome, caused by variants in IFT140 . We suggest the possibility that variants in IFT140 may underlie hearing impairment. Moreover, we show that urine provides an excellent source to obtain patient-derived cells in a non-invasive manner to study the pathogenicity of variants detected by genetic testing.
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Cellular ciliary phenotyping indicates pathogenicity of novel variants in IFT140 and confirms a Mainzer–Saldino syndrome diagnosis
Cilia, 2018Co-Authors: Machteld M. Oud, Miriam Schmidts, Brooke L. Latour, Zeineb Bakey, Stef J. Letteboer, Dorien Lugtenberg, Elisabeth A. M. Cornelissen, Helger G. Yntema, Ronald RoepmanAbstract:Background Mainzer–Saldino syndrome (MZSDS) is a skeletal ciliopathy and part of the short-rib thoracic dysplasia (SRTD) group of ciliary disorders. The main characteristics of MZSDS are short limbs, mild narrow thorax, blindness, and renal failure. Thus far, variants in two genes are associated with MZSDS: IFT140, and IFT172. In this study, we describe a 1-year-old girl presenting with mild skeletal abnormalities, Leber congenital amaurosis, and bilateral hearing difficulties. For establishing an accurate diagnosis, we combined clinical, molecular, and functional analyses.
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cellular ciliary phenotyping indicates pathogenicity of novel variants in IFT140 and confirms a mainzer saldino syndrome diagnosis
Cilia, 2018Co-Authors: Machteld M. Oud, Miriam Schmidts, Brooke L. Latour, Zeineb Bakey, Stef J. Letteboer, Dorien Lugtenberg, Elisabeth A. M. Cornelissen, Helger G. Yntema, Ronald Roepman, Ernie M. H. F. BongersAbstract:Background Mainzer–Saldino syndrome (MZSDS) is a skeletal ciliopathy and part of the short-rib thoracic dysplasia (SRTD) group of ciliary disorders. The main characteristics of MZSDS are short limbs, mild narrow thorax, blindness, and renal failure. Thus far, variants in two genes are associated with MZSDS: IFT140, and IFT172. In this study, we describe a 1-year-old girl presenting with mild skeletal abnormalities, Leber congenital amaurosis, and bilateral hearing difficulties. For establishing an accurate diagnosis, we combined clinical, molecular, and functional analyses.
Philippe Bastin - One of the best experts on this subject based on the ideXlab platform.
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Intraflagellar transport is required for the maintenance of the trypanosome flagellum composition but not its length.
Journal of Cell Science, 2016Co-Authors: Cécile Fort, Linda Kohl, Serge Bonnefoy, Philippe BastinAbstract:Intraflagellar transport (IFT) is required for construction of most cilia and flagella. Here, we used electron microscopy, immunofluorescence and live video microscopy to show that IFT is absent or arrested in the mature flagellum of Trypanosoma brucei upon RNA interference (RNAi)-mediated knockdown of IFT88 and IFT140, respectively. Flagella assembled prior to RNAi did not shorten, showing that IFT is not essential for the maintenance of flagella length. Although the ultrastructure of the axoneme was not visibly affected, flagellar beating was strongly reduced and the distribution of several flagellar components was drastically modified. The R subunit of the protein kinase A was no longer concentrated in the flagellum but was largely found in the cell body whereas the kinesin 9B motor was accumulating at the distal tip of the flagellum. In contrast, the distal tip protein FLAM8 was dispersed along the flagellum. This reveals that IFT also functions in maintaining the distribution of some flagellar proteins after construction of the organelle is completed.
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The intraflagellar transport dynein complex of trypanosomes is made of a heterodimer of dynein heavy chains and of light and intermediate chains of distinct functions
Molecular Biology of the Cell, 2014Co-Authors: Thierry Blisnick, Sabrina Absalon, Johanna Buisson, Alexandra Marie, Nadège Cayet, Philippe BastinAbstract:Cilia and flagella are assembled by intraflagellar transport (IFT) of protein complexes that bring tubulin and other precursors to the incorporation site at their distal tip. Anterograde transport is driven by kinesin, whereas retrograde transport is ensured by a specific dynein. In the protist Trypanosoma brucei, two distinct genes encode fairly different dynein heavy chains (DHCs; -40% identity) termed DHC2.1 and DHC2.2, which form a heterodimer and are both essential for retrograde IFT. The stability of each heavy chain relies on the presence of a dynein light intermediate chain (DLI1; also known as XBX-1/D1bLIC). The presence of both heavy chains and of DLI1 at the base of the flagellum depends on the intermediate dynein chain DIC5 (FAP133/WDR34). In the IFT140(RNAi) mutant, an IFT-A protein essential for retrograde transport, the IFT dynein components are found at high concentration at the flagellar base but fail to penetrate the flagellar compartment. We propose a model by which the IFT dynein particle is assembled in the cytoplasm, reaches the base of the flagellum, and associates with the IFT machinery in a manner dependent on the IFT-A complex.
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A novel function for the atypical small G protein Rab-like 5 in the assembly of the trypanosome flagellum
Journal of Cell Science, 2009Co-Authors: Christine Adhiambo, Thierry Blisnick, Géraldine Toutirais, Emmanuelle Delannoy, Philippe BastinAbstract:The atypical small G protein Rab-like 5 has been shown to traffic in sensory cilia of Caenorhabditis elegans, where it participates in signalling processes but not in cilia construction. In this report, we demonstrate that RABL5 colocalises with intraflagellar transport (IFT) proteins at the basal body and in the flagellum matrix of the protist Trypanosoma brucei. RABL5 fused to GFP exhibits anterograde movement in the flagellum of live trypanosomes, suggesting it could be associated with IFT. Accordingly, RABL5 accumulates in the short flagella of the retrograde IFT140 RNAi mutant and is restricted to the basal body region in the IFT88 RNAi anterograde mutant, a behaviour that is identical to other IFT proteins. Strikingly, RNAi silencing reveals an essential role for RABL5 in trypanosome flagellum construction. RNAi knock-down produces a phenotype similar to inactivation of retrograde IFT with formation of short flagella that are filled with a high amount of IFT proteins. These data reveal for the first time a functional difference for a conserved flagellar matrix protein between two different ciliated species and raise questions related to cilia diversity.
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Intraflagellar Transport and Functional Analysis of Genes Required for Flagellum Formation in Trypanosomes.
Molecular Biology of the Cell, 2008Co-Authors: Sabrina Absalon, Linda Kohl, Thierry Blisnick, Géraldine Toutirais, Daria Julkowska, Gwénola Doré, Arounie Tavenet, Philippe BastinAbstract:Intraflagellar transport (IFT) is the bidirectional movement of protein complexes required for cilia and flagella formation. We investigated IFT by analyzing nine conventional IFT genes and five novel putative IFT genes (PIFT) in Trypanosoma brucei that maintain its existing flagellum while assembling a new flagellum. Immunostaining against IFT172 or expression of tagged IFT20 or green fluorescent protein GFP::IFT52 revealed the presence of IFT proteins along the axoneme and at the basal body and probasal body regions of both old and new flagella. IFT particles were detected by electron microscopy and exhibited a strict localization to axonemal microtubules 3-4 and 7-8, suggesting the existence of specific IFT tracks. Rapid (>3 mum/s) bidirectional intraflagellar movement of GFP::IFT52 was observed in old and new flagella. RNA interference silencing demonstrated that all individual IFT and PIFT genes are essential for new flagellum construction but the old flagellum remained present. Inhibition of IFTB proteins completely blocked axoneme construction. Absence of IFTA proteins (IFT122 and IFT140) led to formation of short flagella filled with IFT172, indicative of defects in retrograde transport. Two PIFT proteins turned out to be required for retrograde transport and three for anterograde transport. Finally, flagellum membrane elongation continues despite the absence of axonemal microtubules in all IFT/PIFT mutant.
Machteld M. Oud - One of the best experts on this subject based on the ideXlab platform.
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Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease
Orphanet Journal of Rare Diseases, 2020Co-Authors: Joanna Walczak-sztulpa, Miriam Schmidts, Heleen H. Arts, Machteld M. Oud, Renata Posmyk, Ewelina M. Bukowska-olech, Anna Wawrocka, Aleksander Jamsheer, Anna Latos-bielenska, Anna WasilewskaAbstract:Background Sensenbrenner syndrome, which is also known as cranioectodermal dysplasia (CED), is a rare, autosomal recessive ciliary chondrodysplasia characterized by a variety of clinical features including a distinctive craniofacial appearance as well as skeletal, ectodermal, liver and renal anomalies. Progressive renal disease can be life-threatening in this condition. CED is a genetically heterogeneous disorder. Currently, variants in any of six genes ( IFT122, WDR35, IFT140, IFT43, IFT52 and WDR19 ) have been associated with this syndrome. All of these genes encode proteins essential for intraflagellar transport (IFT) a process that is required for cilium assembly, maintenance and function. Intra- and interfamilial clinical variability has been reported in CED, which is consistent with CED’s genetic heterogeneity and is indicative of genetic background effects. Results Two male CED patients from two unrelated Polish families were included in this study. Clinical assessment revealed distinctive clinical features of Sensenbrenner syndrome, such as dolichocephaly, shortening of long bones and early onset renal failure. Ectodermal anomalies also included thin hair, short and thin nails, and small teeth in both patients. Next generation sequencing (NGS) techniques were performed in order to determine the underlying genetic cause of the disorder using whole exome sequencing (WES) for patient 1 and a custom NGS-based panel for patient 2. Subsequent qPCR and duplex PCR analysis were conducted for both patients. Genetic analyses identified compound heterozygous variants in the IFT140 gene in both affected individuals. Both patients harbored a tandem duplication variant p.Tyr1152_Thr1394dup on one allele. In addition, a novel missense variant, p.(Leu109Pro), and a previously described p.(Gly522Glu) variant were identified in the second allele in patients 1 and 2, respectively. Segregation analysis of the variants was consistent with the expected autosomal recessive disease inheritance pattern. Both patients had severe renal failure requiring kidney transplantation in early childhood. Conclusion The finding of compound heterozygous IFT140 mutations in two unrelated CED patients provide further evidence that IFT140 gene mutations are associated with this syndrome. Our studies confirm that IFT140 changes in patients with CED are associated with early onset end-stage renal disease. Moreover, this report expands our knowledge of the clinical- and molecular genetics of Sensenbrenner syndrome and it highlights the importance of multidisciplinary approaches in the care of CED patients.
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Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease
Orphanet Journal of Rare Diseases, 2020Co-Authors: Joanna Walczak-sztulpa, Miriam Schmidts, Heleen H. Arts, Machteld M. Oud, Renata Posmyk, Ewelina M. Bukowska-olech, Anna Wawrocka, Aleksander Jamsheer, Anna Latos-bielenska, Anna WasilewskaAbstract:Sensenbrenner syndrome, which is also known as cranioectodermal dysplasia (CED), is a rare, autosomal recessive ciliary chondrodysplasia characterized by a variety of clinical features including a distinctive craniofacial appearance as well as skeletal, ectodermal, liver and renal anomalies. Progressive renal disease can be life-threatening in this condition. CED is a genetically heterogeneous disorder. Currently, variants in any of six genes (IFT122, WDR35, IFT140, IFT43, IFT52 and WDR19) have been associated with this syndrome. All of these genes encode proteins essential for intraflagellar transport (IFT) a process that is required for cilium assembly, maintenance and function. Intra- and interfamilial clinical variability has been reported in CED, which is consistent with CED’s genetic heterogeneity and is indicative of genetic background effects. Two male CED patients from two unrelated Polish families were included in this study. Clinical assessment revealed distinctive clinical features of Sensenbrenner syndrome, such as dolichocephaly, shortening of long bones and early onset renal failure. Ectodermal anomalies also included thin hair, short and thin nails, and small teeth in both patients. Next generation sequencing (NGS) techniques were performed in order to determine the underlying genetic cause of the disorder using whole exome sequencing (WES) for patient 1 and a custom NGS-based panel for patient 2. Subsequent qPCR and duplex PCR analysis were conducted for both patients. Genetic analyses identified compound heterozygous variants in the IFT140 gene in both affected individuals. Both patients harbored a tandem duplication variant p.Tyr1152_Thr1394dup on one allele. In addition, a novel missense variant, p.(Leu109Pro), and a previously described p.(Gly522Glu) variant were identified in the second allele in patients 1 and 2, respectively. Segregation analysis of the variants was consistent with the expected autosomal recessive disease inheritance pattern. Both patients had severe renal failure requiring kidney transplantation in early childhood. The finding of compound heterozygous IFT140 mutations in two unrelated CED patients provide further evidence that IFT140 gene mutations are associated with this syndrome. Our studies confirm that IFT140 changes in patients with CED are associated with early onset end-stage renal disease. Moreover, this report expands our knowledge of the clinical- and molecular genetics of Sensenbrenner syndrome and it highlights the importance of multidisciplinary approaches in the care of CED patients.
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Cellular ciliary phenotyping indicates pathogenicity of novel variants in IFT140 and confirms a Mainzer–Saldino syndrome diagnosis
Cilia, 2018Co-Authors: Machteld M. Oud, Miriam Schmidts, Brooke L. Latour, Zeineb Bakey, Stef J. Letteboer, Dorien Lugtenberg, Elisabeth A. M. Cornelissen, Helger G. Yntema, Ronald RoepmanAbstract:Background Mainzer–Saldino syndrome (MZSDS) is a skeletal ciliopathy and part of the short-rib thoracic dysplasia (SRTD) group of ciliary disorders. The main characteristics of MZSDS are short limbs, mild narrow thorax, blindness, and renal failure. Thus far, variants in two genes are associated with MZSDS: IFT140, and IFT172. In this study, we describe a 1-year-old girl presenting with mild skeletal abnormalities, Leber congenital amaurosis, and bilateral hearing difficulties. For establishing an accurate diagnosis, we combined clinical, molecular, and functional analyses.
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cellular ciliary phenotyping indicates pathogenicity of novel variants in IFT140 and confirms a mainzer saldino syndrome diagnosis
Cilia, 2018Co-Authors: Machteld M. Oud, Miriam Schmidts, Brooke L. Latour, Zeineb Bakey, Stef J. Letteboer, Dorien Lugtenberg, Elisabeth A. M. Cornelissen, Helger G. Yntema, Ronald Roepman, Ernie M. H. F. BongersAbstract:Background Mainzer–Saldino syndrome (MZSDS) is a skeletal ciliopathy and part of the short-rib thoracic dysplasia (SRTD) group of ciliary disorders. The main characteristics of MZSDS are short limbs, mild narrow thorax, blindness, and renal failure. Thus far, variants in two genes are associated with MZSDS: IFT140, and IFT172. In this study, we describe a 1-year-old girl presenting with mild skeletal abnormalities, Leber congenital amaurosis, and bilateral hearing difficulties. For establishing an accurate diagnosis, we combined clinical, molecular, and functional analyses.
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Mainzer-Saldino syndrome is a ciliopathy caused by mutations in the IFT140 gene
Cilia, 2012Co-Authors: Isabelle Perrault, Albane A Bizet, Sophie Saunier, Sylvain Hanein, Emilie Filhol, Felicity Collins, Mustafa A. Salih, Eduardo Silva, Véronique Baudouin, Machteld M. OudAbstract:Ciliopathies is an emerging class of genetic disorders due to altered cilia assembly, maintenance or function. Syndromic ciliopathies affecting bone development have been classified as skeletal ciliopathies. Mutations in genes encoding components of the intraflagellar transport (IFT) complex A, that drives retrograde ciliary transport, are a major cause of skeletal ciliopathies. Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal cone-shaped epiphyses, chronic renal failure and early-onset severe retinal dystrophy.
Ernie M. H. F. Bongers - One of the best experts on this subject based on the ideXlab platform.
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Cellular ciliary phenotyping indicates pathogenicity of novel variants in IFT140 and confirms a Mainzer–Saldino syndrome diagnosis
Cilia, 2018Co-Authors: Brooke L. Latour, Miriam Schmidts, Zeineb Bakey, Stef J. Letteboer, Dorien Lugtenberg, Ka Man Wu, Elisabeth A. M. Cornelissen, Helger G. Yntema, Ronald Roepman, Ernie M. H. F. BongersAbstract:Background Mainzer–Saldino syndrome (MZSDS) is a skeletal ciliopathy and part of the short-rib thoracic dysplasia (SRTD) group of ciliary disorders. The main characteristics of MZSDS are short limbs, mild narrow thorax, blindness, and renal failure. Thus far, variants in two genes are associated with MZSDS: IFT140, and IFT172 . In this study, we describe a 1-year-old girl presenting with mild skeletal abnormalities, Leber congenital amaurosis, and bilateral hearing difficulties. For establishing an accurate diagnosis, we combined clinical, molecular, and functional analyses. Methods We performed diagnostic whole-exome sequencing (WES) analysis to determine the genetic cause of the disease and analyzed two gene panels, containing all currently known genes in vision disorders, and in hearing impairment. Upon detection of the likely causative variants, ciliary phenotyping was performed in patient urine-derived renal epithelial cells (URECs) and rescue experiments were performed in CRISPR/Cas9-derived IFT140 knock out cells to determine the pathogenicity of the detected variants in vitro. Cilium morphology, cilium length, and intraflagellar transport (IFT) were evaluated by immunocytochemistry. Results Diagnostic WES revealed two novel compound heterozygous variants in IFT140 , encoding IFT140. Thorough investigation of WES data did not reveal any variants in candidate genes associated with hearing impairment. Patient-derived URECs revealed an accumulation of IFT-B protein IFT88 at the ciliary tip in 41% of the cells indicative of impaired retrograde IFT, while this was absent in cilia from control URECs. Furthermore, transfection of CRISPR/Cas9-derived IFT140 knock out cells with an IFT140 construct containing the patient mutation p.Tyr923Asp resulted in a significantly higher percentage of IFT88 tip accumulation than transfection with the wild-type IFT140 construct. Conclusions By combining the clinical, genetic, and functional data from this study, we could conclude that the patient has SRTD9, also called Mainzer–Saldino syndrome, caused by variants in IFT140 . We suggest the possibility that variants in IFT140 may underlie hearing impairment. Moreover, we show that urine provides an excellent source to obtain patient-derived cells in a non-invasive manner to study the pathogenicity of variants detected by genetic testing.
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cellular ciliary phenotyping indicates pathogenicity of novel variants in IFT140 and confirms a mainzer saldino syndrome diagnosis
Cilia, 2018Co-Authors: Machteld M. Oud, Miriam Schmidts, Brooke L. Latour, Zeineb Bakey, Stef J. Letteboer, Dorien Lugtenberg, Elisabeth A. M. Cornelissen, Helger G. Yntema, Ronald Roepman, Ernie M. H. F. BongersAbstract:Background Mainzer–Saldino syndrome (MZSDS) is a skeletal ciliopathy and part of the short-rib thoracic dysplasia (SRTD) group of ciliary disorders. The main characteristics of MZSDS are short limbs, mild narrow thorax, blindness, and renal failure. Thus far, variants in two genes are associated with MZSDS: IFT140, and IFT172. In this study, we describe a 1-year-old girl presenting with mild skeletal abnormalities, Leber congenital amaurosis, and bilateral hearing difficulties. For establishing an accurate diagnosis, we combined clinical, molecular, and functional analyses.
Joanna Walczak-sztulpa - One of the best experts on this subject based on the ideXlab platform.
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Prenatal genetic diagnosis of cranioectodermal dysplasia in a Polish family with compound heterozygous variants in WDR35.
American Journal of Medical Genetics Part A, 2020Co-Authors: Joanna Walczak-sztulpa, Heleen H. Arts, Anna Wawrocka, Anna Latos-bielenska, Beata Leszczyńska, Boyana Mikulska, Ewelina Bukowska-olech, Maria Daniel, Maciej R. Krawczynski, Ewa ObersztynAbstract:The ciliary chondrodysplasias represent a group of clinically and genetically heterogeneous disorders that affect skeleton development. Cilia are organelles that project from the surface of many cell types and play an important role during prenatal and postnatal human development. Cranioectodermal dysplasia (Sensenbrenner syndrome, CED) is a ciliopathy primarily characterized by craniofacial, skeletal, and ectodermal abnormalities. To date six genes have been associated with CED: IFT122, WDR35, WDR19, IFT140, IFT43, and IFT52. Prenatal diagnosis of CED is challenging, and genetic testing can facilitate making a correct diagnosis. Here, we report on a family with two male siblings affected by CED: a 3.5 year-old patient and his 2 year-old brother. Molecular analysis of the proband at 1 year of age revealed compound heterozygous variants in WDR35: c.3G>A [p.(Met1-Ala30delinsMetfsTer4)] and c.2522A>T [p.(Asp841Val)]. Ultrasound examination during the second pregnancy revealed an increased nuchal translucency of 4.5 mm and a hypoplastic nasal bone at 12 weeks of gestation. Prenatal diagnostic testing was offered because of an increased risk for chromosomal abnormalities and recurrence risk for CED. Prenatal genetic analysis of a chorionic villus sample detected the WDR35 variants previously identified in the elder brother. This is the first report of a prenatal genetic diagnosis in CED.
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Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease
Orphanet Journal of Rare Diseases, 2020Co-Authors: Joanna Walczak-sztulpa, Miriam Schmidts, Heleen H. Arts, Machteld M. Oud, Renata Posmyk, Ewelina M. Bukowska-olech, Anna Wawrocka, Aleksander Jamsheer, Anna Latos-bielenska, Anna WasilewskaAbstract:Background Sensenbrenner syndrome, which is also known as cranioectodermal dysplasia (CED), is a rare, autosomal recessive ciliary chondrodysplasia characterized by a variety of clinical features including a distinctive craniofacial appearance as well as skeletal, ectodermal, liver and renal anomalies. Progressive renal disease can be life-threatening in this condition. CED is a genetically heterogeneous disorder. Currently, variants in any of six genes ( IFT122, WDR35, IFT140, IFT43, IFT52 and WDR19 ) have been associated with this syndrome. All of these genes encode proteins essential for intraflagellar transport (IFT) a process that is required for cilium assembly, maintenance and function. Intra- and interfamilial clinical variability has been reported in CED, which is consistent with CED’s genetic heterogeneity and is indicative of genetic background effects. Results Two male CED patients from two unrelated Polish families were included in this study. Clinical assessment revealed distinctive clinical features of Sensenbrenner syndrome, such as dolichocephaly, shortening of long bones and early onset renal failure. Ectodermal anomalies also included thin hair, short and thin nails, and small teeth in both patients. Next generation sequencing (NGS) techniques were performed in order to determine the underlying genetic cause of the disorder using whole exome sequencing (WES) for patient 1 and a custom NGS-based panel for patient 2. Subsequent qPCR and duplex PCR analysis were conducted for both patients. Genetic analyses identified compound heterozygous variants in the IFT140 gene in both affected individuals. Both patients harbored a tandem duplication variant p.Tyr1152_Thr1394dup on one allele. In addition, a novel missense variant, p.(Leu109Pro), and a previously described p.(Gly522Glu) variant were identified in the second allele in patients 1 and 2, respectively. Segregation analysis of the variants was consistent with the expected autosomal recessive disease inheritance pattern. Both patients had severe renal failure requiring kidney transplantation in early childhood. Conclusion The finding of compound heterozygous IFT140 mutations in two unrelated CED patients provide further evidence that IFT140 gene mutations are associated with this syndrome. Our studies confirm that IFT140 changes in patients with CED are associated with early onset end-stage renal disease. Moreover, this report expands our knowledge of the clinical- and molecular genetics of Sensenbrenner syndrome and it highlights the importance of multidisciplinary approaches in the care of CED patients.
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Compound heterozygous IFT140 variants in two Polish families with Sensenbrenner syndrome and early onset end-stage renal disease
Orphanet Journal of Rare Diseases, 2020Co-Authors: Joanna Walczak-sztulpa, Miriam Schmidts, Heleen H. Arts, Machteld M. Oud, Renata Posmyk, Ewelina M. Bukowska-olech, Anna Wawrocka, Aleksander Jamsheer, Anna Latos-bielenska, Anna WasilewskaAbstract:Sensenbrenner syndrome, which is also known as cranioectodermal dysplasia (CED), is a rare, autosomal recessive ciliary chondrodysplasia characterized by a variety of clinical features including a distinctive craniofacial appearance as well as skeletal, ectodermal, liver and renal anomalies. Progressive renal disease can be life-threatening in this condition. CED is a genetically heterogeneous disorder. Currently, variants in any of six genes (IFT122, WDR35, IFT140, IFT43, IFT52 and WDR19) have been associated with this syndrome. All of these genes encode proteins essential for intraflagellar transport (IFT) a process that is required for cilium assembly, maintenance and function. Intra- and interfamilial clinical variability has been reported in CED, which is consistent with CED’s genetic heterogeneity and is indicative of genetic background effects. Two male CED patients from two unrelated Polish families were included in this study. Clinical assessment revealed distinctive clinical features of Sensenbrenner syndrome, such as dolichocephaly, shortening of long bones and early onset renal failure. Ectodermal anomalies also included thin hair, short and thin nails, and small teeth in both patients. Next generation sequencing (NGS) techniques were performed in order to determine the underlying genetic cause of the disorder using whole exome sequencing (WES) for patient 1 and a custom NGS-based panel for patient 2. Subsequent qPCR and duplex PCR analysis were conducted for both patients. Genetic analyses identified compound heterozygous variants in the IFT140 gene in both affected individuals. Both patients harbored a tandem duplication variant p.Tyr1152_Thr1394dup on one allele. In addition, a novel missense variant, p.(Leu109Pro), and a previously described p.(Gly522Glu) variant were identified in the second allele in patients 1 and 2, respectively. Segregation analysis of the variants was consistent with the expected autosomal recessive disease inheritance pattern. Both patients had severe renal failure requiring kidney transplantation in early childhood. The finding of compound heterozygous IFT140 mutations in two unrelated CED patients provide further evidence that IFT140 gene mutations are associated with this syndrome. Our studies confirm that IFT140 changes in patients with CED are associated with early onset end-stage renal disease. Moreover, this report expands our knowledge of the clinical- and molecular genetics of Sensenbrenner syndrome and it highlights the importance of multidisciplinary approaches in the care of CED patients.
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Clinical and molecular genetic characterization of a male patient with Sensenbrenner syndrome (cranioectodermal dysplasia) and biallelic WDR35 mutations.
Birth defects research, 2017Co-Authors: Joanna Walczak-sztulpa, Anna Wawrocka, Aleksander Jamsheer, Anna Latos-bielenska, Anna Swiader-lesniak, Magdalena Socha, Dorota Drozdz, Katarzyna ZachwiejaAbstract:Background Sensenbrenner syndrome (cranioectodermal dysplasia, CED) is a very rare autosomal recessive ciliopathy first described by Judith Sensenbrenner in 1975. CED is a complex disorder characterized by craniofacial, skeletal, and ectodermal abnormalities. The clinical symptoms are variable and the CED phenotype may present intrafamilial and interfamilial differences. Sensenbrenner syndrome belongs to a group of ciliary chondrodysplasias and is a genetically heterogeneous disease. Mutations in six genes: IFT122, WDR35, IFT43, WDR19, IFT52, and IFT140 have been associated with this disorder. All known CED genes encode proteins that are part of the intraflagellar transport complex, which plays an important role in the assembly and maintenance of cilia. Case We report a on 2-year-old male patient affected by Sensenbrenner syndrome. Dysmorphic features included short stature with rhizomelic shortening of limbs, short fingers, narrow chest, high forehead, epicanthal folds, telecanthus, broad nasal bridge, low-set ears, sparse hair, and widely space teeth. Craniosynostosis was surgically corrected at the age of 4 months. The patient presented chronic renal disease. Nephrologic picture showed early stages of nephronophthisis. Psychomotor development was apparently normal. Molecular analysis of the affected individual revealed compound heterozygosity for a novel nonsense p.(Arg113*) and a missense p.(Asp841Val) variant in the WDR35 gene. Conclusions The observations of the CED patient in this study provide additional clinical data and expand the molecular spectrum of Sensenbrenner syndrome. Moreover, the two variants identified in the proband provide further evidence for the WDR35 mutations as the most common cause of this rare syndrome.
