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Brunella Franco - One of the best experts on this subject based on the ideXlab platform.
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Fifteen years of research on oral–facial–digital syndromes: from 1 to 16 causal genes
Journal of medical genetics, 2017Co-Authors: Angeline Bruel, Estelle Lopez, Julien Thevenon, Yannis Duffourd, Brunella Franco, Laurence Jego, Jean-françois Deleuze, Diane Doummar, Rachel H. Giles, Colin A. JohnsonAbstract:Oral-facial-digital syndromes (OFDS) gather rare genetic disorders characterised by facial, oral and digital abnormalities associated with a wide range of additional features (polycystic kidney disease, cerebral malformations and several others) to delineate a growing list of OFDS subtypes. The most frequent, OFD type I, is caused by a heterozygous mutation in the OFD1 gene encoding a centrosomal protein. The wide clinical heterogeneity of OFDS suggests the involvement of other ciliary genes. For 15 years, we have aimed to identify the molecular bases of OFDS. This effort has been greatly helped by the recent development of whole-exome sequencing (WES). Here, we present all our published and unpublished results for WES in 24 cases with OFDS. We identified causal variants in five new genes (C2CD3, TMEM107, INTU, KIAA0753 and IFT57) and related the clinical spectrum of four genes in other ciliopathies (C5orf42, TMEM138, TMEM231 and WDPCP) to OFDS. Mutations were also detected in two genes previously implicated in OFDS. Functional studies revealed the involvement of centriole elongation, transition zone and intraflagellar transport defects in OFDS, thus characterising three ciliary protein modules: the complex KIAA0753-FOPNL-OFD1, a regulator of centriole elongation; the Meckel-Gruber syndrome module, a major component of the transition zone; and the CPLANE complex necessary for IFT-A assembly. OFDS now appear to be a distinct subgroup of ciliopathies with wide heterogeneity, which makes the initial classification obsolete. A clinical classification restricted to the three frequent/well-delineated subtypes could be proposed, and for patients who do not fit one of these three main subtypes, a further classification could be based on the genotype.
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ofip kiaa0753 forms a complex with OFD1 and for20 at pericentriolar satellites and centrosomes and is mutated in one individual with oral facial digital syndrome
Human Molecular Genetics, 2016Co-Authors: Veronique Chevrier, Angeline Bruel, Brunella Franco, Melissa Lo Scalzo, Frederique Lembo, Stephane Audebert, Emilie Baudelet, Daniel Isnardon, Angelique Bole, Jeanpaul BorgAbstract:Oral-facial-digital (OFD) syndromes are rare heterogeneous disorders characterized by the association of abnormalities of the face, the oral cavity and the extremities, some due to mutations in proteins of the transition zone of the primary cilia or the closely associated distal end of centrioles. These two structures are essential for the formation of functional cilia, and for signaling events during development. We report here causal compound heterozygous mutations of KIAA0753/OFIP in a patient with an OFD VI syndrome. We show that the KIAA0753/OFIP protein, whose sequence is conserved in ciliated species, associates with centrosome/centriole and pericentriolar satellites in human cells and forms a complex with FOR20 and OFD1. The decreased expression of any component of this ternary complex in RPE1 cells causes a defective recruitment onto centrosomes and satellites. The OFD KIAA0753/OFIP mutant loses its capacity to interact with FOR20 and OFD1, which may be the molecular basis of the defect. We also show that KIAA0753/OFIP has microtubule-stabilizing activity. OFD1 and FOR20 are known to regulate the integrity of the centriole distal end, confirming that this structural element is a target of importance for pathogenic mutations in ciliopathies.
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the oral facial digital syndrome gene c2cd3 encodes a positive regulator of centriole elongation
Nature Genetics, 2014Co-Authors: Christel Thauvinrobinet, Estelle Lopez, Brunella Franco, Laurence Jego, Jaclyn S Lee, Toshinobu Shida, Laurent Pasquier, Philippe Loget, Vicente Herranzperez, Nadège GigotAbstract:Centrioles are microtubule-based, barrel-shaped structures that initiate the assembly of centrosomes and cilia. How centriole length is precisely set remains elusive. The microcephaly protein CPAP (also known as MCPH6) promotes procentriole growth, whereas the oral-facial-digital (OFD) syndrome protein OFD1 represses centriole elongation. Here we uncover a new subtype of OFD with severe microcephaly and cerebral malformations and identify distinct mutations in two affected families in the evolutionarily conserved C2CD3 gene. Concordant with the clinical overlap, C2CD3 colocalizes with OFD1 at the distal end of centrioles, and C2CD3 physically associates with OFD1. However, whereas OFD1 deletion leads to centriole hyperelongation, loss of C2CD3 results in short centrioles without subdistal and distal appendages. Because C2CD3 overexpression triggers centriole hyperelongation and OFD1 antagonizes this activity, we propose that C2CD3 directly promotes centriole elongation and that OFD1 acts as a negative regulator of C2CD3. Our results identify regulation of centriole length as an emerging pathogenic mechanism in ciliopathies.
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autophagy promotes primary ciliogenesis by removing OFD1 from centriolar satellites
Nature, 2013Co-Authors: Zaiming Tang, Tim Stearns, Brunella Franco, Mary Grace Lin, Timothy R Stowe, She Chen, Muyuan Zhu, Qing ZhongAbstract:The primary cilium is a microtubule-based organelle that functions in sensory and signalling pathways. Defects in ciliogenesis can lead to a group of genetic syndromes known as ciliopathies. However, the regulatory mechanisms of primary ciliogenesis in normal and cancer cells are incompletely understood. Here we demonstrate that autophagic degradation of a ciliopathy protein, OFD1 (oral-facial-digital syndrome 1), at centriolar satellites promotes primary cilium biogenesis. Autophagy is a catabolic pathway in which cytosol, damaged organelles and protein aggregates are engulfed in autophagosomes and delivered to lysosomes for destruction. We show that the population of OFD1 at the centriolar satellites is rapidly degraded by autophagy upon serum starvation. In autophagy-deficient Atg5 or Atg3 null mouse embryonic fibroblasts, OFD1 accumulates at centriolar satellites, leading to fewer and shorter primary cilia and a defective recruitment of BBS4 (Bardet-Biedl syndrome 4) to cilia. These defects are fully rescued by OFD1 partial knockdown that reduces the population of OFD1 at centriolar satellites. More strikingly, OFD1 depletion at centriolar satellites promotes cilia formation in both cycling cells and transformed breast cancer MCF7 cells that normally do not form cilia. This work reveals that removal of OFD1 by autophagy at centriolar satellites represents a general mechanism to promote ciliogenesis in mammalian cells. These findings define a newly recognized role of autophagy in organelle biogenesis.
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OFD1 Controls Dorso-Ventral Patterning and Axoneme Elongation during Embryonic Brain Development.
PLoS ONE, 2012Co-Authors: Anna D'angelo, Amalia De Angelis, Roberta Tammaro, Bice Avallone, Immacolata Piscopo, Michèle Studer, Brunella FrancoAbstract:Oral-facial-digital type I syndrome (OFDI) is a human X-linked dominant-male-lethal developmental disorder caused by mutations in the OFD1 gene. Similar to other inherited disorders associated to ciliary dysfunction OFD type I patients display neurological abnormalities. We characterized the neuronal phenotype that results from OFD1 inactivation in early phases of mouse embryonic development and at post-natal stages. We determined that OFD1 plays a crucial role in forebrain development, and in particular, in the control of dorso-ventral patterning and early corticogenesis. We observed abnormal activation of Sonic hedgehog (Shh), a major pathway modulating brain development. Ultrastructural studies demonstrated that early OFD1 inactivation results in the absence of ciliary axonemes despite the presence of mature basal bodies that are correctly orientated and docked. OFD1 inducible-mediated inactivation at birth does not affect ciliogenesis in the cortex, suggesting a developmental stage-dependent role for a basal body protein in ciliogenesis. Moreover, we showed defects in cytoskeletal organization and apical-basal polarity in OFD1 mutant embryos, most likely due to lack of ciliary axonemes. Thus, the present study identifies OFD1 as a developmental disease gene that is critical for forebrain development and ciliogenesis in embryonic life, and indicates that OFD1 functions after docking and before elaboration of the axoneme in vivo.
Roland Lill - One of the best experts on this subject based on the ideXlab platform.
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Function and crystal structure of the dimeric P-loop ATPase CFD1 coordinating an exposed [4Fe-4S] cluster for transfer to apoproteins
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Oliver Stehling, Jae-hun Jeoung, Sven A. Freibert, Viktoria Désirée Paul, Sebastian Bänfer, Brigitte Niggemeyer, Ralf Rösser, Holger Dobbek, Roland LillAbstract:Maturation of iron-sulfur (Fe-S) proteins in eukaryotes requires complex machineries in mitochondria and cytosol. Initially, Fe-S clusters are assembled on dedicated scaffold proteins and then are trafficked to target apoproteins. Within the cytosolic Fe-S protein assembly (CIA) machinery, the conserved P-loop nucleoside triphosphatase Nbp35 performs a scaffold function. In yeast, Nbp35 cooperates with the related Cfd1, which is evolutionary less conserved and is absent in plants. Here, we investigated the potential scaffold function of human CFD1 (NUBP2) in CFD1-depleted HeLa cells by measuring Fe-S enzyme activities or 55Fe incorporation into Fe-S target proteins. We show that CFD1, in complex with NBP35 (NUBP1), performs a crucial role in the maturation of all tested cytosolic and nuclear Fe-S proteins, including essential ones involved in protein translation and DNA maintenance. CFD1 also matures iron regulatory protein 1 and thus is critical for cellular iron homeostasis. To better understand the scaffold function of CFD1-NBP35, we resolved the crystal structure of Chaetomium thermophilum holo-Cfd1 (ctCfd1) at 2.6-A resolution as a model Cfd1 protein. Importantly, two ctCfd1 monomers coordinate a bridging [4Fe-4S] cluster via two conserved cysteine residues. The surface-exposed topology of the cluster is ideally suited for both de novo assembly and facile transfer to Fe-S apoproteins mediated by other CIA factors. ctCfd1 specifically interacted with ATP, which presumably associates with a pocket near the Cfd1 dimer interface formed by the conserved Walker motif. In contrast, ctNbp35 preferentially bound GTP, implying differential regulation of the two fungal scaffold components during Fe-S cluster assembly and/or release.
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a bridging 4fe 4s cluster and nucleotide binding are essential for function of the cfd1 nbp35 complex as a scaffold in iron sulfur protein maturation
Journal of Biological Chemistry, 2012Co-Authors: Daili J A Netz, Antonio J Pierik, Martin Stumpfig, Anil K Sharma, William E Walden, Eckhard Bill, Leif Pallesen, Roland LillAbstract:The essential P-loop NTPases Cfd1 and Nbp35 of the cytosolic iron-sulfur (Fe-S) protein assembly machinery perform a scaffold function for Fe-S cluster synthesis. Both proteins contain a nucleotide binding motif of unknown function and a C-terminal motif with four conserved cysteine residues. The latter motif defines the Mrp/Nbp35 subclass of P-loop NTPases and is suspected to be involved in transient Fe-S cluster binding. To elucidate the function of these two motifs, we first created cysteine mutant proteins of Cfd1 and Nbp35 and investigated the consequences of these mutations by genetic, cell biological, biochemical, and spectroscopic approaches. The two central cysteine residues (CPXC) of the C-terminal motif were found to be crucial for cell viability, protein function, coordination of a labile [4Fe-4S] cluster, and Cfd1-Nbp35 hetero-tetramer formation. Surprisingly, the two proximal cysteine residues were dispensable for all these functions, despite their strict evolutionary conservation. Several lines of evidence suggest that the C-terminal CPXC motifs of Cfd1-Nbp35 coordinate a bridging [4Fe-4S] cluster. Upon mutation of the nucleotide binding motifs Fe-S clusters could no longer be assembled on these proteins unless wild-type copies of Cfd1 and Nbp35 were present in trans. This result indicated that Fe-S cluster loading on these scaffold proteins is a nucleotide-dependent step. We propose that the bridging coordination of the C-terminal Fe-S cluster may be ideal for its facile assembly, labile binding, and efficient transfer to target Fe-S apoproteins, a step facilitated by the cytosolic iron-sulfur (Fe-S) protein assembly proteins Nar1 and Cia1 in vivo.
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the essential cytosolic iron sulfur protein nbp35 acts without cfd1 partner in the green lineage
Journal of Biological Chemistry, 2008Co-Authors: Katrine Bych, Roland Lill, Daili J A Netz, Antonio J Pierik, Eckhard Bill, Gianpiero Vigani, Janneke BalkAbstract:In photosynthetic eukaryotes assembly components of iron-sulfur (Fe-S) cofactors have been studied in plastids and mitochondria, but how cytosolic and nuclear Fe-S cluster proteins are assembled is not known. We have characterized a plant P loop NTPase with sequence similarity to Nbp35 of yeast and mammals, a protein of the cytosolic Cfd1-Nbp35 complex mediating Fe-S cluster assembly. Genome analysis revealed that NBP35 is conserved in the green lineage but that CFD1 is absent. Moreover, plant and algal NBP35 proteins lack the characteristic CXXC motif in the C terminus, thought to be required for Fe-S cluster binding. Nevertheless, chemical reconstitution and spectroscopy showed that Arabidopsis (At) NBP35 bound a [4Fe-4S] cluster in the C terminus as well as a stable [4Fe-4S] cluster in the N terminus. Holo-AtNBP35 was able to transfer an Fe-S cluster to an apoprotein in vitro. When expressed in yeast, AtNBP35 bound 55Fe dependent on the cysteine desulfurase Nfs1 and was able to partially rescue the growth of a cfd1 mutant but not of an nbp35 mutant. The AtNBP35 gene is constitutively expressed in planta, and its disruption was associated with an arrest of embryo development. These results show that despite considerable divergence from the yeast Cfd1-Nbp35 Fe-S scaffold complex, AtNBP35 has retained similar Fe-S cluster binding and transfer properties and performs an essential function.
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the cfd1 nbp35 complex acts as a scaffold for iron sulfur protein assembly in the yeast cytosol
Nature Chemical Biology, 2007Co-Authors: Daili J A Netz, Ulrich Mühlenhoff, Antonio J Pierik, Martin Stumpfig, Roland LillAbstract:The Cfd1–Nbp35 complex acts as a scaffold for iron-sulfur protein assembly in the yeast cytosol
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the cfd1 nbp35 complex acts as a scaffold for iron sulfur protein assembly in the yeast cytosol
Nature Chemical Biology, 2007Co-Authors: Daili J A Netz, Ulrich Mühlenhoff, Antonio J Pierik, Martin Stumpfig, Roland LillAbstract:Biogenesis of iron-sulfur ([Fe-S]) proteins in eukaryotes requires the function of complex proteinaceous machineries in both mitochondria and cytosol. In contrast to the mitochondrial pathway, little is known about [Fe-S] protein assembly in the cytosol. So far, four highly conserved proteins (Cfd1, Nbp35, Nar1 and Cia1) have been identified as members of the cytosolic [Fe-S] protein assembly machinery, but their molecular function is unresolved. Using in vivo and in vitro approaches, we found that the soluble P-loop NTPases Cfd1 and Nbp35 form a complex and bind up to three [4Fe-4S] clusters, one at the N terminus of Nbp35 and one each at a new C-terminal cysteine-rich motif present in both proteins. These labile [Fe-S] clusters can be rapidly transferred and incorporated into target [Fe-S] apoproteins in a Nar1- and Cia1-dependent fashion. Our data suggest that the Cfd1-Nbp35 complex functions as a novel scaffold for [Fe-S] cluster assembly in the eukaryotic cytosol.
Daili J A Netz - One of the best experts on this subject based on the ideXlab platform.
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a bridging 4fe 4s cluster and nucleotide binding are essential for function of the cfd1 nbp35 complex as a scaffold in iron sulfur protein maturation
Journal of Biological Chemistry, 2012Co-Authors: Daili J A Netz, Antonio J Pierik, Martin Stumpfig, Anil K Sharma, William E Walden, Eckhard Bill, Leif Pallesen, Roland LillAbstract:The essential P-loop NTPases Cfd1 and Nbp35 of the cytosolic iron-sulfur (Fe-S) protein assembly machinery perform a scaffold function for Fe-S cluster synthesis. Both proteins contain a nucleotide binding motif of unknown function and a C-terminal motif with four conserved cysteine residues. The latter motif defines the Mrp/Nbp35 subclass of P-loop NTPases and is suspected to be involved in transient Fe-S cluster binding. To elucidate the function of these two motifs, we first created cysteine mutant proteins of Cfd1 and Nbp35 and investigated the consequences of these mutations by genetic, cell biological, biochemical, and spectroscopic approaches. The two central cysteine residues (CPXC) of the C-terminal motif were found to be crucial for cell viability, protein function, coordination of a labile [4Fe-4S] cluster, and Cfd1-Nbp35 hetero-tetramer formation. Surprisingly, the two proximal cysteine residues were dispensable for all these functions, despite their strict evolutionary conservation. Several lines of evidence suggest that the C-terminal CPXC motifs of Cfd1-Nbp35 coordinate a bridging [4Fe-4S] cluster. Upon mutation of the nucleotide binding motifs Fe-S clusters could no longer be assembled on these proteins unless wild-type copies of Cfd1 and Nbp35 were present in trans. This result indicated that Fe-S cluster loading on these scaffold proteins is a nucleotide-dependent step. We propose that the bridging coordination of the C-terminal Fe-S cluster may be ideal for its facile assembly, labile binding, and efficient transfer to target Fe-S apoproteins, a step facilitated by the cytosolic iron-sulfur (Fe-S) protein assembly proteins Nar1 and Cia1 in vivo.
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the essential cytosolic iron sulfur protein nbp35 acts without cfd1 partner in the green lineage
Journal of Biological Chemistry, 2008Co-Authors: Katrine Bych, Roland Lill, Daili J A Netz, Antonio J Pierik, Eckhard Bill, Gianpiero Vigani, Janneke BalkAbstract:In photosynthetic eukaryotes assembly components of iron-sulfur (Fe-S) cofactors have been studied in plastids and mitochondria, but how cytosolic and nuclear Fe-S cluster proteins are assembled is not known. We have characterized a plant P loop NTPase with sequence similarity to Nbp35 of yeast and mammals, a protein of the cytosolic Cfd1-Nbp35 complex mediating Fe-S cluster assembly. Genome analysis revealed that NBP35 is conserved in the green lineage but that CFD1 is absent. Moreover, plant and algal NBP35 proteins lack the characteristic CXXC motif in the C terminus, thought to be required for Fe-S cluster binding. Nevertheless, chemical reconstitution and spectroscopy showed that Arabidopsis (At) NBP35 bound a [4Fe-4S] cluster in the C terminus as well as a stable [4Fe-4S] cluster in the N terminus. Holo-AtNBP35 was able to transfer an Fe-S cluster to an apoprotein in vitro. When expressed in yeast, AtNBP35 bound 55Fe dependent on the cysteine desulfurase Nfs1 and was able to partially rescue the growth of a cfd1 mutant but not of an nbp35 mutant. The AtNBP35 gene is constitutively expressed in planta, and its disruption was associated with an arrest of embryo development. These results show that despite considerable divergence from the yeast Cfd1-Nbp35 Fe-S scaffold complex, AtNBP35 has retained similar Fe-S cluster binding and transfer properties and performs an essential function.
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the cfd1 nbp35 complex acts as a scaffold for iron sulfur protein assembly in the yeast cytosol
Nature Chemical Biology, 2007Co-Authors: Daili J A Netz, Ulrich Mühlenhoff, Antonio J Pierik, Martin Stumpfig, Roland LillAbstract:The Cfd1–Nbp35 complex acts as a scaffold for iron-sulfur protein assembly in the yeast cytosol
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the cfd1 nbp35 complex acts as a scaffold for iron sulfur protein assembly in the yeast cytosol
Nature Chemical Biology, 2007Co-Authors: Daili J A Netz, Ulrich Mühlenhoff, Antonio J Pierik, Martin Stumpfig, Roland LillAbstract:Biogenesis of iron-sulfur ([Fe-S]) proteins in eukaryotes requires the function of complex proteinaceous machineries in both mitochondria and cytosol. In contrast to the mitochondrial pathway, little is known about [Fe-S] protein assembly in the cytosol. So far, four highly conserved proteins (Cfd1, Nbp35, Nar1 and Cia1) have been identified as members of the cytosolic [Fe-S] protein assembly machinery, but their molecular function is unresolved. Using in vivo and in vitro approaches, we found that the soluble P-loop NTPases Cfd1 and Nbp35 form a complex and bind up to three [4Fe-4S] clusters, one at the N terminus of Nbp35 and one each at a new C-terminal cysteine-rich motif present in both proteins. These labile [Fe-S] clusters can be rapidly transferred and incorporated into target [Fe-S] apoproteins in a Nar1- and Cia1-dependent fashion. Our data suggest that the Cfd1-Nbp35 complex functions as a novel scaffold for [Fe-S] cluster assembly in the eukaryotic cytosol.
Magda Badura - One of the best experts on this subject based on the ideXlab platform.
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a novel x linked recessive mental retardation syndrome comprising macrocephaly and ciliary dysfunction is allelic to oral facial digital type i syndrome
Human Genetics, 2006Co-Authors: B Budny, Wei Chen, Heymut Omran, Manfred Fliegauf, Andreas Tzschach, Marzena Wisniewska, Lars R Jensen, Martine Raynaud, Sarah A Shoichet, Magda BaduraAbstract:We report on a large family in which a novel X-linked recessive mental retardation (XLMR) syndrome comprising macrocephaly and ciliary dysfunction co-segregates with a frameshift mutation in the OFD1 gene. Mutations of OFD1 have been associated with oral–facial–digital type 1 syndrome (OFD1S) that is characterized by X-chromosomal dominant inheritance and lethality in males. In contrast, the carrier females of our family were clinically inconspicuous, and the affected males suffered from severe mental retardation, recurrent respiratory tract infections and macrocephaly. All but one of the affected males died from respiratory problems in infancy; and impaired ciliary motility was confirmed in the index patient by high-speed video microscopy examination of nasal epithelium. This family broadens the phenotypic spectrum of OFD1 mutations in an unexpected way and sheds light on the complexity of the underlying disease mechanisms.
Lihadh Algazali - One of the best experts on this subject based on the ideXlab platform.
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a de novo splice site deletion in the OFD1 gene is responsible for oral facial digital type 1 syndrome in an emirati child
HAMDAN MEDICAL JOURNAL, 2015Co-Authors: M A Aljneibe, K M Khozaimy, K M Alkathiri, S S Alameri, Salma Bensalem, Bassam R Ali, Lihadh AlgazaliAbstract:Introduction: Oral– facial– digital type 1 (OFD1) syndrome is an X-linked dominant disease characterized by dysmorphic face, oral cavity and digits. This syndrome is associated with polycystic kidney disease, which is a typical feature of OFD1. Heterozygous mutations in the OFD1 gene are responsible for this condition. This gene encodes acentrosomal and basal body cilia proteins that play an important role in the early development of the brain, face, limbs and the kidneys. Objectives: In this study we clinically evaluated an Emirati female exhibiting OFD1 syndrome features. Material and methods: Screening of the OFD1 gene was carried out using Sanger DNA sequencing. Moreover, bioinformatics tools have been used to predict the pathogenicity of the identified mutation. Results: We identified a heterozygous single-nucleotide deletion in the donor splice site of exon 20 (c.2757+1delG). Since both parents were homozygous for the wild-type alleles, we concluded that the deletion is a ‘de novo’ mutation. Prediction analyses showed that the deletion abolishes the authentic splice site leading to the generation of a cryptic splice site, resulting in a frame-shift mutation and premature termination codon (p.Lys920ArgfsX2). Conclusions: We described the clinical features and molecular studies of a sporadic case of an Emirati female with OFD1 syndrome. Acknowledgements: Professor Bassam Ali for supervising the project.
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a novel splice site deletion in the OFD1 gene is responsible for oral facial digital syndrome type1 in an emirati child
HAMDAN MEDICAL JOURNAL, 2015Co-Authors: Salma Bensalem, M A Aljneibe, K M Khozaimy, K M Alkathiri, S S Alameri, Bassam R Ali, Lihadh AlgazaliAbstract:Oral – facial – digital syndrome type 1 (OFD1) is a male-lethal X-linked dominant disorder characterized by a dysmorphic face, associated with oral cavity and digital anomalies. Polycystic kidney disease is another typical feature of this syndrome. Heterozygous mutations in the OFD1 gene are responsible for this condition. This gene encodes a centrosomal and basal body cilia protein that plays an important role in the early development of the brain, face, limbs and kidneys. In this study we clinically evaluated an affected Emirati female child exhibiting features of OFD1 syndrome. Screening of the OFD1 gene was carried out using a Sanger DNA sequencing method. Moreover, bioinformatics tools were used to predict the pathogenicity of the identified mutation. As a result, we identified a heterozygous single-nucleotide deletion in the donor splice site of exon 20 (c.2757+1delG). Both parents were homozygous for the wild-type alleles. The deletion might be a de novo mutation in nature, but we cannot exclude the possibility of mosaicism in the mother. Prediction analyses showed that the deletion abolishes the authentic splice site leading to the generation of a cryptic splice site. Subsequently, this mutation will result in a frameshift and premature termination codon (p.Lys920ArgfsX2). In this report, we describe the clinical features and molecular studies of an Emirati child with OFD1 syndrome. To our knowledge this is the first report of the clinical and molecular aspect of OFD1 from the UAE.
