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Graca Raposo - One of the best experts on this subject based on the ideXlab platform.
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Mitochondria and melanosomes establish physical contacts modulated by Mfn2 and involved in organelle biogenesis
Current biology : CB, 2014Co-Authors: Tiziana Daniele, Graca Raposo, Ilse Hurbain, Riccardo Vago, Giorgio Casari, Carlo Tacchetti, Maria Vittoria SchiaffinoAbstract:Summary Background To efficiently supply ATP to sites of high-energy demand and finely regulate calcium signaling, mitochondria adapt their metabolism, shape, and distribution within the cells, including relative positioning with respect to other organelles. However, physical contacts between mitochondria and the secretory/endocytic pathway have been demonstrated so far only with the ER, through structural and functional interorganellar connections. Results Here we show by electron tomography that mitochondria physically contact melanosomes, specialized lysosome-related organelles of pigment cells, through fibrillar bridges resembling the protein tethers linking mitochondria and the ER. Mitofusin (Mfn) 2, which bridges ER to mitochondria, specifically localizes also to melanosome-mitochondrion contacts, and its knockdown significantly reduces the interorganellar connections. Contacts are associated to the melanogenesis process, as indicated by the fact that they are reduced in a model of aberrant melanogenesis whereas they are enhanced both where melanosome biogenesis takes place in the perinuclear area and when it is actively stimulated by OA1, a G protein-coupled receptor implicated in Ocular Albinism and organellogenesis. Consistently, Mfn2 knockdown prevents melanogenesis activation by OA1, and the pharmacological inhibition of mitochondrial ATP synthesis severely reduces contact formation and impairs melanosome biogenesis, by affecting in particular the developing organelles showing the highest frequency of contacts. Conclusions Altogether, our findings reveal the presence of an unprecedented physical and functional connection between mitochondria and the secretory/endocytic pathway that goes beyond the ER-mitochondria linkage and is spatially and timely associated to secretory organelle biogenesis.
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the Ocular Albinism type 1 oa1 gpcr is ubiquitinated and its traffic requires endosomal sorting complex responsible for transport escrt function
Proceedings of the National Academy of Sciences of the United States of America, 2011Co-Authors: Francesca Giordano, Sabrina Simoes, Graca RaposoAbstract:The function of signaling receptors is tightly controlled by their intracellular trafficking. One major regulatory mechanism within the endo-lysosomal system required for receptor localization and down-regulation is protein modification by ubiquitination and downstream interactions with the endosomal sorting complex responsible for transport (ESCRT) machinery. Whether and how these mechanisms operate to regulate endosomal sorting of mammalian G protein-coupled receptors (GPCRs) remains unclear. Here, we explore the involvement of ubiquitin and ESCRTs in the trafficking of OA1, a pigment cell-specific GPCR, target of mutations in Ocular Albinism type 1, which localizes intracellularly to melanosomes to regulate their biogenesis. Using biochemical and morphological methods in combination with overexpression and inactivation approaches we show that OA1 is ubiquitinated and that its intracellular sorting and down-regulation requires functional ESCRT components. Depletion or overexpression of subunits of ESCRT-0, -I, and -III markedly inhibits OA1 degradation with concomitant retention within the modified endosomal system. Our data further show that OA1 ubiquitination is uniquely required for targeting to the intralumenal vesicles of multivesicular endosomes, thereby regulating the balance between down-regulation and delivery to melanosomes. This study highlights the role of ubiquitination and the ESCRT machinery in the intracellular trafficking of mammalian GPCRs and has implications for the physiopathology of Ocular Albinism type 1.
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the Ocular Albinism type 1 oa1 g protein coupled receptor functions with mart 1 at early stages of melanogenesis to control melanosome identity and composition
Human Molecular Genetics, 2009Co-Authors: Francesca Giordano, Graca Raposo, Ciro Bonetti, Enrico Maria Surace, Valeria MarigoAbstract:OA1 (GPR143; GPCR, G-protein-coupled receptor), the protein product of the Ocular Albinism type 1 gene, encodes a pigment-cell-specific GPCR that localizes intracellularly to melanosomes. OA1 mutations result in Ocular Albinism due to alterations in melanosome formation, suggesting that OA1 is a key player in the biogenesis of melanosomes. To address the function of OA1 in melanosome biogenesis, we have used siRNA inactivation and combined morphological and biochemical methods to investigate melanosome ultrastructure, melanosomal protein localization and expression in human pigmented melanocytic cells. OA1 loss of function leads to decreased pigmentation and causes formation of enlarged aberrant premelanosomes harboring disorganized fibrillar structures and displaying proteins of mature melanosomes and lysosomes at their membrane. Moreover, we show that OA1 interacts biochemically with the premelanosomal protein MART-1. Inactivation of MART-1 by siRNA leads to a decreased stability of OA1 and is accompanied by similar defects in premelanosome biogenesis and composition. These data show for the first time that melanosome composition and identity are regulated at early stages by OA1 and that MART-1 likely acts as an escort protein for this GPCR.
Andrea Ballabio - One of the best experts on this subject based on the ideXlab platform.
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the Ocular Albinism type 1 oa1 gene controls melanosome maturation and size
Investigative Ophthalmology & Visual Science, 2005Co-Authors: Katia Cortese, Andrea Ballabio, Francesca Giordano, Enrico Maria Surace, Carlo Tacchetti, Consuelo Venturi, Valeria MarigoAbstract:PURPOSE. The authors took advantage of the Oal mutant mouse in combination with other Albinism mouse models (i.e., Tyrosinase and membrane-associated transporter protein [Matp]) to study the function of Oal, the gene mutated in Ocular Albinism type 1, in the RPE during development and after birth. METHODS. Enzyme activity and protein localization were analyzed by immunohistochemistry of tyrosinase (Tyr) in Oal-null mice. Ultrastructural analysis and morphometry were performed by electron microscopy, of the RPE in Oal-knockout mouse and double-mutant mice of Oal with either Tyr or Matp. RESULTS. Differently from other Albinism models, Tyr activity was not impaired in Oa1 -/- eyes. Hypopigmentation of the RPE in Oa1 -/- mice is due to a reduced number of melanosomes. Analysis of Oa1 -/- ;Tyr c-2J /Tyr c-2J and Oa1 -/- ;Matp uw / Matp double-knockout mice, which display a block at stages II and III of melanosome maturation, respectively, revealed that Oal controls the rate of melanosome biogenesis at early stages of the organellogenesis, whereas the control on the organelle size is exerted at the final stage of melanosome development (stage IV). CONCLUSIONS. The findings indicate that Oal is involved in the regulation of melanosome maturation at two steps. Acting at early maturation stages, Oal controls the abundance of melanosomes in RPE cells. At later stages, Oal has a function in the maintenance of a correct melanosomal size. This study helps to define Ocular Albinism type 1 as a defect in melanosome organellogenesis and not in melanin production.
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the microphthalmia transcription factor mitf controls expression of the Ocular Albinism type 1 gene link between melanin synthesis and melanosome biogenesis
Molecular and Cellular Biology, 2004Co-Authors: Francesco Vetrini, Andrea Ballabio, Alberto Auricchio, Barbara Angeletti, David E Fisher, Valeria MarigoAbstract:Melanogenesis is the process that regulates skin and eye pigmentation. Albinism, a genetic disease causing pigmentation defects and visual disorders, is caused by mutations in genes controlling either melanin synthesis or melanosome biogenesis. Here we show that a common transcriptional control regulates both of these processes. We performed an analysis of the regulatory region of Oa1, the murine homolog of the gene that is mutated in the X-linked form of Ocular Albinism, as Oa1's function affects melanosome biogenesis. We demonstrated that Oa1 is a target of Mitf and that this regulatory mechanism is conserved in the human gene. Tissue-specific control of Oa1 transcription lies within a region of 617 bp that contains the E-box bound by Mitf. Finally, we took advantage of a virus-based system to assess tissue specificity in vivo. To this end, a small fragment of the Oa1 promoter was cloned in front of a reporter gene in an adeno-associated virus. After we injected this virus into the subretinal space, we observed reporter gene expression specifically in the retinal pigment epithelium, confirming the cell-specific expression of the Oa1 promoter in the eye. The results obtained with this viral system are a preamble to the development of new gene delivery approaches for the treatment of retinal pigment epithelium defects.
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cloning of the gene for Ocular Albinism type 1 from the distal short arm of the x chromosome
Nature Genetics, 1995Co-Authors: Maria Teresa Bassi, Maria Vittoria Schiaffino, Alessandra Renieri, F De Nigris, Lucia Galli, Mirella Bruttini, M Gebbia, A A Bergen, R A Lewis, Andrea BallabioAbstract:Ocular Albinism type 1 (OA1) is an X–linked disorder characterized by severe impairment of visual acuity, retinal hypopigmentation and the presence of macromelanosomes. We isolated a novel transcript from the OA1 critical region in Xp22.3–22.2 which is expressed at high levels in RNA samples from retina, including the retinal pigment epithelium, and from melanoma. This gene encodes a protein of 424 amino acids displaying several putative transmembrane domains and sharing no similarities with previously identified molecules. Five intragenic deletions and a 2 bp insertion resulting in a premature stop codon were identified from DMA analysis of patients with OA1, indicating that we have identified the OA1 gene.
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A YAC-based binning strategy facilitating the rapid assembly of cosmid contigs: 1.6 Mb of overlapping cosmids in Xp22
Human molecular genetics, 1994Co-Authors: Martin C Wapenaar, Laura Schaefer, Huda Y. Zoghbi, Maria Teresa Bassi, M. Vittoria Schiaffino, A. Craig Chinault, Andrea BallabioAbstract:We have applied a yeast artificial chromosome (YAC)-based cosmid isolation and binning strategy to convert a YAC contig in Xp22 into 1.6 Mb of overlapping cosmids. This strategy is based on the screening of a high-density arrayed X chromosome-specific cosmid library with large YAC-derived restriction fragments and entire YAC probes. Cosmids selected in this way were gridded on dot blots and further mapped into bins defined by the overlap intervals of the YACs and YAC fragments. This rapid binning of cosmids simplified the subsequent assembly of cosmid contigs by restriction fingerprint hybridization. In total, we identified 139 cosmids spanning the entire 1.6 Mb region with a minimal overlap set of 53 clones. These cosmids were assigned to 17 bins and 9 contigs. One of the contigs is 665 kb in length and is one of the largest uninterrupted cosmid contigs in humans reported to date. The gaps between the contigs are minor and, together, they represent less than 7% of the region covered. Two previously identified genes are contained in these cosmids, the gene for amelogenin (AMG) and the recently isolated putative chloride channel gene CICN4. In addition, two disease loci have been mapped to this region: X-linked Ocular Albinism type 1 (OA1) and the microphthalmia with linear skin defects (MLS) syndrome. The assembly of the cosmid maps allowed us to determine the size of the deletion intervals for these two loci, which were estimated to be 110 kb for OA1 and 570 kb for MLS.(ABSTRACT TRUNCATED AT 250 WORDS)
Valeria Marigo - One of the best experts on this subject based on the ideXlab platform.
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Melanoregulin, Product of the dsu Locus, Links the BLOC-Pathway and Oa1 in Organelle Biogenesis
2016Co-Authors: Rivka A. Rachel, Valeria Marigo, Kunio Nagashima, Norene T. O’sullivan, Laura S. Frost, Frank P. Stefano, Kathleen Boesze-battagliaAbstract:Humans with Hermansky-Pudlak Syndrome (HPS) or Ocular Albinism (OA1) display abnormal aspects of organelle biogenesis. The multigenic disorder HPS displays broad defects in biogenesis of lysosome-related organelles including melanosomes, platelet dense granules, and lysosomes. A phenotype of Ocular pigmentation in OA1 is a smaller number of macromelanosomes, in contrast to HPS, where in many cases the melanosomes are smaller than normal. In these studies we define the role of the Mregdsu gene, which suppresses the coat color dilution of Myo5a, melanophilin, and Rab27a mutant mice in maintaining melanosome size and distribution. We show that the product of the Mregdsu locus, melanoregulin (MREG), interacts both with members of the HPS BLOC-2 complex and with Oa1 in regulating melanosome size. Loss of MREG function facilitates increase in the size of micromelanosomes in the choroid of the HPS BLOC-2 mutants ruby, ruby2, and cocoa, while a transgenic mouse overexpressing melanoregulin corrects the size of retinal pigment epithelium (RPE) macromelanosomes in Oa1ko/ko mice. Collectively, these results suggest that MREG levels regulate pigment incorporation into melanosomes. Immunohistochemical analysis localizes melanoregulin not to melanosomes, but to small vesicles in the cytoplasm of the RPE, consistent with a role for this protein in regulating membrane interactions during melanosome biogenesis. These results provide the first link between the BLOC pathway and Oa1 in melanosom
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Melanoregulin, Product of the dsu Locus, Links the BLOC-Pathway and Oa1 in Organelle Biogenesis
2012Co-Authors: Rivka A. Rachel, Valeria Marigo, Kunio Nagashima, Laura S. Frost, Frank P. Stefano, Norene T. O'sullivan, Kathleen Boesze-battagliaAbstract:Humans with Hermansky-Pudlak Syndrome (HPS) or Ocular Albinism (OA1) display abnormal aspects of organelle biogenesis. The multigenic disorder HPS displays broad defects in biogenesis of lysosome-related organelles including melanosomes, platelet dense granules, and lysosomes. A phenotype of Ocular pigmentation in OA1 is a smaller number of macromelanosomes, in contrast to HPS, where in many cases the melanosomes are smaller than normal. In these studies we define the role of the Mregdsu gene, which suppresses the coat color dilution of Myo5a, melanophilin, and Rab27a mutant mice in maintaining melanosome size and distribution. We show that the product of the Mregdsu locus, melanoregulin (MREG), interacts both with members of the HPS BLOC-2 complex and with Oa1 in regulating melanosome size. Loss of MREG function facilitates increase in the size of micromelanosomes in the choroid of the HPS BLOC-2 mutants ruby, ruby2, and cocoa, while a transgenic mouse overexpressing melanoregulin corrects the size of retinal pigment epithelium (RPE) macromelanosomes in Oa1ko/ko mice. Collectively, these results suggest that MREG levels regulate pigment incorporation into melanosomes. Immunohistochemical analysis localizes melanoregulin not to melanosomes, but to small vesicles in the cytoplasm of the RPE, consistent with a role for this protein in regulating membrane interactions during melanosome biogenesis. These results provide the first link between the BLOC pathway and Oa1 in melanosome biogenesis, thus supporting the hypothesis that intracellular G-protein coupled receptors may be involved in the biogenesis of other organelles. Furthermore these studies provide the foundation for therapeutic approaches to correct the pigment defects in the RPE of HPS and OA1.
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the Ocular Albinism type 1 oa1 g protein coupled receptor functions with mart 1 at early stages of melanogenesis to control melanosome identity and composition
Human Molecular Genetics, 2009Co-Authors: Francesca Giordano, Graca Raposo, Ciro Bonetti, Enrico Maria Surace, Valeria MarigoAbstract:OA1 (GPR143; GPCR, G-protein-coupled receptor), the protein product of the Ocular Albinism type 1 gene, encodes a pigment-cell-specific GPCR that localizes intracellularly to melanosomes. OA1 mutations result in Ocular Albinism due to alterations in melanosome formation, suggesting that OA1 is a key player in the biogenesis of melanosomes. To address the function of OA1 in melanosome biogenesis, we have used siRNA inactivation and combined morphological and biochemical methods to investigate melanosome ultrastructure, melanosomal protein localization and expression in human pigmented melanocytic cells. OA1 loss of function leads to decreased pigmentation and causes formation of enlarged aberrant premelanosomes harboring disorganized fibrillar structures and displaying proteins of mature melanosomes and lysosomes at their membrane. Moreover, we show that OA1 interacts biochemically with the premelanosomal protein MART-1. Inactivation of MART-1 by siRNA leads to a decreased stability of OA1 and is accompanied by similar defects in premelanosome biogenesis and composition. These data show for the first time that melanosome composition and identity are regulated at early stages by OA1 and that MART-1 likely acts as an escort protein for this GPCR.
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the Ocular Albinism type 1 oa1 gene controls melanosome maturation and size
Investigative Ophthalmology & Visual Science, 2005Co-Authors: Katia Cortese, Andrea Ballabio, Francesca Giordano, Enrico Maria Surace, Carlo Tacchetti, Consuelo Venturi, Valeria MarigoAbstract:PURPOSE. The authors took advantage of the Oal mutant mouse in combination with other Albinism mouse models (i.e., Tyrosinase and membrane-associated transporter protein [Matp]) to study the function of Oal, the gene mutated in Ocular Albinism type 1, in the RPE during development and after birth. METHODS. Enzyme activity and protein localization were analyzed by immunohistochemistry of tyrosinase (Tyr) in Oal-null mice. Ultrastructural analysis and morphometry were performed by electron microscopy, of the RPE in Oal-knockout mouse and double-mutant mice of Oal with either Tyr or Matp. RESULTS. Differently from other Albinism models, Tyr activity was not impaired in Oa1 -/- eyes. Hypopigmentation of the RPE in Oa1 -/- mice is due to a reduced number of melanosomes. Analysis of Oa1 -/- ;Tyr c-2J /Tyr c-2J and Oa1 -/- ;Matp uw / Matp double-knockout mice, which display a block at stages II and III of melanosome maturation, respectively, revealed that Oal controls the rate of melanosome biogenesis at early stages of the organellogenesis, whereas the control on the organelle size is exerted at the final stage of melanosome development (stage IV). CONCLUSIONS. The findings indicate that Oal is involved in the regulation of melanosome maturation at two steps. Acting at early maturation stages, Oal controls the abundance of melanosomes in RPE cells. At later stages, Oal has a function in the maintenance of a correct melanosomal size. This study helps to define Ocular Albinism type 1 as a defect in melanosome organellogenesis and not in melanin production.
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the microphthalmia transcription factor mitf controls expression of the Ocular Albinism type 1 gene link between melanin synthesis and melanosome biogenesis
Molecular and Cellular Biology, 2004Co-Authors: Francesco Vetrini, Andrea Ballabio, Alberto Auricchio, Barbara Angeletti, David E Fisher, Valeria MarigoAbstract:Melanogenesis is the process that regulates skin and eye pigmentation. Albinism, a genetic disease causing pigmentation defects and visual disorders, is caused by mutations in genes controlling either melanin synthesis or melanosome biogenesis. Here we show that a common transcriptional control regulates both of these processes. We performed an analysis of the regulatory region of Oa1, the murine homolog of the gene that is mutated in the X-linked form of Ocular Albinism, as Oa1's function affects melanosome biogenesis. We demonstrated that Oa1 is a target of Mitf and that this regulatory mechanism is conserved in the human gene. Tissue-specific control of Oa1 transcription lies within a region of 617 bp that contains the E-box bound by Mitf. Finally, we took advantage of a virus-based system to assess tissue specificity in vivo. To this end, a small fragment of the Oa1 promoter was cloned in front of a reporter gene in an adeno-associated virus. After we injected this virus into the subretinal space, we observed reporter gene expression specifically in the retinal pigment epithelium, confirming the cell-specific expression of the Oa1 promoter in the eye. The results obtained with this viral system are a preamble to the development of new gene delivery approaches for the treatment of retinal pigment epithelium defects.
Pratiwi Rarastoeti - One of the best experts on this subject based on the ideXlab platform.
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MUTASI MISSENSE (P.374PHE/LEU) PADA EKSON 5 GEN MATP, PENYEBAB OCULOCUTANEOUS Albinism TIPE 4 (OCA4) DI WONOSOBO, JAWA TENGAH
Prodi Pendidikan Biologi FKIP UNS, 2013Co-Authors: Nur Handayani, Niken Satuti, Sukmawati Feri, Pratiwi RarastoetiAbstract:ABSTRAK Albinisme merupakan kelainan genetik autosomal resesif berupa gangguan sintesis melanin yang terjadi pada manusia. Albinisme dibagi menjadi dua kelompok besar, yaitu Ocular Albinism (OA) dan Oculocutaneous Albinism (OCA). Berdasarkan gen yang mengalami mutasi, OCA dibedakan menjadi 4 tipe yaitu OCA1, OCA2, OCA3 dan OCA4. OCA4 disebabkan mutasi pada gen MATP. Penelitian yang telah dilakukan dengan PCR-SSCP (Polymerase Chain Reaction-Single Stranded Conformation Polymorphism) mendeteksi adanya mutasi pada ekson 5 gen MATP, pada penderita Albinisme di Wonosobo, Jawa Tengah. Sekuensing ekson 5 gen MATP dilakukan untuk mengidentifikasi tipe mutasinya. DNA diisolasi dari sampel darah penderita dan digunakan sebagai template untuk amplifikasi ekson 5 gen MATP dengan metode PCR. Produk PCR selanjutnya digunakan sebagai template untuk sekuensing dengan metode Sanger. Hasil sekuensing dianalisis menggunakan program Clustal-W dan dibandingkan dengan sekuens ekson 5 gen MATP dari International DNA Data Base (nomer akses AF172849.1). Hasil analisis menunjukkan adanya pada perubahan basa nukleotida no.1122 dari C menjadi G (c.1122 C>G) yang mengakibatkan mutasi missense, yaitu fenilalanin menjadi leusin, pada asam amino nomer 374 (p.374 Phe/Leu). Kata kunci : OCA4, mutasi, ekson 5, gen MAT
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MUTASI MISSENSE (P.374PHE/LEU) PADA EKSON 5 GEN MATP, PENYEBAB OCULOCUTANEOUS Albinism TIPE 4 (OCA4) DI WONOSOBO, JAWA TENGAH
2011Co-Authors: Satuti Nur Handayani Niken, Sukmawati Feri, Pratiwi RarastoetiAbstract:Albinisme merupakan kelainan genetik autosomal resesif berupa gangguan sintesis melanin yang terjadi pada manusia. Albinisme dibagi menjadi dua kelompok besar, yaitu Ocular Albinism (OA) dan Oculocutaneous Albinism (OCA). Berdasarkan gen yang mengalami mutasi, OCA dibedakan menjadi 4 tipe yaitu OCA1, OCA2, OCA3 dan OCA4. OCA4 disebabkan mutasi pada gen MATP. Penelitian yang telah dilakukan dengan PCR-SSCP (Polymerase Chain Reaction-Single Stranded Conformation Polymorphism) mendeteksi adanya mutasi pada ekson 5 gen MATP, pada penderita Albinisme di Wonosobo, Jawa Tengah. Sekuensing ekson 5 gen MATP dilakukan untuk mengidentifikasi tipe mutasinya. DNA diisolasi dari sampel darah penderita dan digunakan sebagai template untuk amplifikasi ekson 5 gen MATP dengan metode PCR. Produk PCR selanjutnya digunakan sebagai template untuk sekuensing dengan metode Sanger. Hasil sekuensing dianalisis menggunakan program Clustal-W dan dibandingkan dengan sekuens ekson 5 gen MATP dari International DNA Data Base (nomer akses AF172849.1). Hasil analisis menunjukkan adanya pada perubahan basa nukleotida no.1122 dari C menjadi G (c.1122 C>G) yang mengakibatkan mutasi missense, yaitu fenilalanin menjadi leusin, pada asam amino nomer 374 (p.374 Phe/Leu)
Chris P Ponting - One of the best experts on this subject based on the ideXlab platform.
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a new sequence motif linking lissencephaly treacher collins and oral facial digital type 1 syndromes microtubule dynamics and cell migration
Human Molecular Genetics, 2001Co-Authors: Richard D Emes, Chris P PontingAbstract:: A previously unidentified sequence motif has been identified in the products of genes mutated in Miller-Dieker lissencephaly, Treacher Collins, oral-facial-digital type 1 and contiguous syndrome Ocular Albinism with late onset sensorineural deafness syndromes. An additional homologous motif was detected in a gene product fused to the fibroblast growth factor receptor type 1 in patients with an atypical stem cell myeloproliferative disorder. In total, over 100 eukaryotic intracellular proteins are shown to possess a LIS1 homology (LisH) motif, including several katanin p60 subunits, muskelin, tonneau, LEUNIG, Nopp140, aimless and numerous WD repeat-containing beta-propeller proteins. It is suggested that LisH motifs contribute to the regulation of microtubule dynamics, either by mediating dimerization, or else by binding cytoplasmic dynein heavy chain or microtubules directly. The predicted secondary structure of LisH motifs, and their occurrence in homologues of Gbeta beta-propeller subunits, suggests that they are analogues of Ggamma subunits, and might associate with the periphery of beta-propeller domains. The finding of LisH motifs in both treacle and Nopp140 reinforces previous observations of functional similarities between these nucleolar proteins. Uncharacterized LisH motif-containing proteins represent candidates for other diseases associated with aberrant microtubule dynamics and defects of cell migration, nucleokinesis or chromosome segregation.
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a new sequence motif linking lissencephaly treacher collins and oral facial digital type 1 syndromes microtubule dynamics and cell migration
Human Molecular Genetics, 2001Co-Authors: Richard D Emes, Chris P PontingAbstract:A previously unidentified sequence motif has been identified in the products of genes mutated in Miller-Dieker lissencephaly, Treacher Collins, oral-facial-digital type 1 and contiguous syndrome Ocular Albinism with late onset sensorineural deafness syndromes. An additional homologous motif was detected in a gene product fused to the fibroblast growth factor receptor type 1 in patients with an atypical stem cell myeloproliferative disorder. In total, over 100 eukaryotic intracellular proteins are shown to possess a LIS1 homology (LisH) motif, including several katanin p60 subunits, muskelin, tonneau, LEUNIG, Nopp140, aimless and numerous WD repeat-containing beta-propeller proteins. It is suggested that LisH motifs contribute to the regulation of microtubule dynamics, either by mediating dimerization, or else by binding cytoplasmic dynein heavy chain or microtubules directly. The predicted secondary structure of LisH motifs, and their occurrence in homologues of Gbeta beta-propeller subunits, suggests that they are analogues of Ggamma subunits, and might associate with the periphery of beta-propeller domains. The finding of LisH motifs in both treacle and Nopp140 reinforces previous observations of functional similarities between these nucleolar proteins. Uncharacterized LisH motif-containing proteins represent candidates for other diseases associated with aberrant microtubule dynamics and defects of cell migration, nucleokinesis or chromosome segregation.
