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Broad phenotypic spectrum and genotype-phenotype correlations in GMPPB-related dystroglycanopathies: an Italian cross-sectional study

BACKGROUND: Dystroglycanopathy (α-DG) is a relatively common, clinically and genetically heterogeneous category of congenital forms of muscular dystrophy (CMD) and limb-girdle muscular dystrophy (LGMD) associated with hypoglycosylated α-dystroglycan. To date, mutations in at least 19 genes have been...

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Autores principales: Astrea, Guja, Romano, Alessandro, Angelini, Corrado, Antozzi, Carlo Giuseppe, Barresi, Rita, Battini, Roberta, Battisti, Carla, Bertini, Enrico, Bruno, Claudio, Cassandrini, Denise, Fanin, Marina, Fattori, Fabiana, Fiorillo, Chiara, Guerrini, Renzo, Maggi, Lorenzo, Mercuri, Eugenio, Morani, Federica, Mora, Marina, Moro, Francesca, Pezzini, Ilaria, Picillo, Esther, Pinelli, Michele, Politano, Luisa, Rubegni, Anna, Sanseverino, Walter, Savarese, Marco, Striano, Pasquale, Torella, Annalaura, Trevisan, Carlo Pietro, Trovato, Rosanna, Zaraieva, Irina, Muntoni, Francesco, Nigro, Vincenzo, D’Amico, Adele, Santorelli, Filippo M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158856/
https://www.ncbi.nlm.nih.gov/pubmed/30257713
http://dx.doi.org/10.1186/s13023-018-0863-x
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author Astrea, Guja
Romano, Alessandro
Angelini, Corrado
Antozzi, Carlo Giuseppe
Barresi, Rita
Battini, Roberta
Battisti, Carla
Bertini, Enrico
Bruno, Claudio
Cassandrini, Denise
Fanin, Marina
Fattori, Fabiana
Fiorillo, Chiara
Guerrini, Renzo
Maggi, Lorenzo
Mercuri, Eugenio
Morani, Federica
Mora, Marina
Moro, Francesca
Pezzini, Ilaria
Picillo, Esther
Pinelli, Michele
Politano, Luisa
Rubegni, Anna
Sanseverino, Walter
Savarese, Marco
Striano, Pasquale
Torella, Annalaura
Trevisan, Carlo Pietro
Trovato, Rosanna
Zaraieva, Irina
Muntoni, Francesco
Nigro, Vincenzo
D’Amico, Adele
Santorelli, Filippo M.
author_facet Astrea, Guja
Romano, Alessandro
Angelini, Corrado
Antozzi, Carlo Giuseppe
Barresi, Rita
Battini, Roberta
Battisti, Carla
Bertini, Enrico
Bruno, Claudio
Cassandrini, Denise
Fanin, Marina
Fattori, Fabiana
Fiorillo, Chiara
Guerrini, Renzo
Maggi, Lorenzo
Mercuri, Eugenio
Morani, Federica
Mora, Marina
Moro, Francesca
Pezzini, Ilaria
Picillo, Esther
Pinelli, Michele
Politano, Luisa
Rubegni, Anna
Sanseverino, Walter
Savarese, Marco
Striano, Pasquale
Torella, Annalaura
Trevisan, Carlo Pietro
Trovato, Rosanna
Zaraieva, Irina
Muntoni, Francesco
Nigro, Vincenzo
D’Amico, Adele
Santorelli, Filippo M.
author_sort Astrea, Guja
collection PubMed
description BACKGROUND: Dystroglycanopathy (α-DG) is a relatively common, clinically and genetically heterogeneous category of congenital forms of muscular dystrophy (CMD) and limb-girdle muscular dystrophy (LGMD) associated with hypoglycosylated α-dystroglycan. To date, mutations in at least 19 genes have been associated with α-DG. One of them, GMPPB, encoding the guanosine-diphosphate-mannose (GDP-mannose) pyrophosphorylase B protein, has recently been associated with a wide clinical spectrum ranging from severe Walker-Warburg syndrome to pseudo-metabolic myopathy and even congenital myasthenic syndromes. We re-sequenced the full set of known disease genes in 73 Italian patients with evidence of either reduced or nearly absent α-dystroglycan to assess genotype-phenotype correlations in this cohort. We used innovative bioinformatic tools to calculate the effects of all described GMPPB mutations on protein function and attempted to correlate them with phenotypic expressions. RESULTS: We identified 13 additional cases from 12 families and defined seven novel mutations. Patients displayed variable phenotypes including less typical pictures, ranging from asymptomatic hyperCKemia, to arthrogryposis and congenital clubfoot at birth, and also showed neurodevelopmental comorbidities, such as seizures and ataxic gait, as well as autism-spectrum disorder, which is seldom described in clinical reports of dystroglycanopathies. We also demonstrated that few mutations recur in the Italian GMPPB-mutated population and that alterations of protein stability are the main effects of GMPPB missense variants. CONCLUSION: This work adds to the data on genotype-phenotype correlations in α-DG and offers new bionformatic tools to provide the conceptual framework needed to understand the complexity of these disorders. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13023-018-0863-x) contains supplementary material, which is available to authorized users.
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spelling pubmed-61588562018-10-01 Broad phenotypic spectrum and genotype-phenotype correlations in GMPPB-related dystroglycanopathies: an Italian cross-sectional study Astrea, Guja Romano, Alessandro Angelini, Corrado Antozzi, Carlo Giuseppe Barresi, Rita Battini, Roberta Battisti, Carla Bertini, Enrico Bruno, Claudio Cassandrini, Denise Fanin, Marina Fattori, Fabiana Fiorillo, Chiara Guerrini, Renzo Maggi, Lorenzo Mercuri, Eugenio Morani, Federica Mora, Marina Moro, Francesca Pezzini, Ilaria Picillo, Esther Pinelli, Michele Politano, Luisa Rubegni, Anna Sanseverino, Walter Savarese, Marco Striano, Pasquale Torella, Annalaura Trevisan, Carlo Pietro Trovato, Rosanna Zaraieva, Irina Muntoni, Francesco Nigro, Vincenzo D’Amico, Adele Santorelli, Filippo M. Orphanet J Rare Dis Research BACKGROUND: Dystroglycanopathy (α-DG) is a relatively common, clinically and genetically heterogeneous category of congenital forms of muscular dystrophy (CMD) and limb-girdle muscular dystrophy (LGMD) associated with hypoglycosylated α-dystroglycan. To date, mutations in at least 19 genes have been associated with α-DG. One of them, GMPPB, encoding the guanosine-diphosphate-mannose (GDP-mannose) pyrophosphorylase B protein, has recently been associated with a wide clinical spectrum ranging from severe Walker-Warburg syndrome to pseudo-metabolic myopathy and even congenital myasthenic syndromes. We re-sequenced the full set of known disease genes in 73 Italian patients with evidence of either reduced or nearly absent α-dystroglycan to assess genotype-phenotype correlations in this cohort. We used innovative bioinformatic tools to calculate the effects of all described GMPPB mutations on protein function and attempted to correlate them with phenotypic expressions. RESULTS: We identified 13 additional cases from 12 families and defined seven novel mutations. Patients displayed variable phenotypes including less typical pictures, ranging from asymptomatic hyperCKemia, to arthrogryposis and congenital clubfoot at birth, and also showed neurodevelopmental comorbidities, such as seizures and ataxic gait, as well as autism-spectrum disorder, which is seldom described in clinical reports of dystroglycanopathies. We also demonstrated that few mutations recur in the Italian GMPPB-mutated population and that alterations of protein stability are the main effects of GMPPB missense variants. CONCLUSION: This work adds to the data on genotype-phenotype correlations in α-DG and offers new bionformatic tools to provide the conceptual framework needed to understand the complexity of these disorders. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13023-018-0863-x) contains supplementary material, which is available to authorized users. BioMed Central 2018-09-26 /pmc/articles/PMC6158856/ /pubmed/30257713 http://dx.doi.org/10.1186/s13023-018-0863-x Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Astrea, Guja
Romano, Alessandro
Angelini, Corrado
Antozzi, Carlo Giuseppe
Barresi, Rita
Battini, Roberta
Battisti, Carla
Bertini, Enrico
Bruno, Claudio
Cassandrini, Denise
Fanin, Marina
Fattori, Fabiana
Fiorillo, Chiara
Guerrini, Renzo
Maggi, Lorenzo
Mercuri, Eugenio
Morani, Federica
Mora, Marina
Moro, Francesca
Pezzini, Ilaria
Picillo, Esther
Pinelli, Michele
Politano, Luisa
Rubegni, Anna
Sanseverino, Walter
Savarese, Marco
Striano, Pasquale
Torella, Annalaura
Trevisan, Carlo Pietro
Trovato, Rosanna
Zaraieva, Irina
Muntoni, Francesco
Nigro, Vincenzo
D’Amico, Adele
Santorelli, Filippo M.
Broad phenotypic spectrum and genotype-phenotype correlations in GMPPB-related dystroglycanopathies: an Italian cross-sectional study
title Broad phenotypic spectrum and genotype-phenotype correlations in GMPPB-related dystroglycanopathies: an Italian cross-sectional study
title_full Broad phenotypic spectrum and genotype-phenotype correlations in GMPPB-related dystroglycanopathies: an Italian cross-sectional study
title_fullStr Broad phenotypic spectrum and genotype-phenotype correlations in GMPPB-related dystroglycanopathies: an Italian cross-sectional study
title_full_unstemmed Broad phenotypic spectrum and genotype-phenotype correlations in GMPPB-related dystroglycanopathies: an Italian cross-sectional study
title_short Broad phenotypic spectrum and genotype-phenotype correlations in GMPPB-related dystroglycanopathies: an Italian cross-sectional study
title_sort broad phenotypic spectrum and genotype-phenotype correlations in gmppb-related dystroglycanopathies: an italian cross-sectional study
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158856/
https://www.ncbi.nlm.nih.gov/pubmed/30257713
http://dx.doi.org/10.1186/s13023-018-0863-x
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