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

Loredana Maggi, Eugenio Maria Mercuri, Alberto Romano, Roberta Battini, Enrico Silvio Bertini, Carmine Bruno, Francesca Moro, Adele D'Amico, Guja Astrea, Alessandro Romano, Corrado Angelini, Carlo Giuseppe Antozzi, Rita Barresi, Carla Battisti, Claudio Bruno, Denise Cassandrini, Marina Fanin, Fabiana Fattori, Chiara Fiorillo, Renzo GuerriniLorenzo Maggi, Federica Morani, Marina Mora, Ilaria Pezzini, Esther Picillo, Michele Pinelli, Luisa Politano, Anna Rubegni, Walter Sanseverino, Marco Savarese, Pasquale Striano, Annalaura Torella, Carlo Pietro Trevisan, Rosanna Trovato, Irina Zaraieva, Francesco Muntoni, Vincenzo Nigro, Filippo M. Santorelli, Angela Berardinelli, Giacomo Comi, Maria Alice Donati, Maria Teresa Dotti, Marina Grandis, Francesca Magri, Maria A. Maioli, Alessandro Malandrini, Francesco Mari, Roberto Massa, Luciano Merlini, Maurizio Moggio, Lucia O. Morandi, Olimpia Musumeci, Antonella Pini, Elena Pegoraro, Elena M. Pennisi, Lorenzo Peverelli, Giulia Ricci, Carmelo Rodolico, Lucia Ruggiero, Michele Sacchini, Lucio Santoro, Gabriele Siciliano, Alessandro Simonati, Paola Tonin, Antonio Toscano

Risultato della ricerca: Contributo in rivistaArticolo in rivista

12 Citazioni (Scopus)

Abstract

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.
Lingua originaleEnglish
pagine (da-a)170-170
Numero di pagine1
RivistaOrphanet Journal of Rare Diseases
DOI
Stato di pubblicazionePubblicato - 2018

Keywords

  • Dystriglycanopathies

Fingerprint

Entra nei temi di ricerca di 'Broad phenotypic spectrum and genotype-phenotype correlations in GMPPB-related dystroglycanopathies: an Italian cross-sectional study.'. Insieme formano una fingerprint unica.

Cita questo