Dataset Information

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

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.

SUBMITTER: Astrea G

PROVIDER: S-EPMC6158856 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Astrea Guja G Romano Alessandro A Angelini Corrado C Antozzi Carlo Giuseppe CG Barresi Rita R Battini Roberta R Battisti Carla C Bertini Enrico E Bruno Claudio C Cassandrini Denise D Fanin Marina M Fattori Fabiana F Fiorillo Chiara C Guerrini Renzo R Maggi Lorenzo L Mercuri Eugenio E Morani Federica F Mora Marina M Moro Francesca F Pezzini Ilaria I Picillo Esther E Pinelli Michele M Politano Luisa L Rubegni Anna A Sanseverino Walter W Savarese Marco M Striano Pasquale P Torella Annalaura A Trevisan Carlo Pietro CP Trovato Rosanna R Zaraieva Irina I Muntoni Francesco F Nigro Vincenzo V D'Amico Adele A Santorelli Filippo M FM

Orphanet journal of rare diseases 20180926 1

<h4>Background</h4>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 rangi ...[more]

PMID: 30257713

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Dataset Information

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

Background

Results

Conclusion

Publications

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

Similar Datasets

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