Congenital muscular dystrophies with defective glycosylation of dystroglycan

Mercuri, Eugenio; Messina, Sonia; Bruno, Cristina; Mora, Marina; Pegoraro, Elena; Comi, Giacomo P.; D'Amico, A.; Aiello, Chiara; Biancheri, Roberta; Berardinelli, Angela; Boffi, P.; Cassandrini, Denise; Laverda, A. M.; Moggio, Maurizio; Morandi, L.; Moroni, Isabella; Pane, Marika; Pezzani, Raffaele; Pichiecchio, Anna; Pini, Antonella; Minetti, Carlo; Mongini, Tiziana; Mottarelli, E.; Ricci, Enzo; Ruggieri, Alessandra; Saredi, Simona; Scuderi, Carmela; Tessa, Alessandra; Toscano, Antonio; Tortorella, Gaetano; Trevisan, CP; Uggetti, Carla; Vasco, Gessica; Santorelli, Filippo M.; Bertini, Enrico

doi:10.1212/01.wnl.0000346518.68110.60

Cited by 166 publications

(154 citation statements)

References 39 publications

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“…23 In addition, a reduction in dystroglycan glycosylation in S2 and S3 suggest an overlap with less severe forms of dystroglycanopathies, where CMD is present with cataracts and ID. 6,7 Similar cases of merosin-positive CMD with cataracts and ID have been previously reported, 24,25 also suggesting that this disorder may represent a distinct clinical entity.…”

supporting

confidence: 64%

“…5 The most severe forms of dystroglycanopathy present with CMD associated with lissencephaly (smooth brain) and a variety of eye malformations affecting both the retina and the anterior chamber (e.g., cataracts, glaucoma), but multiple case subjects have only CMD with intellectual disability and more subtle brain findings. 6,7 Marinesco-Sjögren syndrome (MSS [MIM:248800]) is a form of myopathy with a similar constellation of findings including muscle involvement, intellectual disability, cataracts, brain MRI findings, and other signs of central nervous system (CNS) involvement. 8,9 Cerebellar atrophy is often considered the most prominent neuroradiologic finding in MSS, but it is not an obligatory finding.…”

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confidence: 99%

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Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy

Osborn

Pond

Mazaheri

et al. 2017

The American Journal of Human Genetics

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Congenital muscular dystrophies display a wide phenotypic and genetic heterogeneity. The combination of clinical, biochemical, and molecular genetic findings must be considered to obtain the precise diagnosis and provide appropriate genetic counselling. Here we report five individuals from four families presenting with variable clinical features including muscular dystrophy with a reduction in dystroglycan glycosylation, short stature, intellectual disability, and cataracts, overlapping both the dystroglycanopathies and Marinesco-Sjögren syndrome. Whole-exome sequencing revealed homozygous missense and compound heterozygous mutations in INPP5K in the affected members of each family. INPP5K encodes the inositol polyphosphate-5-phosphatase K, also known as SKIP (skeletal muscle and kidney enriched inositol phosphatase), which is highly expressed in the brain and muscle. INPP5K localizes to both the endoplasmic reticulum and to actin ruffles in the cytoplasm. It has been shown to regulate myoblast differentiation and has also been implicated in protein processing through its interaction with the ER chaperone HSPA5/BiP. We show that morpholino-mediated inpp5k loss of function in the zebrafish results in shortened body axis, microphthalmia with disorganized lens, microcephaly, reduced touch-evoked motility, and highly disorganized myofibers. Altogether these data demonstrate that mutations in INPP5K cause a congenital muscular dystrophy syndrome with short stature, cataracts, and intellectual disability.

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confidence: 64%

mentioning

confidence: 99%

Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy

Osborn

Pond

Mazaheri

et al. 2017

The American Journal of Human Genetics

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“…MDC1D due to mutations in LARGE is the rarest of the adystroglycanopathies identified to date, with only three confirmed families previously described. [6][7][8] Affected children have had typical neurological and muscle abnormalities associated with the a-dystroglycanopathies, but with very different severities; one family had mild muscle-eye-brain disease (MEB) and the other two had typical WWS. Another WWS patient has been reported with a single heterozygous nonsense mutation in LARGE.…”

Section: Introductionmentioning

confidence: 99%

Congenital muscular dystrophy type 1D (MDC1D) due to a large intragenic insertion/deletion, involving intron 10 of the LARGE gene

et al. 2011

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Mutation of the LARGE gene is the rarest of the six known genetic causes of a-dystroglycanopathy. We report further a family with MDC1D due to a complex genomic rearrangement that was not apparent on standard sequencing of LARGE. Two sisters in a consanguineous family had moderate mental retardation and cerebellar malformations, together with dystrophic changes and markedly reduced a-dystroglycan glycosylation staining on muscle biopsy. There was homozygous linkage to the LARGE locus but sequencing of LARGE coding regions was normal. Analysis of LARGE cDNA showed an abnormal sequence inserted between exons 10 and 11, in most of the transcripts, predicted to introduce a premature stop codon. The abnormal sequence mapped to a spliced EST (DA935254) of unknown function, normally located at 100 kb centromeric of LARGE on chromosome 22q12.3. Quantitative PCR analysis of the EST and adjacent regions showed twice the normal copy number in patients' genomic DNA samples, consistent with a large intra-chromosomal duplication inserted into intron 10 of LARGE in a homozygous state. This insertion was associated with deletion of a central region of intron 10, but the exact break points of the deletion/ duplication were not found, suggesting that an even more complex rearrangement may have occurred. The exact function of LARGE, a golgi protein, remains uncertain. POMT and POMGnT enzyme activities were normal in patients' lymphoblast cells, suggesting that defects in LARGE do not affect the initiation of O-mannosyl glycans.

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“…To exclude that patients may have been referred by other physicians, we also checked all the molecular genetic centers performing analysis of the CMD genes. Other sources available for this study included the Collagen VI Database held at the University of Ferrara and the CMD Dystroglycan Database, a nationwide database used for our previous study 9,10 and that is constantly updated.…”

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confidence: 99%

Prevalence of congenital muscular dystrophy in Italy

et al. 2015

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Objective: We provide a nationwide population study of patients with congenital muscular dystrophy in Italy.Methods: Cases were ascertained from the databases in all the tertiary referral centers for pediatric neuromuscular disorders and from all the genetic diagnostic centers in which diagnostic tests for these forms are performed. Results:The study includes 336 patients with a point prevalence of 0.563 per 100,000. Mutations were identified in 220 of the 336 (65.5%). The cohort was subdivided into diagnostic categories based on the most recent classifications on congenital muscular dystrophies. The most common forms were those with a-dystroglycan glycosylation deficiency (40.18%) followed by those with laminin a2 deficiency (24.11%) and collagen VI deficiency (20.24%). The forms of congenital muscular dystrophy related to mutations in SEPN1 and LMNA were less frequent (6.25% and 5.95%, respectively). Conclusions:Our study provides for the first time comprehensive epidemiologic information and point prevalence figures for each of the major diagnostic categories on a large cohort of congenital muscular dystrophies. The study also reflects the diagnostic progress in this field with an accurate classification of the cases according to the most recent gene discoveries. The term congenital muscular dystrophy (CMD) classically includes a group of genetically, clinically, and biochemically distinct entities sharing clinical and pathologic features such as early presentation of weakness and hypotonia and dystrophic features on muscle biopsy. 1 The rapidly increasing identification of several genes responsible for different forms of CMD has dramatically expanded the spectrum of the known forms, allowing a better understanding of the individual forms and different underlying pathomechanisms. 2 The incidence and prevalence of CMD in populations is not sufficiently known with only a few studies reporting incidence or point prevalence in relatively small regions. 3-5 Furthermore, several new genes have only been described in the last few years and the subtyping and classification in those reports is therefore not updated.

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Congenital muscular dystrophies with defective glycosylation of dystroglycan

Abstract: Our data broaden the clinical spectrum associated with mutations in glycosyltransferases and provide data on their prevalence in the Italian population.

Cited by 166 publications

References 39 publications

Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy

Mutations in INPP5K Cause a Form of Congenital Muscular Dystrophy Overlapping Marinesco-Sjögren Syndrome and Dystroglycanopathy

Congenital muscular dystrophy type 1D (MDC1D) due to a large intragenic insertion/deletion, involving intron 10 of the LARGE gene

Prevalence of congenital muscular dystrophy in Italy

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