Mutations in GDP-Mannose Pyrophosphorylase B Cause Congenital and Limb-Girdle Muscular Dystrophies Associated with Hypoglycosylation of α-Dystroglycan

Abstract

Congenital muscular dystrophies with hypoglycosylation of α-dystroglycan (α-DG) are a heterogeneous group of disorders often associated with brain and eye defects in addition to muscular dystrophy. Causative variants in 14 genes thought to be involved in the glycosylation of α-DG have been identified thus far. Allelic mutations in these genes might also cause milder limb-girdle muscular dystrophy phenotypes. Using a combination of exome and Sanger sequencing in eight unrelated individuals, we present evidence that mutations in guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) can result in muscular dystrophy variants with hypoglycosylated α-DG. GMPPB catalyzes the formation of GDP-mannose from GTP and mannose-1-phosphate. GDP-mannose is required for O-mannosylation of proteins, including α-DG, and it is the substrate of cytosolic mannosyltransferases. We found reduced α-DG glycosylation in the muscle biopsies of affected individuals and in available fibroblasts. Overexpression of wild-type GMPPB in fibroblasts from an affected individual partially restored glycosylation of α-DG. Whereas wild-type GMPPB localized to the cytoplasm, five of the identified missense mutations caused formation of aggregates in the cytoplasm or near membrane protrusions. Additionally, knockdown of the GMPPB ortholog in zebrafish caused structural muscle defects with decreased motility, eye abnormalities, and reduced glycosylation of α-DG. Together, these data indicate that GMPPB mutations are responsible for congenital and limb-girdle muscular dystrophies with hypoglycosylation of α-DG.

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

“…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.…”

“…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.…”

A POGLUT1 mutation causes a muscular dystrophy with reduced notch signaling and satellite cell loss

“…In contrast, other forms of dystroglycanopathy usually exhibit markedly diminished or no binding for both laminin and agrin in muscle, together with defective muscular basement membrane compaction Hara et al, 2011;Willer et al, 2012;Goddeeris et al, 2013). Moreover, the published results show that secondary dystroglycanopathies caused by mutations in known genes result in reduced functional a-dystroglycan glycosylation in patient fibroblasts, and in the majority of patients, the level of a-dystroglycan glycosylation is comparable in fibroblasts and skeletal muscle from the same patient (Carss et al, 2013). These observations further support the notion that, although decreased laminin binding in muscle is likely to contribute to pathology in our ◀ Figure 7.…”

“…However, the agrinbinding activity to the patients' muscle extracts showed no difference compared with controls ( Fig 2B). Moreover, in skin fibroblasts from patients, the level of both functional a-dystroglycan glycosylation, examined by Western blot and flow cytometry (Stevens et al, 2013b), and its ability to bind laminin ( Fig 2B and Appendix Fig S5B) were normal, unlike known secondary dystroglycanopathies, which usually result in decreased functional a-dystroglycan glycosylation in both muscle and the skin fibroblasts (Willer et al, 2012;Carss et al, 2013;Stevens et al, 2013a). Finally, although basement membrane defects are commonly observed in dystroglycanopathies (Yamamoto et al, 1997;Goddeeris et al, 2013), transmission electron microscopy showed normal muscle ultrastructure in patients, with no alterations in basement membrane compaction (Fig 2C and Appendix Fig S5C).…”

Gènes impliqués dans les alpha-dystroglycanopathies

“…Le GDP-Man est à l'origine du Dol P-Man, substrat des mannosyltransférases qui vont initier la synthèse des cores M1, M2 et M3. Une dizaine de patients CMD ou LGMD [54,55] …”