A mutation in mannose‐phosphate‐dolichol utilization defect 1 reveals clinical symptoms of congenital disorders of glycosylation type I and dystroglycanopathy

Tol, Walinka van; Ashikov, Angel; Korsch, Eckhard; Bakar, Nurulamin Abu; Willemsen, M.A.A.P.; Thiel, Christian; Lefeber, Dirk

doi:10.1002/jmd2.12060

Cited by 12 publications

(17 citation statements)

References 28 publications

(73 reference statements)

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“…Indeed, the hypoglycosylation of α-dystroglycan did not become apparent in the muscle of Inpp5k fl/fl MCK-Cre mice until 24 weeks of age when disease was advanced ( Supplemental Figure 2, B and D ). Additionally, no differences were observed in the expression of 20 genes required for the glycosylation of α-dystroglycan that are linked to muscular dystrophy ( 41 , 45 , 46 ) ( Supplemental Figure 2E ). Therefore, muscle disease in Inpp5k fl/fl MCK-Cre mice was consistent with that observed in patients with INPP5K mutations ( 37 , 38 ), and the onset of muscle disease was uncoupled from effects on α-dystroglycan glycosylation.…”

Section: Resultsmentioning

confidence: 99%

“…This interaction is essential for several processes, including the preservation of muscle fiber integrity. Mutations in α-dystroglycan ( DAG1) cause muscular dystrophy ( 42 – 44 ), as do mutations in many proteins (at least 20) that function in the biochemical pathway responsible for α-dystroglycan glycosylation ( 41 , 45 , 46 ). These are called dystroglycanopathies and result from α-dystroglycan hypoglycosylation.…”

Section: Resultsmentioning

confidence: 99%

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Defective lysosome reformation during autophagy causes skeletal muscle disease

Mcgrath¹,

Eramo²,

Gurung³

et al. 2021

Journal of Clinical Investigation

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The regulation of autophagy-dependent lysosome homeostasis in vivo is unclear. We show the inositol polyphosphate 5-phosphatase INPP5K regulates autophagic lysosome reformation (ALR), a lysosome recycling pathway, in muscle. INPP5K hydrolyses phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) to phosphatidylinositol 4-phosphate (PI(4)P) and INPP5K mutations cause muscular dystrophy by unknown mechanisms. We report loss of INPP5K in muscle causes severe disease, autophagy inhibition and lysosome depletion. Reduced PI(4,5)P2 turnover on autolysosomes in Inpp5k-/muscle suppresses autophagy and lysosome repopulation via ALR inhibition. Defective ALR in Inpp5k-/myoblasts was characterised by enlarged autolysosomes and the persistence of hyperextended reformation tubules, structures that participate in membrane-recycling to form lysosomes. Reduced disengagement of the PI(4,5)P2 effector clathrin was observed on reformation tubules which we propose interferes with ALR completion. Inhibition of PI(4,5)P2 synthesis, or expression of wild-type, but not INPP5K-disease mutants in INPP5K-depleted myoblasts restored lysosomal homeostasis. Therefore, bidirectional interconversion of PI(4)P/PI(4,5)P2 on autolysosomes is integral to lysosome replenishment and autophagy function in muscle. Activation of TFEB-dependent de novo lysosome biogenesis did not compensate for loss of ALR in Inpp5k-/muscle, revealing a dependence on this lysosome recycling pathway. Therefore, in muscle, ALR is indispensable for lysosome homeostasis during autophagy and when defective is associated with muscular dystrophy.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Defective lysosome reformation during autophagy causes skeletal muscle disease

Mcgrath¹,

Eramo²,

Gurung³

et al. 2021

Journal of Clinical Investigation

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“…In the description of 7 patients presented so far, severe epilepsy phenotype with apnea, hypertonic seizures in infancy (with good reaction on VPA) and febrile seizures were mentioned. In the EEG tracing multifocal sharp waves, spikes or generalized background slowing dominated [ 51 ]. The clinical picture was complemented by psychomotor retardation, hypotonia, facial dysmorphism, eye defects, apnea and skin abnormalities such as ichthyosis.…”

Section: Epileptic Encephalopathiesmentioning

confidence: 99%

Congenital Disorders of Glycosylation from a Neurological Perspective

Paprocka

Jezela‐Stanek²,

Tylki‐Szymańska

et al. 2021

Brain Sciences

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Most plasma proteins, cell membrane proteins and other proteins are glycoproteins with sugar chains attached to the polypeptide-glycans. Glycosylation is the main element of the post-translational transformation of most human proteins. Since glycosylation processes are necessary for many different biological processes, patients present a diverse spectrum of phenotypes and severity of symptoms. The most frequently observed neurological symptoms in congenital disorders of glycosylation (CDG) are: epilepsy, intellectual disability, myopathies, neuropathies and stroke-like episodes. Epilepsy is seen in many CDG subtypes and particularly present in the case of mutations in the following genes: ALG13, DOLK, DPAGT1, SLC35A2, ST3GAL3, PIGA, PIGW, ST3GAL5. On brain neuroimaging, atrophic changes of the cerebellum and cerebrum are frequently seen. Brain malformations particularly in the group of dystroglycanopathies are reported. Despite the growing number of CDG patients in the world and often neurological symptoms dominating in the clinical picture, the number of performed screening tests eg transferrin isoforms is systematically decreasing as broadened genetic testing is recently more favored. The aim of the review is the summary of selected neurological symptoms in CDG described in the literature in one paper. It is especially important for pediatric neurologists not experienced in the field of metabolic medicine. It may help to facilitate the diagnosis of this expanding group of disorders. Biochemically, this paper focuses on protein glycosylation abnormalities.

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“…Due to similar clinical image and common location of mutation, studied children were the first ones diagnosed with CDG1F (MIM 609180; 17p13.1) (14), which was followed in the same year with a diagnosis of another CDG1F case with more pronounced cerebellar symptoms (15). Recently five more CDG1F patients of Arabic origin were reported, presenting a uniform set of symptoms, reminiscent of ones shown in both previous studies (16,17). Most of the CDG1F patients presented generalized onset motor seizures (14)(15)(16)(17), however one of them experienced only focal tonic and clonic seizures (16).…”

Section: Mpdu1 (Mannose-p-dolichol Utilization Defect 1 Mim 604041)mentioning

confidence: 67%

Spectrum of Neurological Symptoms in Glycosylphosphatidylinositol Biosynthesis Defects: Systematic Review

et al. 2022

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Background: Mutations of genes involved in the synthesis of glycosylphosphatidylinositol and glycosylphosphatidylinositol-anchored proteins lead to rare syndromes called glycosylphosphatidylinositol-anchored proteins biosynthesis defects. Alterations of their structure and function in these disorders impair often fundamental processes in cells, resulting in severe clinical image. This study aimed to provide a systematic review of GPIBD cases reports published in English-language literature.Methods: The browsing of open-access databases (PubMed, PubMed Central. and Medline) was conducted, followed by statistical analysis of gathered information concerning neurological symptomatology. The inclusion criteria were: studies on humans, age at onset (<18 y.o.), and report of GPIBD cases with adequate data on the genetic background and symptomatology. Exclusion criteria were: publication type (manuscripts, personal communication, review articles); reports of cases of GPI biosynthesis genes mutations in terms of other disorders; reports of GPIBD cases concentrating on non-neurological symptoms; or articles concentrating solely on the genetic issues of GPI biosynthesis. Risk of bias was assessed using Joanna Brigs Institute Critical Appraisal Checklists. Data synthesis was conducted using STATISTICA 13.3.721.1 (StatSoft Polska Sp. z.o.o.). Used tests were chi-square, Fisher's exact test (for differences in phenotype), and Mann-Whitney U test (for differences in onset of developmental delay).Results: Browsing returned a total of 973 articles which, after ruling out the repetitions and assessing the inclusion and exclusion criteria, led to final inclusion of 77 articles (337 GPIBD cases) in the analysis. The main outcomes were prevalence of neurological symptoms, onset and semiology of seizures and their response to treatment, and onset of developmental delay. Based on this data a synthesis of phenotypical differences between the groups of GPIBD cases and the general GPIBD cases population was made.Discussion: A synthetical analysis of neurological components in clinical image of GPIBD patients was presented. It highlights the main features of these disorders, which might be useful in clinical practice for consideration in differential diagnosis with children presenting with early-onset seizures and developmental delay. The limitation of this review is the scarcity of the specific data in some reports, concerning the semiology and onset of two main features of GPIBD.

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A mutation in mannose‐phosphate‐dolichol utilization defect 1 reveals clinical symptoms of congenital disorders of glycosylation type I and dystroglycanopathy

Cited by 12 publications

References 28 publications

Defective lysosome reformation during autophagy causes skeletal muscle disease

Defective lysosome reformation during autophagy causes skeletal muscle disease

Congenital Disorders of Glycosylation from a Neurological Perspective

Spectrum of Neurological Symptoms in Glycosylphosphatidylinositol Biosynthesis Defects: Systematic Review

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