POMT1-CDG is a rare inherited condition that affects many parts of the body. To date, there are at least 105 patients reported in the medical literature. POMT1-CDG is classified as a disorder of O-linked protein glycosylation and more specifically, a disorder of O-mannosylation. POMT1-CDG is also classified as a dystroglycanopathy, which refers to a group disorder that affects the glycosylation of the protein alpha-dystroglycan. The alpha-dystroglycan protein plays an important role in muscle, brain and eye development. POMT1-CDG is caused when an individual has mutations in both copies of their POMT1 gene, which encodes an enzyme that attaches the simple sugar mannose to a protein during O-glycosylation. Mutations in the POMT1 gene cause proteins to be under glycosylated, meaning these proteins have less sugars attached than healthy forms of the proteins. POMT1-CDG can present as three different forms that range in severity, with symptoms beginning from birth or in adolescence depending on the form. POMT1-CDG is primarily characterized by muscle, brain, eye, and heart problems. Screening tests are available for POMT1-CDG, but a definitive diagnosis is achieved through genetic testing. Treatment is focused on the management of specific symptoms and preventing complications.
Protein O-mannosyltransferase 1 congenital disorder of glycosylation (POMT1-CDG) is a rare autosomal recessive genetic disorder. The first case of POMT1-CDG was reported in 20021, and there are at least 105 reported cases in the literature to date1–18. The POMT1 gene encodes an enzyme, protein O-mannosyltransferase 1 (POMT1), which is responsible for adding the first mannose to serine or threonine residues on a protein during O-glycosylation. Deficiency of POMT1 results in deficient O-mannosylation of the the protein alpha-dystroglycan—a protein that is part of the dystrophin-glycoprotein complex that is needed for a range of roles, such as stabilizing muscle tissue and cell signalling19-20. POMT1-CDG is also classified as a dystroglycanopathy, which refers to a group disorders that affect O-mannosylation of alpha-dystroglycan13.
POMT1-CDG may present as three different forms; Muscular dystrophy-dystroglycanopathy -type A1, -type B1 or -type C1, which vary in clinical presentation and symptom severity. The characteristic clinical presentation of POMT1-CDG includes muscle, brain, and eye problems. Definitive diagnosis can only be achieved through molecular genetic testing. There are currently no approved treatments for POMT1-CDG.
- Autosomal recessive limb-girdle muscular dystrophy type 2K
- Limb-girdle muscular dystrophy type 2K (LGMD2K)
- Limb-girdle muscular dystrophy-intellectual disability syndrome
- POMT1-related LGMD R11
- POMT1-related hydrocephalus
- Muscular dystrophy-dystroglycanopathy, type A1 (MDDGA1)
- Muscular dystrophy-dystroglycanopathy, type B1 (MDDGB1)
- Muscular dystrophy-dystroglycanopathy, type C1 (MDDGC1)
POMT1-CDG is inherited in an autosomal recessive fashion, where a mutation is inherited from each parent (asymptomatic carriers).
POMT1 encodes a mannosyltransferase enzyme, protein O-mannosyltransferase 1 (POMT1). Mannosyltransferases are enzymes that enable the transfer of mannose during glycosylation. POMT1 is located in the ER membrane, with exposed sections in the cytoplasm and the ER lumen. POMT1 adds mannose to a serine or threonine amino acid residue of a protein during O-glycosylation in the ER13. POMT1 must form a complex with a separate enzyme, O-mannosyltransferase 2 (POMT2), to transfer mannose to a protein21. Alpha-dystroglycan is an O-mannosylated protein that has been reported to be abnormally glycosylated in POMT1-CDG patients.
O-mannosylation of alpha-dystroglycan
Alpha-dystroglycan is an O-mannosylated glycoprotein that is found on various cells, such as muscle, heart, and nerve22. O-mannosylation is a type of O-glycosylation which involved the attachment of mannose to serine or threonine residues on a protein. Alpha-dystroglycan is the central component of the dystrophin-glycoprotein complex, which links the extracellular matrix to the intracellular cytoskeleton of muscle cells. Glycosylated alpha-dystroglycan binds to components of the extracellular matrix, such as laminin, and to beta-dystroglycan—which is a protein that is in the cell membrane that joins to the intracellular protein dystrophin23. Alpha-dystroglycan needs to be O-glycosylated to bind to laminin. Alpha-dystroglycan is also needed for a variety of other processes, such as development and cell signalling19,23.
Alpha-dystroglycan O-glycans can have variable structures, where different tissues can have alpha-dystroglycan with different O-glycans. The o-mannosylated glycans on alpha-dystroglycan can be categorized into three core structures – M1, M2, and M3 – which can then be further modified (Figure 1) 24.
However, the first step of O-mannosylation of alpha-dystroglycan requires an initial mannose to be added to the protein. For this, POMT1 forms a complex with POMT2 and transfers mannose from dolichol-phosphate mannose (Dol-P-mannose) to a serine or threonine residue on alpha-dystroglycan in the ER21. Depending on the final structure, additional enzymes modify the O-glycan in the ER and/or Golgi (Figure 2)25.
Mutations in the POMT1 gene lead to POMT1 having a reduced ability or inability to transfer mannose onto a protein during O-glycosylation. Alpha-dystroglycan has been reported to be hypoglycosylated in POMT1-CDG patients. As alpha-dystroglycan is present in various tissues, such as muscle, nerve, and eye, clinical features of POMT1-CDG may be due to hypoglycosylation of alpha-dystroglycan, which prevents alpha-dystroglycan from functioning properly26,27.
The POMT1 gene is located on chromosome 9 (9q34.13). At least 76 pathogenic mutations have been reported for the POMT1 gene, such as missense, deletion, splicing, nonsense, and insertion mutations20. The various phenotypes of POMT1-CDG are linked to the level of POMT1 activity. More severe phenotypes, like Walker-Warburg syndrome, are caused my mutations resulting in stop codons or deletions in highly conserved domains, resulting in truncated proteins and disrupting POMT1 activity27. A milder phenotype is found in patients with missense mutations. The mutation, p.Ala200Pro, has been found in patients who present with no brain malformations but with intellectual disability 5.
Signs & Symptoms
Individuals with POMT1-CDG can be classified into three phenotypes which range in their severity: Muscular dystrophy-dystroglycanopathy type A1, type B1 and type C1. 20,27:
Muscular dystrophy-dystroglycanopathy type A1 (MDDGA1)
MDDGA1 is a severe form of congenital muscular dystrophy-dystroglycanopathy, typically presenting prenatally or at birth and is characterized by brain and eye defects. It includes disorders such as Walker-Warburg syndrome (WWS) and muscle-eye-brain disease (MEB). The clinical presentation may include a combination of:
- Neurological – a build-up of fluid in the brain (hydrocephalus), defective brain development, a sac-like bulge that pokes out of the skull (encephalocele), intellectual disability, and seizures
- Musculoskeletal – hypotonia, delayed milestones, contractures, and impaired ability to walk and speech
- Ophthalmological – microphthalmia, exophthalmia, enlarged eye, megalocornea, glaucoma, hypertelorism, and myopia
Muscular dystrophy-dystroglycanopathy type B1 (MDDGB1)
MDDGB1 is a moderate severe form of congenital muscular dystrophy-dystroglycanopathy with or without intellectual disability. MDDGB1 clinical presentation is milder than MDDGA1 and may include a combination of:
- Neurological – intellectual disability, microcephaly, and cerebellar hypoplasia
- Musculoskeletal – hypotonia, contractures, delayed motor milestones, scoliosis, and hypertrophy
- Ophthalmological – myopia, retinal degeneration, and cataracts
Muscular dystrophy-dystroglycanopathy type C1 (MDDGC1)
MDDGC1 is a mild form of limb-girdle muscular dystrophy with or without intellectual disability, presenting with late-onset progressive muscle weakness. MDDGC1 clinical presentation may include a combination of:
- Neurological – intellectual disability
- Musculoskeletal – delayed motor milestones, hypertrophy, limb–girdle weakness, muscle weakness, dystrophic and myopathic changes
- Cardiac – cardiomyopathy
Other clinical presentations of POMT1-CDG may involve cardiac defects, absence of speech and unable to walk1–18.
Biochemical abnormalities observed in individuals with POMT1-CDG include elevated serum creatine levels.
POMT1-CDG is classified as a disorder of O-linked protein glycosylation and, within this group, a disorder of O-mannosylation.
Although diagnosis of POMT1-CDG may be suspected based on the presentation of symptoms and a detailed patient history, direct molecular genetic testing is the only definitive diagnostic test. Screening tests in suspected patients can involve immunostaining of alpha-dystroglycan from muscle cell samples and POMT1 enzyme analysis.
Muscle biopsies taken from patients are stained or immunolabeled with antibodies that bind to glycosylated alpha-dystroglycan. Consequently, hypoglycosylated alpha-dystroglycan will have lower binding levels and immunolabeling than healthy alpha-dystroglycan. More severe POMT1-CDG phenotypes have less immunolabelling that milder forms28.
POMT1 Enzyme Analysis
POMT1 enzyme activity is measured using patient fibroblasts samples. POMT1 activity is reduced in POMT1-CDG samples compared to control samples, with activity being more impaired with more severe POMT1-CDG phenotypes10.
There are currently no biomarkers described for POMT1-CDG.
Prognosis of POMT1-CDG may vary depending on the severity of an individual’s symptoms and the specific form. Severely affected patients, such as those with MDDGA1, may not survive beyond the first few months of life, with some surviving to the age of 327,29. Less severely affected patients, such as those with MDDGC1, may not present symptoms until adulthood12,27.
In patients with less severe types of POMT1-CDG, patients usually achieve mobility before the onset of progressive muscular weakness. The progressive muscle weakness typically first affects voluntary muscles in the shoulder and pelvic gridles27.
Management of symptoms may include combinations of physical therapy, occupational therapy, vision therapy, and palliative measures.
There are currently no treatment options available for POMT1-CDG. Treatment is focused on the management of symptoms and prevention of complications.
Several POMT1 models have been generated, such as in flies, fish, mice, and human cells.
Fly (D. melanogaster)
Drosophila gene dPOMT1 is orthologous to human POMT1. Mutations in dPOMT1 can lead to synaptic defects30. Glycosylation of Dg by POMT1 and POMT2 are important to Dg function in maintaining cell integrity in the muscles of larval Drosophila. Mutations in dPMOT1 in larvae show defects in muscle attachment and contraction in phenotypes with impaired or hypoglycosylated dystroglycan31.
Fish (D. rerio)
POMT1 orthologue has been identified in zebrafish32.
Mouse (M. musculus)
Pomt1 Expression in Mice
Mouse gene mPomt1 is orthologous to human POMT1 and expression is detected in different mouse tissues, such as muscle, eye, brain, and testes33.
Homozygous Pomt1-/- Knockout Mice
Pomt1 knockout mice were found to be embryonic lethal between embryonic days 7.5 and 9.534.
Pomt1 Photoreceptor-specific Conditional Knockout Mice
Knockout of Pomt1 in the photoreceptor cells in mice showed impaired alpha-dystroglycan O-mannosylation as well as additional effects, such as morphological changes35.
Human Cell Lines
Human Embryonic Kidney Stem Cells (HEK293T)
Plasmids with POMT1 and POMT2 transfected into HEK293T cells showed that POMT1 and POMT2 must be co-expressed to form an active enzyme complex36.
The Frontiers in Congenital Disorder of Glycosylation Disorders Consortium (FCDGC) is conducting a 5-year natural history study on all CDG types, including POMT1-CDG. The purpose of this study is to define the natural history and clinical symptoms of CDGs, develop new diagnostic techniques, identify clinical biomarkers that can be used in future clinical trials and evaluate whether dietary treatments improve clinical symptoms and quality of life.
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