Alternative titles; symbols
HGNC Approved Gene Symbol: GMPPB
SNOMEDCT: 732930007;
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:49,719,916-49,723,951 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.31 | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 14 | 615350 | Autosomal recessive | 3 |
| Muscular dystrophy-dystroglycanopathy (congenital with impaired intellectual development), type B, 14 | 615351 | Autosomal recessive | 3 | |
| Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 14 | 615352 | Autosomal recessive | 3 |
The GMPPB gene encodes the beta subunit of an essential enzyme, GDP-mannose pyrophosphorylase (EC 2.7.7.13), that catalyzes the conversion of mannose-1-phosphate and GTP to inorganic diphosphate and GDP-mannose, a major mannosyl donor for mannose-containing polymers (Ning and Elbein, 2000). GDP-mannose is required in 4 glycosylation pathways, including O-mannosylation of membrane and secretory glycoproteins, such as alpha-dystroglycan (DAG1; 128239) (summary by Carss et al., 2013).
By searching databases for sequences similar to porcine Gmpp-beta, Ning and Elbein (2000) identified human GMPPB, as well as GMPPB orthologs in several lower species, including nematode, yeast, and plants. The 360-amino acid human protein shares 96% identity with porcine Gmpp-beta.
The GMPPB protein contains 2 main functional domains: a nucleotidyl transferase domain and a bacterial transferase hexapeptide domain. Carss et al. (2013) determined that the GMPPB gene is transcribed as 2 isoforms in human tissues. The longer isoform (GenBank NM_021971.1) was strongly expressed in all fetal and adult tissues tested, including brain and skeletal muscle, whereas the shorter isoform (GenBank NM_013334.2) was weakly expressed in the tissues tested. There appeared to be no developmental difference in the expression of the 2 isoforms.
By sequencing clones obtained from a size-fractionated adult brain cDNA library, Nagase et al. (2001) obtained a clone, which they designated KIAA1851, containing 2 coding regions separated by 2.4 kb. They identified the upstream coding region as that of GMPPB and suggested that KIAA1851 may represent a read-through transcript of the GMPPB gene. Hartz (2014) determined that the KIAA1851 sequence (GenBank AB058754) includes the sequence of AMIGO3 (615691) (GenBank AY237003) in addition to that of GMPPB.
The coding DNA sequence of one isoform of the GMPPB gene (GenBank NM_021971.1) contains 10 exons, whereas that of another isoform (GenBank NM_013334.2) contains 8 exons (Carss et al., 2013).
Hartz (2013) mapped the GMPPB gene to chromosome 3p21.31 based on an alignment of the GMPPB sequence (GenBank AB058754) with the genomic sequence (GRCh37).
Ning and Elbein (2000) found that recombinant porcine Gmpp-beta catalyzed bidirectional conversion of mannose-1-phosphate and GTP to inorganic diphosphate and GDP-mannose. Compared with purified pig liver Gmpp, which was a dimer of alpha and beta subunits, recombinant Gmpp-beta showed much lower activity as a GDP-glucose pyrophosphorylase (EC 2.7.7.34). Divalent cations, particularly Mn(2+), enhanced the Gmpp-beta reaction, whereas Mg(2+) was the preferred cofactor for the endogenous dimeric enzyme.
By exome sequencing combined with Sanger sequencing of 8 unrelated patients with various forms of congenital muscular dystrophy, Carss et al. (2013) identified 8 different mutations in the GMPPB gene (GenBank NM_02197.1) (615320.0001-615320.0008). All mutations occurred in homozygous or compound heterozygous state and segregated with the disorder in the families in whom parental DNA was available. All affected individuals had at least 1 mutation affecting the highly conserved nucleotidyl transferase domain. The phenotype was highly variable. The most severely affected patient had muscle weakness at birth with severely delayed psychomotor development, retinal dysfunction, and pontocerebellar hypoplasia, reminiscent of muscle-eye-brain disease and consistent with congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A14 (MDDGA14; 615350). Four patients presented with a slightly milder phenotype with onset of muscle weakness in the first months of life with milder intellectual disability with or without cerebellar hypoplasia, consistent with congenital muscular dystrophy-dystroglycanopathy with impaired intellectual disability type B14 (MDDGB14; 615351). The least severe phenotype, limb-girdle muscular dystrophy-dystroglycanopathy type C14 (MDDGC14; 615352), also known as LGMDR19 and LGMD2T, was present in 3 unrelated patients, 1 of whom had onset at age 4 and normal intellectual function. Variable features seen in some patients included microcephaly, seizures, cataracts, and cardiac dysfunction. All patients had dystrophic features on muscle biopsy, and immunohistochemical and flow cytometric analysis of patient cells showed reduced glycosylation of alpha-dystroglycan. Overexpression of wildtype GMPPB in fibroblasts from an affected individual partially restored glycosylation of DAG1. Whereas wildtype GMPPB localized to the cytoplasm, 5 of the identified missense mutations caused formation of aggregates in the cytoplasm or near membrane protrusions. Knockdown of the GMPPB ortholog in zebrafish caused structural muscle defects with decreased motility, eye abnormalities, and reduced glycosylation of DAG1. None of the patients had evidence of abnormal serum transferrin glycoforms.
In 7 patients from 5 unrelated families with MDDGC14 with features of congenital myasthenic syndrome, Belaya et al. (2015) identified homozygous or compound heterozygous mutations in the GMPPB gene (see, e.g., 615320.0007; 615320.0009-615320.0011). The mutations in the first patient were found by whole-exome sequencing; mutations in subsequent patients were found by screening of the GMPPB gene in a cohort of patients diagnosed with congenital myasthenic syndrome. The patients with GMPPB mutations showed decrement of compound muscle action potentials on repetitive nerve stimulation as well as myopathic findings on muscle biopsy and increased serum creating kinase. The findings indicated that GMPPB mutations can lead to a wide spectrum of clinical features including defects in neuromuscular transmission.
Carss et al. (2013) found that zebrafish gmppb is expressed throughout development. Morpholino knockdown of gmppb in zebrafish resulted in smaller embryos with multiple anomalies, including bent tails, hypopigmentation, microphthalmia, hydrocephalus, and reduced motility. Muscle fibers in mutant zebrafish were sparse and disorganized, and the myosepta were damaged or incompletely developed. There was also evidence of sarcolemmal damage. Immunostaining showed defective glycosylation of DAG1 associated with abnormal structure of the basement membrane. These findings were reminiscent of the muscular dystrophy phenotype found in humans with GMPPB mutations.
In a patient (P1) with congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A14 (MDDGA14; 615350), Carss et al. (2013) identified compound heterozygous mutations in the GMPPB gene: a c.1000G-A transition resulting in an asp334-to-asn (D334N) substitution at a highly conserved residue at the C terminus, and a c.220C-T transition resulting in an arg74-to-ter (R74X; 615320.0002) substitution. The mutations were identified by exome sequencing and confirmed by Sanger sequencing. Each unaffected parent was heterozygous for 1 of the mutations. Transfection of the D334N mutation into myoblasts caused the protein to form cytoplasmic aggregates. The R74X mutation, which occurs in the nucleotidyl transferase domain, is predicted to cause a severely truncated protein and nonsense-mediated mRNA. The patient had severely delayed psychomotor development, sensorineural hearing loss, retinal dysfunction, and pontine and cerebellar hypoplasia on brain MRI. Studies of the patient's skeletal muscle and fibroblasts showed decreased glycosylation of alpha-dystroglycan (DAG1; 128239), which was partially restored by transfection of wildtype GMPPB. An unrelated patient (P2) with a somewhat less severe phenotype, limb-girdle muscular dystrophy-dystroglycanopathy type C14 (MDDGC14; 615352) with mental retardation, was found to be compound heterozygous for D334N and a c.64C-T transition resulting in a pro22-to-ser (P22S; 615320.0003) substitution at a highly conserved residue in the nucleotidyl transferase domain. Transfection of the P22S mutation into myoblasts caused the protein to aggregate near membrane protrusions into the cytoplasm.
For discussion of the arg74-to-ter (R74X) mutation in the GMPPB gene that was found in compound heterozygous state in a patient with congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A14 (MDDGA14; 615350) by Carss et al. (2013), see 615320.0001.
For discussion of the pro22-to-ser (P22S) mutation in the GMPPB gene that was found in compound heterozygous state in a patient with limb-girdle muscular dystrophy-dystroglycanopathy type C14 (MDDGC14; 615352) by Carss et al. (2013), see 615320.0001.
In 2 unrelated Mexican patients (P3 and P4) with congenital muscular dystrophy-dystroglycanopathy with mental retardation type B14 (MDDGB14; 615351), Carss et al. (2013) identified a homozygous c.553C-T transition in the GMPPB gene, resulting in an arg185-to-cys (R185C) substitution at a highly conserved residue in the nucleotidyl transferase domain. The mutations were found in 1 of the patients by exome sequencing and confirmed in both patients by Sanger sequencing. The unaffected mother of 1 of the patients was heterozygous for the mutation. Exome sequencing of an Egyptian patient (P8) with a somewhat less severe phenotype, limb-girdle muscular dystrophy-dystroglycanopathy type C14 (MDDGC14; 615352) with mental retardation and cardiorespiratory dysfunction, also yielded a homozygous R185C mutation. The unaffected parents of this patient were heterozygous for the mutation. Transfection of the R185C mutation into myoblasts caused the protein to remain evenly distributed in the cytoplasm and had no discernible changes compared to wildtype.
In 2 unrelated Italian girls (P5 and P6) with congenital muscular dystrophy-dystroglycanopathy with impaired intellectual development type B14 (MDDGB14; 615351), previously reported by Messina et al. (2009), Carss et al. (2013) identified compound heterozygosity for 2 mutations in the GMPPB gene: a c.95C-T transition resulting in a pro32-to-leu (P32L) substitution at a highly conserved residue in the nucleotidyl transferase domain, and a c.860G-A transition resulting in an arg287-to-gln (R287Q; 615320.0006) substitution. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. P32L had not been reported, and R287Q is rare and has a minor allele frequency of less than or equal to 0.001 in database controls. Transfection of both mutations into myoblasts caused the protein to form aggregates within the cytoplasm.
For discussion of the arg287-to-gln (R287Q) mutation in the GMPPB gene that was found in compound heterozygous state in 2 patients with congenital muscular dystrophy-dystroglycanopathy with impaired intellectual development type B14 (MDDGB14; 615351) by Carss et al. (2013), see 615320.0005.
In a 6-year-old English boy (P7) with muscular dystrophy-dystroglycanopathy type C14 (MDDGC14; 615352) without mental retardation, Carss et al. (2013) identified compound heterozygous mutations in the GMPPB gene: a c.79G-C transversion, resulting in an asp27-to-his (D27H) substitution at a highly conserved residue in the nucleotidyl transferase domain, and a c.988G-A transition, resulting in a val330-to-ile (V330I; 615320.0008) substitution at a highly conserved residue in the C terminus. Each unaffected parent was heterozygous for 1 of the mutations. Both variants are rare, with minor allele frequencies of less than or equal to 0.001 in database controls. Transfection of the D27H mutation into myoblasts caused the protein to remain evenly distributed in the cytoplasm and had no discernible changes compared to wildtype, whereas transfection of V330I caused the protein to form aggregates within the cytoplasm. The patient had a mild form of the disorder, presenting only with exercise intolerance at age 4 years.
For discussion of the D27H mutation (c.79G-C, NM_021971) in the GMPPB gene that was found in compound heterozygous state in patients with MDDGC14 with features of congenital myasthenic syndrome by Belaya et al. (2015), see 615320.0009 and 615320.0010. Belaya et al. (2015) found the D27H mutation at a low frequency (0.077%) in the Exome Variant Server database. D27H mutant protein expression was decreased compared to wildtype in transfected HEK293 cells.
NM_021971
For discussion of the val330-to-ile (V330I) mutation in the GMPPB gene that was found in compound heterozygous state in a patient with muscular dystrophy-dystroglycanopathy type C14 (MDDGC14; 615352) without mental retardation by Carss et al. (2013), see 615320.0007.
In a 48-year-old woman with muscular dystrophy-dystroglycanopathy type C14 (MDDGC14; 615352) with features of congenital myasthenic syndrome, Belaya et al. (2015) identified compound heterozygous mutations in the GMPPB gene: a c.859C-T transition (c.859C-T, NM_021971), resulting in an arg287-to-trp (R287W) substitution, and D27H (615320.0007). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Both mutations were found at low frequencies in the Exome Variant Server database (0.077% for D27H and 0.008% for R287W). In transfected HEK293 cells, R287W protein expression was undetectable, whereas D27H expression was decreased compared to wildtype. In a transfected mouse muscle cell line, R287W mutant protein expression was drastically reduced, and the protein that was expressed displayed a punctate pattern of localization, suggesting abnormal protein aggregation.
In a 28-year-old woman with muscular dystrophy-dystroglycanopathy type C14 (MDDGC14; 615352) with features of congenital myasthenic syndrome, Belaya et al. (2015) identified compound heterozygous mutations in the GMPPB gene: a c.760G-A transition (c.760G-A, NM_021971), resulting in a val254-to-met (V254M) substitution at a conserved residue and D27H (615320.0007). The mutations segregated with the disorder in the family. In transfected HEK293 cells, V254M protein expression was undetectable, whereas D27H expression was decreased compared to wildtype. In a transfected mouse muscle cell line, V254M mutant protein expression was drastically reduced, and the protein that was expressed displayed a punctate pattern of localization, suggesting abnormal protein aggregation.
In 3 adult sibs, born of consanguineous Iranian parents, with muscular dystrophy-dystroglycanopathy type C14 (MDDGC14; 615352) with features of a congenital myasthenic syndrome, Belaya et al. (2015) identified a homozygous c.308C-T transition (c.308C-T, NM_021971) in the GMPPB gene, resulting in a pro103-to-leu (P103L) substitution at a conserved residue in the nucleotidyl transferase domain. The mutation segregated with the disorder in the family. In transfected HEK293 cells, P103L protein expression was slightly decreased compared to wildtype.
Belaya, K., Rodriguez Cruz, P. M., Liu, W. W., Maxwell, S., McGowan, S., Farrugia, M. E., Petty, R., Walls, T. J., Sedghi, M., Basiri, K., Yue, W. W., Sarkozy, A., and 10 others. Mutations in GMPPB cause congenital myasthenic syndrome and bridge myasthenic disorders with dystroglycanopathies. Brain 138: 2493-2504, 2015. [PubMed: 26133662] [Full Text: https://doi.org/10.1093/brain/awv185]
Carss, K. J., Stevens, E., Foley, A. R., Cirak, S., Riemersma, M., Torelli, S., Hoischen, A., Willer, T., van Scherpenzeel, M., Moore, S. A., Messina, S., Bertini, E., and 24 others. Mutations in GDP-mannose pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of alpha-dystroglycan. Am. J. Hum. Genet. 93: 29-41, 2013. [PubMed: 23768512] [Full Text: https://doi.org/10.1016/j.ajhg.2013.05.009]
Hartz, P. A. Personal Communication. Baltimore, Md. 7/19/2013.
Hartz, P. A. Personal Communication. Baltimore, Md. 3/12/2014.
Messina, S., Tortorella, G., Concolino, D., Spano, M., D'Amico, A., Bruno, C., Santorelli, F. M., Mercuri, E., Bertini, E. Congenital muscular dystrophy with defective alpha-dystroglycan, cerebellar hypoplasia, and epilepsy. Neurology 73: 1599-1601, 2009. [PubMed: 19901254] [Full Text: https://doi.org/10.1212/WNL.0b013e3181c0d47a]
Nagase, T., Nakayama, M., Nakajima, D., Kikuno, R., Ohara, O. Prediction of the coding sequences of unidentified human genes. XX. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 8: 85-95, 2001. [PubMed: 11347906] [Full Text: https://doi.org/10.1093/dnares/8.2.85]
Ning, B., Elbein, A. D. Cloning, expression and characterization of the pig liver GDP-mannose pyrophosphorylase: evidence that GDP-mannose and GDP-Glc pyrophosphorylases are different proteins. Europ. J. Biochem. 267: 6866-6874, 2000. [PubMed: 11082198] [Full Text: https://doi.org/10.1046/j.1432-1033.2000.01781.x]