| Structural highlights
Disease
[PMM2_HUMAN] Defects in PMM2 are the cause of congenital disorder of glycosylation type 1A (CDG1A) [MIM:212065]; also known as carbohydrate-deficient glycoprotein syndrome type Ia (CDGS1A) or Jaeken syndrome. Congenital disorders of glycosylation are metabolic deficiencies in glycoprotein biosynthesis that usually cause severe mental and psychomotor retardation. They are characterized by under-glycosylated serum glycoproteins. CDG1A is an autosomal recessive disorder characterized by a severe encephalopathy with axial hypotonia, abnormal eye movement, and pronounced psychomotor retardation, as well as peripheral neuropathy, cerebellar hypoplasia, and retinitis pigmentosa. Patients show a peculiar distribution of subcutaneous fat, nipple retraction, and hypogonadism.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
Function
[PMM2_HUMAN] Involved in the synthesis of the GDP-mannose and dolichol-phosphate-mannose required for a number of critical mannosyl transfer reactions (By similarity).
Publication Abstract from PubMed
Phosphomannomutase 2 (PMM2) deficiency, the most frequent congenital disorder of glycosylation (PMM2-CDG), is a severe condition, which has no cure. Due to the identification of destabilizing mutations, our group aims at increasing residual activity in PMM2-CDG patients, searching for pharmacochaperones. Detailed structural knowledge of hPMM2 might help identify variants amenable to pharmacochaperoning. hPMM2 structural information is limited to one incomplete structure deposited in the Protein Databank without associated publication, which lacked ligands and residues from a crucial loop. Here we report five complete crystal structures of hPMM2, three for wild-type and two for the p.Thr237Met variant frequently found among Spanish PMM2-CDG patients, free and bound to the essential activator glucose-1,6-bisphosphate (Glc-1,6-P2 ). In the hPMM2 homodimer, each subunit has a different conformation, reflecting movement of the distal core domain relative to the dimerization cap domain, supporting an opening/closing process during catalysis. Two Mg(2+) ions bind to the core domain, one catalytic and one structural. In the cap domain, the site for Glc-1,6-P2 is well delineated, while a Cl(-) ion binding at the intersubunit interface is predicted to strengthen dimerization. Patient-found amino acid substitutions are nonhomogeneously distributed throughout hPMM2, reflecting differential functional or structural importance for various parts of the protein. We classify 93 of 101 patient-reported single amino acid variants according to five potential pathogenetic mechanism affecting folding of the core and cap domains, linker 2 flexibility, dimerization, activator binding, and catalysis. We propose that ~80% and ~50% of the respective core and cap domains substitutions are potential candidates for pharmacochaperoning treatment.
Insight on molecular pathogenesis and pharmacochaperoning potential in phosphomannomutase 2 deficiency, provided by novel human phosphomannomutase 2 structures.,Briso-Montiano A, Del Cano-Ochoa F, Vilas A, Velazquez-Campoy A, Rubio V, Perez B, Ramon-Maiques S J Inherit Metab Dis. 2021 Dec 3. doi: 10.1002/jimd.12461. PMID:34859900[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Matthijs G, Schollen E, Pardon E, Veiga-Da-Cunha M, Jaeken J, Cassiman JJ, Van Schaftingen E. Mutations in PMM2, a phosphomannomutase gene on chromosome 16p13, in carbohydrate-deficient glycoprotein type I syndrome (Jaeken syndrome). Nat Genet. 1997 May;16(1):88-92. PMID:9140401 doi:10.1038/ng0597-88
- ↑ Matthijs G, Schollen E, Van Schaftingen E, Cassiman JJ, Jaeken J. Lack of homozygotes for the most frequent disease allele in carbohydrate-deficient glycoprotein syndrome type 1A. Am J Hum Genet. 1998 Mar;62(3):542-50. PMID:9497260 doi:S0002-9297(07)63834-8
- ↑ Kjaergaard S, Skovby F, Schwartz M. Absence of homozygosity for predominant mutations in PMM2 in Danish patients with carbohydrate-deficient glycoprotein syndrome type 1. Eur J Hum Genet. 1998 Jul-Aug;6(4):331-6. PMID:9781039 doi:10.1038/sj.ejhg.5200194
- ↑ Kondo I, Mizugishi K, Yoneda Y, Hashimoto T, Kuwajima K, Yuasa I, Shigemoto K, Kuroda Y. Missense mutations in phosphomannomutase 2 gene in two Japanese families with carbohydrate-deficient glycoprotein syndrome type 1. Clin Genet. 1999 Jan;55(1):50-4. PMID:10066032
- ↑ Kjaergaard S, Skovby F, Schwartz M. Carbohydrate-deficient glycoprotein syndrome type 1A: expression and characterisation of wild type and mutant PMM2 in E. coli. Eur J Hum Genet. 1999 Dec;7(8):884-8. PMID:10602363 doi:10.1038/sj.ejhg.5200398
- ↑ Vuillaumier-Barrot S, Barnier A, Cuer M, Durand G, Grandchamp B, Seta N. Characterization of the 415G>A (E139K) PMM2 mutation in carbohydrate-deficient glycoprotein syndrome type Ia disrupting a splicing enhancer resulting in exon 5 skipping. Hum Mutat. 1999 Dec;14(6):543-4. PMID:10571956 doi:<543::AID-HUMU17>3.0.CO;2-S 10.1002/(SICI)1098-1004(199912)14:6<543::AID-HUMU17>3.0.CO;2-S
- ↑ Matthijs G, Schollen E, Bjursell C, Erlandson A, Freeze H, Imtiaz F, Kjaergaard S, Martinsson T, Schwartz M, Seta N, Vuillaumier-Barrot S, Westphal V, Winchester B. Mutations in PMM2 that cause congenital disorders of glycosylation, type Ia (CDG-Ia). Hum Mutat. 2000 Nov;16(5):386-94. PMID:11058895 doi:<386::AID-HUMU2>3.0.CO;2-Y 10.1002/1098-1004(200011)16:5<386::AID-HUMU2>3.0.CO;2-Y
- ↑ Bjursell C, Erlandson A, Nordling M, Nilsson S, Wahlstrom J, Stibler H, Kristiansson B, Martinsson T. PMM2 mutation spectrum, including 10 novel mutations, in a large CDG type 1A family material with a focus on Scandinavian families. Hum Mutat. 2000 Nov;16(5):395-400. PMID:11058896 doi:<395::AID-HUMU3>3.0.CO;2-T 10.1002/1098-1004(200011)16:5<395::AID-HUMU3>3.0.CO;2-T
- ↑ Imtiaz F, Worthington V, Champion M, Beesley C, Charlwood J, Clayton P, Keir G, Mian N, Winchester B. Genotypes and phenotypes of patients in the UK with carbohydrate-deficient glycoprotein syndrome type 1. J Inherit Metab Dis. 2000 Mar;23(2):162-74. PMID:10801058
- ↑ Westphal V, Enns GM, McCracken MF, Freeze HH. Functional analysis of novel mutations in a congenital disorder of glycosylation Ia patient with mixed Asian ancestry. Mol Genet Metab. 2001 May;73(1):71-6. PMID:11350185 doi:10.1006/mgme.2001.3174
- ↑ Schollen E, Martens K, Geuzens E, Matthijs G. DHPLC analysis as a platform for molecular diagnosis of congenital disorders of glycosylation (CDG). Eur J Hum Genet. 2002 Oct;10(10):643-8. PMID:12357336 doi:10.1038/sj.ejhg.5200858
- ↑ Le Bizec C, Vuillaumier-Barrot S, Barnier A, Dupre T, Durand G, Seta N. A new insight into PMM2 mutations in the French population. Hum Mutat. 2005 May;25(5):504-5. PMID:15844218 doi:10.1002/humu.9336
- ↑ Schollen E, Keldermans L, Foulquier F, Briones P, Chabas A, Sanchez-Valverde F, Adamowicz M, Pronicka E, Wevers R, Matthijs G. Characterization of two unusual truncating PMM2 mutations in two CDG-Ia patients. Mol Genet Metab. 2007 Apr;90(4):408-13. Epub 2007 Feb 16. PMID:17307006 doi:S1096-7192(07)00027-3
- ↑ Briso-Montiano A, Del Cano-Ochoa F, Vilas A, Velazquez-Campoy A, Rubio V, Perez B, Ramon-Maiques S. Insight on molecular pathogenesis and pharmacochaperoning potential in phosphomannomutase 2 deficiency, provided by novel human phosphomannomutase 2 structures. J Inherit Metab Dis. 2021 Dec 3. doi: 10.1002/jimd.12461. PMID:34859900 doi:http://dx.doi.org/10.1002/jimd.12461
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