POMT1

Protein O-mannosyltransferase 1, glycosyltransferase (EC 2.4.1.109) that catalyzes the first committed step in protein O-mannose glycan biosynthesis by transferring mannose from dolichol-phosphate-mannose to serine/threonine hydroxyl groups on target proteins. Forms obligate heteromeric complex with POMT2 in 1:1 stoichiometry - individually neither subunit has enzymatic activity, only the POMT1/POMT2 complex is functional. ER-resident integral membrane protein with ~10 transmembrane helices and luminal catalytic domains facing ER lumen. Belongs to GT-C superfamily of glycosyltransferases with conserved acidic residues in first luminal loop forming active site that binds dolichol-P-mannose. Contains MIR domains and TPR repeats predicted to mediate protein substrate recognition; no short consensus sequence motif identified - substrate recognition depends on folded protein context and structural features rather than linear sequence. Primary physiological substrate: α-dystroglycan (α-DG), an ECM receptor glycoprotein requiring O-mannose glycan (matriglycan) to bind laminin, agrin, and perlecan. POMT1/2 initiate attachment of mannose on specific Thr residues (e.g. Thr-317, Thr-379) which primes sites for elongation into core M1/M2/M3 glycan structures - subsequent enzymes add GalNAc, xylose, ribitol-phosphate, and ultimately LARGE1 polymerizes matriglycan repeating disaccharide that directly binds ECM ligands. Without initial mannose from POMT1, entire carbohydrate scaffold cannot be built. Loss of POMT1 causes hypoglycosylation of α-dystroglycan, disrupting muscle-ECM anchorage. Other substrates: receptor protein tyrosine phosphatases (RPTPζ/phosphacan) carrying O-mannose glycans with HNK-1 epitopes in neural development, KIAA1549, PTP69D in fly for sensory axon guidance. POMT1-mediated O-mannosylation extends to cell-surface receptors in neural circuit formation. Critical for basement membrane assembly: Pomt1 knockout mice are embryonically lethal due to failure of Reichert's membrane formation (non-functional dystroglycan). Dystrophin-glycoprotein complex: α-dystroglycan (heavily O-mannosylated) binds extracellular laminin while β-dystroglycan links to cytoskeleton via dystrophin, stabilizing muscle fibers during contraction. Mutations cause Walker-Warburg syndrome (WWS, ~20% of cases), severe congenital muscular dystrophy with brain malformations (cobblestone lissencephaly, hydrocephalus), eye defects (retinal dysplasia), early lethality; also limb-girdle muscular dystrophy 2K (LGMD2K) with later-onset milder muscle weakness but often intellectual disability. POMT1 mutations tend to have CNS involvement even in milder forms. One of three mammalian protein O-mannosyltransferase families (others: TMTC1-4 for cadherins, TMEM260 for plexin/RON/MET) - POMT1/2 uniquely responsible for dystroglycan-type pathways, occupying non-redundant niche. Acts early in secretory pathway modifying nascent polypeptides in ER lumen before Golgi trafficking. Essential for muscle fiber integrity, brain cortical layering, eye development, peripheral nerve myelination. Substrate specificity is broad in function but narrow in occurrence - targets select set of large extracellular/membrane proteins requiring O-mannose for function.

Disorders

Relationship is the entry's genetic[].relationship_type. untyped means the entry has a genetic record for the gene but does not type it; its free-text association is shown instead.

An entry matches when ClinGen's MONDO disease is the entry's own disease term, a subtype term, or an exact-match mapping. An amber status marks an entry ClinGen supports the gene for (Definitive, Strong or Moderate) whose own record does not type it. A Limited, Disputed or Refuted tier on such an entry is not a gap.

• pial_basement_membrane_radial_glial_endfoot_failure via Dystroglycanopathy, Lissencephaly Spectrum Disorders named in the module itself